WO2011162562A2 - [6+5] fused bicycles as a thrombin antagonist, process for preparation thereof and pharmaceutical compositions containing the bicycles - Google Patents

[6+5] fused bicycles as a thrombin antagonist, process for preparation thereof and pharmaceutical compositions containing the bicycles Download PDF

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WO2011162562A2
WO2011162562A2 PCT/KR2011/004607 KR2011004607W WO2011162562A2 WO 2011162562 A2 WO2011162562 A2 WO 2011162562A2 KR 2011004607 W KR2011004607 W KR 2011004607W WO 2011162562 A2 WO2011162562 A2 WO 2011162562A2
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vinyl
fluorophenyl
pyridin
inden
octahydro
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PCT/KR2011/004607
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French (fr)
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WO2011162562A3 (en
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Sun Kyung Lee
Jong Whan Song
Dong Chul Lim
Woo Young Cho
Chul Min Park
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Korea Research Institute Of Chemical Technology
Lg Life Sciences Ltd.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to new [6+5] fused bicycles of the following formula (1)
  • A, E, G, Het, R 1 to R 8 are as defined below, as a thrombin antagonist, pharmaceutically acceptable salts thereof, processes for preparing the same, and pharmaceutical compositions comprising the same.
  • the compounds according to the present invention can be used as an antagonist for thrombin receptor known as a PAR-1 (protease receptor antagonist type 1) antagonist. Accordingly, the composition of the present invention may be effectively used for the treatment and prevention of thrombus, platelet aggregation, atherosclerosis, restenosis, blood coagulation, hypertension, arrhythmia, angina pectoris, heart failure, inflammation and cancer.
  • Clopidogrel (Plavix) of Sanofi Aventis the most widely used current antiplatelet drug, is an antagonist for an ADP receptor P 2 Y 12 , one of the various factors causing platelet aggregation. Although it is a blockbuster, it shows very different responses between patients, and its efficacy needs to be improved.
  • PAR-1 is a receptor that is activated via a mechanism in which the N-terminal amino acid sequence is cleaved and the newly generated N-terminal amino acid sequence interacts with PAR-1 itself.
  • the receptors within the same group known up to now include PAR-2, PAR-3 and PAR-4 ( Nature , 407:258-264, 2000).
  • PAR-1 and PAR-4 exist in human platelets.
  • PAR-1 is activated by a low concentration of thrombin and PAR-4 is activated by a high concentration of thrombin to participate in the platelet aggregation.
  • Thrombin plays a key role in the physiological hemostasis to prevent the loss of blood by the cellular effect of vasoconstriction, platelet aggregation through PAR-1, etc.
  • one object of the present invention is to provide the [6+5] fused bicycle derivatives of formula (1), pharmaceutically acceptable salts or isomers thereof.
  • Another object of the present invention is to provide a process for preparing the new compounds of formula (1).
  • Still another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient the [6+5] fused bicycle derivatives of formula (1), pharmaceutically acceptable salts or isomers thereof together with pharmaceutically acceptable carriers, which is used for the treatment and prevention of thrombus, platelet aggregation, atherosclerosis, restenosis, blood coagulation, hypertension, arrhythmia, angina pectoris, heart failure, inflammation and cancer.
  • the present invention relates to [6+5] fused bicycle derivatives of formula (1)
  • A, E and G independently of one another are selected from carbon, nitrogen and oxygen atoms, and the type of bond and the number of substituent are decided depending on the type of atom,
  • R 1 and R 2 independently of one another represent
  • 5- to 6-membered heteroaryl which has 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms and is optionally mono- or disubstituted by the substituents selected from oxo, C 1 -C 4 -alkyl, C 1 -C 4 -alkylsulfonyl and C 1 -C 4 -alkylcarbonyl,
  • R 1 and R 2 together represent oxo or hydroxyimino, or together with the atoms to which they are attached form a cycle B ( ), wherein the cycle B represents 4- to 7-membered saturated heterocycle which contains 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms and is optionally mono- to trisubstituted by the substituents selected from oxo, C 1 -C 4 -alkyl, C 1 -C 4 -alkylsulfonyl and C 1 -C 4 -alkylcarbonyl,
  • R 3 and R 4 independently of one another represent hydrogen or C 1 -C 4 -alkyl, or
  • R 3 and R 4 together represent oxo
  • R 5 and R 6 independently of one another represent hydrogen, halogen, cyano or amino, represent NR a R b , (CH 2 ) m OR a , O(CH 2 ) m R a , (CH 2 )mC(O)OR a , (CH 2 ) m OC(O)NR a R b , N(R a )C(O)R b , N(R a )C(O)OR b or (CH 2 ) m N(R a )S(O) m R b (wherein m, R a and R b are as defined above), or represent 5- to 6-membered heteroaryl or heterocycle which contains 1 to 3 heteroatoms selected from nitrogen and oxygen atoms,
  • R 5 and R 6 together represent dioxolanyl, oxo or hydroxyimino
  • R 7 and R 8 independently of one another represent hydrogen, halogen, O(CH 2 ) m R a , NR a R b or N(R a )C(O)OR b , wherein m, R a and R b each are as defined above,
  • R 7 and R 8 together represent dioxolanyl
  • Het represents monocyclic, bicyclic or tricyclic 5- to 14-membered heteroaryl or heterocycle which is optionally substituted by 1 to 4 R 1 and contains 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms, wherein oxygen and sulfur atoms cannot exist adjacently, pharmaceutically acceptable salts or isomers thereof.
  • the substituent Het preferably represents 5- to 6-membered heteroaryl which is optionally substituted by C 6 -C 10 -aryl and contains 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur atoms, wherein the oxygen and sulfur atoms cannot exist adjacently and C 6 -C 10 -aryl may be optionally substituted by halogen. More preferably, Het represents (3-fluorophenyl)pyridine.
  • R 1 and R 2 independently of one another represent
  • 5- to 6-membered heteroaryl which has 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms and is optionally mono- or disubstituted by the substituents selected from oxo, C 1 -C 4 -alkyl, C 1 -C 4 -alkylsulfonyl and C 1 -C 4 -alkylcarbonyl,
  • R 1 and R 2 together represent oxo or hydroxyimino, or together with the atoms to which they are attached form a cycle B, wherein the cycle B is 5- to 6-membered saturated heterocycle which contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms and is optionally mono- or disubstituted by the substituents selected from oxo, C 1 -C 4 -alkyl, C 1 -C 4 -alkylsulfonyl and C 1 -C 4 -alkylcarbonyl,
  • R 3 and R 4 independently of one another represent hydrogen or C 1 -C 4 -alkyl, or
  • R 3 and R 4 together represent oxo
  • R 5 and R 6 independently of one another represent hydrogen, halogen, cyano or amino, represent NR a R b , (CH 2 ) m OR a , O(CH 2 ) m R a , (CH 2 ) m C(O)OR a , (CH 2 ) m OC(O)NR a R b , N(R a )C(O)R b , N(R a )C(O)OR b or (CH 2 ) m N(R a )S(O) m R b (wherein m, R a and R b are as defined above), or represent 5- to 6-membered heteroaryl or heterocycle which contains 1 to 3 heteroatoms selected from nitrogen and oxygen atoms,
  • R 5 and R 6 together represent dioxolanyl, oxo or hydroxyimino
  • R 7 and R 8 independently of one another represent hydrogen, halogen, OR a , NR a R b or N(R a )C(O)OR b , wherein R a and R b each are as defined above, or
  • R 7 and R 8 together represent dioxolanyl
  • Het represents 6-membered heteroaryl which is optionally substituted by C 6 -C 10 -aryl and contains 1 or 2 nitrogen atoms, wherein C 6 -C 10 -aryl may be optionally substituted by halogen.
  • the present invention includes all the [6+5] fused bicycle derivatives of formula (1), pharmaceutically acceptable salts thereof, and furthermore includes possible solvates and hydrates that can be prepared therefrom.
  • the new [6+5] fused bicycle derivatives of formula (1) may exist as optically active isomers as well as racemic mixtures.
  • the position of stereocenter that can exist in the structure of [6+5] fused bicycle according to the present invention may be depicted as the following formula 1A.
  • * refers to the chiral center.
  • Example 14 ⁇ ( ⁇ )-(1S,2S,3aR,7aR)-1- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ octahydro-1H-inden-2-yl ⁇ (morpholin-4-yl)methanone;
  • Example 17 ⁇ ( ⁇ )-(1S,2S,3aR,7aR)-1- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ octahydro-1H-inden-2-yl ⁇ (pyrrolidin-1-yl)methanone;
  • Example 18 ⁇ ( ⁇ )-(1S,2S,3aR,7aR)-1- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ octahydro-1H-inden-2-yl ⁇ (piperidin-1-yl)methanone;
  • Example 88 ( ⁇ )-methyl-2- ⁇ (1S,3aR,7aS)-1- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ -1H-isoindole-2-(3H,3aH,4H,5H,6H,7H,7aH)-yl ⁇ acetate;
  • Example 90 ( ⁇ )-2- ⁇ (1S,3aR,7aS)-1- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ -1H-isoindole-2-(3H,3aH,4H,5H,6H,7H,7aH)-yl ⁇ acetic acid;
  • Example 94 ( ⁇ )-(1S,2S)-1- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ -2,3-dihydro-1H-indene-2-(N-acetyl)amine;
  • Example 127 ( ⁇ )-4- ⁇ 2- ⁇ (1'S,3a'R,5'R,7a'R)-1'- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-yloxy ⁇ ethyl ⁇ morpholine;
  • Example 129 > ( ⁇ )-(1'S,3a'R,5'S,7a'R)-1'- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ octahydrospiro[(1,3)dioxolane-2,2'-indene]-5'-carbonitrile;
  • Example 135 ( ⁇ )-(1S,2R,3aR,5R,7aR)-1- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ -5-(methoxymethoxy)octahydro-1H-indene-2-amine;
  • Example 136 ( ⁇ )-N- ⁇ (1S,2R,3aR,5R,7aR)-1- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ -5-(methoxymethoxy)octahydro-1H-inden-2-yl ⁇ methanesulfonamide;
  • Example 139 ( ⁇ )-1- ⁇ (1S,2R,3aR,5R,7aR)-1- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ -5-(methoxymethoxy)octahydro-1H-inden-2-yl ⁇ pyrrolidin-2-one;
  • Example 141 ( ⁇ )-1- ⁇ (1S,2R,3aR,5R,7aR)-1- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ -5-(methoxymethoxy)octahydro-1H-inden-2-yl ⁇ sultam;
  • Example 142 ( ⁇ )-(1S,2R,3aR,5R,7aR)-1- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ -5-(methoxymethoxy)octahydro-1H-inden-2-ol;
  • Example 152 > ( ⁇ )-t-butyl (1'S,3a'R,7a'R) ⁇ 1'- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ octahydro[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate;
  • Example 156 > ( ⁇ )-(1S,2S,3aS,7aR)-5-(t-butoxycarbonylamino)-1- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ octahydro-1H-inden]-2-yl methanesulfonate;
  • Example 165 > ( ⁇ )-t-butyl 1- ⁇ (1S,2S,3aS,7aR)-5-(t-butoxycarbonylamino)-1- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ octahydro-1H-inden-2-yl ⁇ -sultam;
  • Example 175 ( ⁇ )-(1S,2R,3aR,7aR)-5-(t-butoxycarbonylamino)-1- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ octahydro-1H-inden]-2-yl carbamate;
  • ⁇ Example 180 > ( ⁇ )-1- ⁇ (1S,2S,3aR,7aR)-5-(t-butoxycarbonylamino)-1- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ octahydro-1H-inden-2-yl ⁇ -sultam;
  • Example 185 > ( ⁇ )-methyl (1'S,3a'S,7a'R) ⁇ 1'- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ octahydro[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate;
  • Example 201 ( ⁇ )-(1S,3aS,7aR)-5-(t-butyloxycarbonylamino)-1- ⁇ (E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ -2-methyloctahydro-1H-inden-2-yl methanesulfonate;
  • Example 215 > ( ⁇ )-(1S,2R,3aS,7aR)-5,5-difluoro-1- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ -2-methyloctahydrospiro-1H-inden]-2-ylcarbamate;
  • ⁇ Example 220 > ( ⁇ )-N- ⁇ (1S,2S,3aR,7aR)-5,5-difluoro-1- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ -2-methyloctahydro-1H-inden]-2-yl ⁇ acetamide;
  • Example 224 > ( ⁇ )-(1S,3aS,7aR)-5,5-difluoro-1- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ octahydrospiroindene-2,5'-oxathiazolidin-2',2'-dione;
  • Example 240 > ( ⁇ )-(1'S,3a'S,5'S,6'S,7a'R)-6'-fluoro-1'- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-ol;
  • Example 248 > (-)-(1R,2S,3aS,7aS)-5,5-difluoro-1- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ octahydrospiro[indene-2,5'-oxazolidin]-2'-one.
  • Example 251 ( ⁇ )-5-(3-fluorophenyl)-2- ⁇ (E)-2-[(3a'S,4a'R,5'S,7a'S,8a'R)- octahydrospiro[(1,3)dioxolane-2,6'-indeno(5,6-d)(1,3)dioxol]-5'-yl]vinyl ⁇ pyridine;
  • Example 268 > ( ⁇ )-(4aR,5S,7aR)-5- ⁇ (E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ -6-methyloctahydrocyclopenta[c]pyran-6-yl carbamate;
  • the compounds of formula (1) of the present invention may be used in the form of a pharmaceutically acceptable salt.
  • the salts acid addition salts formed by pharmaceutically acceptable free acids are useful.
  • organic acids or inorganic acids may be used.
  • the inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, phosphoric acid, etc.
  • the organic acids include citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, etc.
  • the addition salts according to the present invention may be prepared by a conventional method, for example, by dissolving the compounds of formula (1) in an excess aqueous acid solution and precipitating the resulting salts with water-miscible organic solvents such as methanol, ethanol, acetone or acetonitrile.
  • the salts may also be prepared by heating the same amounts of the compound of formula (1) and acid in water or alcohol (e.g., glycol monomethylether) and then drying the mixture by evaporation, or suction-filtering the precipitated salts.
  • the compounds of the present invention may also be pharmaceutically acceptable metal salts formed by a base.
  • the alkali metal salts or alkaline earth metal salts of the compounds of formula (1) may be prepared, for example, by dissolving the compounds of formula (1) in a solution of excess alkali metal hydroxide or alkaline earth metal hydroxide, filtering off the insoluble materials, evaporating the filtrate and drying.
  • Sodium salt, potassium salt or calcium salt is pharmaceutically suitable.
  • the corresponding silver salts may be obtained by reacting the alkali metal salts or alkaline earth metal salts with suitable silver salts (e.g., silver nitrate).
  • Each optical isomer of the compounds of formula (1) may be prepared by using the corresponding isomer as a starting material.
  • the mixture of optical isomers may be used as a starting material to prepare the compound of formula (1) as a mixture of optical isomers, and the mixture may be subsequently separated into respective pure optical isomers.
  • the separation of optical isomers may be carried out via the conventional column chromatography or recrystallization.
  • the present invention provides a process for preparing the [6+5] fused bicycle compounds of formula (1).
  • the compounds of formula (1) can be prepared by reacting the compounds of formula (2) with the compounds of formula (3), or by reacting the compounds of formula (4) with the compounds of formula (5).
  • A, E, G, Het, R 1 to R 8 are as defined above, and
  • X represents halogen
  • the [6+5] fused bicycle compound (1) substituted by pyridine-vinyl can be prepared by Horner-Wadsworth-Emmons reaction of pyridin-2-yl methyl phosphonate with [6+5] fused bicycle (2) having an aldehyde group.
  • n-BuLi lithium diisopropylamide, potassium t-butoxide, KHMDS, LiHMDS, etc.
  • THF, diethylether, etc. are used as a solvent.
  • the alcohol compounds (1c) can be prepared by treating the ketal compounds (1a) with an acid to give the ketone compounds (1b) and the subsequent reduction using NaBH 4 , etc., or by removing the protecting group from the alcohol compounds having t-butyldimethylsilyl or other suitable protecting group.
  • various alcohol derivatives exemplified in the examples are prepared using various reactions. Furthermore, derivatization of alcohols may be proceeded prior to the Horner-Wadsworth-Emmons reaction or the Stille reaction of Reaction Scheme 1.
  • n denotes an integer of 1 or 2
  • P represents a hydroxy protecting group
  • the compounds of formula (1e) having a primary or secondary amine substituent on the pentacycle are prepared by reacting the ketone compounds (1b) with primary or secondary amines to give imines followed by a reductive amination reaction using a reducing agent such as NaCNBH 3 , NaBH(OAc) 3 , etc.
  • the compounds having a primary, secondary or tertiary amine substituent may be prepared starting from the alcohol compounds (Ic) via mesylates using a suitable base.
  • the present specification provides a process for preparing the amine compounds (Ie) by treating the carboxylic acid-substituted compounds (Id) with a base such as diphenylphosphoryl azide, triethylamine, etc. to perform Curtius reaction and subsequent hydrolysis.
  • Sulfonamides may be prepared from primary or secondary amine compounds, and the various cyclic compounds disclosed in the examples may be prepared using primary amines.
  • E, G, R a , R b , Het and cycle B are as defined above.
  • the ketone compounds (Ib) are alkylated by alkyl lithium or alkyl magnesium bromide to give tertiary alcohol derivatives. Also, compounds such as cyanohydrin, aminonitrile, aminocarboxylate, aminoalcohol, etc. are prepared from ketone compounds, from which the various compounds including spirocycle compounds disclosed in the examples can be prepared. There is also a process for directly preparing the spirocycle compounds from the ketone-substituted compound (Ib).
  • the compounds having a heterocycle on the pentacycle may be prepared from the ester compounds (Ie) through a cyclization reaction.
  • the hydrogen ion of ⁇ -carbon of ester substituent may be removed by a base such as lithium diisopropylamide, NaH, LHMDS, etc. and then alkylated to give a quaternary carbon compound.
  • quaternary carbon compounds having heterocyclic substituents are prepared through cyclization reactions staring from quaternary esters via amides and nitriles.
  • R 1 , R 2 , R 3 and R 4 are as defined above, and
  • P represents a hydroxy-protecting group
  • the compounds of formula (1) having various substituents on the hexacycle may be prepared.
  • aryl vinyl compounds are first prepared and the substituents on the pentacycle or hexacycle may be introduced. Otherwise, the substituents on the pentacycle or hexacycle are first introduced and the aryl vinyl compounds may be prepared according to the process of Reaction Scheme 1.
  • P represents a hydroxy-protecting group
  • the [6+5] fused bicycles containing heteroatoms may be prepared by Pauson -Khand reaction. After the preparation of bicycles, a substituent may be introduced to the pentacycle according to the processes of Reaction Schemes 2 to 5.
  • the compounds of formula (1) as prepared above are identified to confirm their molecular structures through infrared spectrometry, NMR, MS, liquid chromatography, X-ray crystallography, polarimetry, and comparisons between calculated and found elemental analysis of representative compounds.
  • the present invention further provides a pharmaceutical composition as an antagonist against PAR-1, which comprises the [6+5] fused bicycle derivatives of formula (1), pharmaceutically acceptable salts or isomers thereof as an active ingredient together with pharmaceutically acceptable carriers.
  • composition of the present invention is particularly useful for the treatment and prevention of, but not limited to, thrombus, platelet aggregation, atherosclerosis, restenosis, blood coagulation, hypertension, arrhythmia, angina pectoris, heart failure, inflammation and cancer. Also, the composition may be used in the combined treatment with other cardiovascular agents.
  • the present invention still further provides a method for the treatment and/or prevention of thrombus, platelet aggregation, atherosclerosis, restenosis, blood coagulation, hypertension, arrhythmia, angina pectoris, heart failure, inflammation and cancer, characterized by using the [6+5] fused bicycle derivatives of formula (1), pharmaceutically acceptable salts or isomers thereof as an active ingredient.
  • the present invention still further provides a process for preparing the composition as an antagonist against PAR-1, characterized by mixing the [6+5] fused bicycle derivatives of formula (1), pharmaceutically acceptable salts or isomers thereof with pharmaceutically acceptable carriers.
  • pharmaceutical composition means compositions comprising the active compounds of the present invention and other chemical components such as carriers, diluents, excipients, etc.
  • pharmaceutically acceptable carriers, diluents, excipients or their combinations can be contained in said pharmaceutical composition, if necessary.
  • a pharmaceutical composition facilitates the administration of the compound into a living organism. There are a number of techniques to administer the compound, and they include but are not limited to oral, injectable, aerosol, parenteral and topical administration.
  • carrier means a substance that facilitates the incorporation of the compound into cells or tissues.
  • DMSO dimethylsulfoxide
  • carrier facilitates the introduction of various organic compounds into cells or tissues of living organisms.
  • diluent is defined as a substance that is diluted in water, which dissolves the subject compound as well as stabilizes the biologically active form of the compound.
  • the salts dissolved in a buffer solution are utilized as diluents in the art.
  • a typically used buffer solution is phosphate-buffered saline which mimics the salt form of human solution. Buffer diluents rarely alter the biological activities of the compound, as the buffer salts can control the pH of solution at a low concentration.
  • “pharmaceutically acceptable” is defined as a characteristic not to damage the biological activities and physical properties of the compound.
  • the compound of the present invention may be formulated into various forms of pharmaceutical administration depending on the purpose intended.
  • the active component is mixed with various pharmaceutically acceptable carriers that can be selected according to the desired formulation.
  • the pharmaceutical compositions of the present invention can be formulated as an injectable preparation, oral preparation, etc., depending on the purpose intended.
  • the active compound of the present invention may be formulated by conventional methods of using pharmaceutically acceptable carriers and excipients known in the art and then charged in a unit dosage form or a multi-dose container.
  • the injection preparation may take such forms as solutions, suspensions or emulsions in oily or aqueous media, and may contain typical dispersing agents, suspending agents or stabilizing agents.
  • vegetable oils such as propylene glycol, polyethylene glycol or olive oil, injectable esters such as ethyl oleate, etc. may be used as the non-aqueous solvents or suspending media.
  • the active ingredient can be used as a form of dry powder which is intended to be reconstructed by dissolving in sterilized pyrogen-free water prior to use.
  • the compound of the present invention may also be formulated as a suppository utilizing typical suppository bases such as witepsol, macrogol, tween 61, cacao oil, lauric oil, glycerol, cocoa butter or gelatin.
  • typical suppository bases such as witepsol, macrogol, tween 61, cacao oil, lauric oil, glycerol, cocoa butter or gelatin.
  • the solid preparations for oral administration may include capsules, tablets, pills, powders and granules, among which capsules and tablets are particularly advantageous.
  • tablets and pills are prepared as enteric coated forms.
  • the solid preparations may be obtained by mixing the compound of the present invention with one or more inert diluents such as sucrose, lactose, starch, etc. and carriers such as lubricating agents (magnesium stearate, talc, etc.), disintegrating agents, binding agents, extenders, wetting agents, etc.
  • inert diluents such as sucrose, lactose, starch, etc.
  • carriers such as lubricating agents (magnesium stearate, talc, etc.), disintegrating agents, binding agents, extenders, wetting agents, etc.
  • the liquid preparations for oral administration suspensions, oral solutions, emulsions, syrups, etc. are selected, and various excipients, for example, wetting agents, sweeteners, flavouring agents, pre
  • the compounds of the present invention or pharmaceutical compositions comprising the same may be administered in combination with other medicines, for example, other medicines for treating cardiovascular diseases.
  • compositions according to the present invention contain the active ingredient in an amount effective to achieve its intended purpose. More specifically, the therapeutically effective amount means the amount of the active compound effective to prolong the survival of the subject to be treated, or to prevent, alleviate or ameliorate the symptoms of the disease. A skilled artisan would be able to determine the therapeutically effective amount, particularly in light of the detailed description provided herein.
  • the active compounds of the present invention are preferably contained in an amount of about 0.1 to 100 mg per unit dosage.
  • the dosage of the compounds depends on the prescription of a physician, taking into account such factors as body weight or age of a patient, specific nature of the disease, severity of the disease, etc. However, dosage needed for the treatment of an adult is typically from about 0.1 to 100 mg per day, depending on the intensity and frequency of the administration. But for some patients a higher daily dosage may be desirable.
  • the present invention also provides a method for treating or preventing cardiovascular diseases using an effective amount of the compounds of the present invention.
  • treatment means the interruption, delay or amelioration of the progress of the disease when applied to a subject showing the onset of disease symptoms
  • prevention means the interruption, delay or amelioration of the sign of the onset of disease when applied to a subject who does not show, but is at risk of, the onset of disease symptoms.
  • the symbol ( ⁇ ) is used to represent the relative stereochemistry.
  • the title of Preparation 1 “( ⁇ )-(1'R,3a'R,7a'R)-octahydrospiro [[1,3]dioxolane-2,2'-indene]-1'-carbaldehyde” substantially means that the final compound is obtained as a racemic mixture of (+)-(1'S,3a'S,7a'S)-octahydrospiro[[1,3]dioxolane-2,2'-indene]-1'-carbaldehyde and (-)-(1'R,3a'R,7a'R)-octahydrospiro[[1,3]dioxolane-2,2'-indene]-1'-carbaldehyde.
  • the present specification indicates such situation in the manner of introducing a symbol ( ⁇ ) in front of the nomenclature.
  • Step 1 The compound of Step 1 (4.9 g, 0.034 mol) was reacted according to the same procedure as Step 2 of Preparation 1 to give the title compound (9.5 g, 0.032 mol).
  • Step 2 The compound of Step 2 (9.5 g, 0.032 mol) was reacted according to the same procedure as Step 3 of Preparation 1 to give the title compound (5.0 g, 0.030 mol).
  • Step 3 The compound of Step 3 (5.0 g, 0.030 mol) was reacted according to the same procedure as Step 4 of Preparation 1 to give the title compound (4.3 g, 0.026 mol).
  • Step 4 The compound of Step 4 (4.3 g, 0.026 mol) was reacted according to the same procedure as Step 5 of Preparation 1 to give the title compound (5.0 g, 0.024 mol).
  • Step 5 The compound of Step 5 (5.0 g, 0.024 mol) was reacted according to the same procedure as Step 6 of Preparation 1 to give the title compound (5.0 g, 0.024 mol).
  • Step 2 The compound of Step 2 (25 g, 0.17 mol) was reacted according to the same procedure as Step 2 of Preparation 1 to give the title compound (43 g, 85%).
  • Step 3 The compound of Step 3 (65 g, 0.21 mol) was reacted according to the same procedure as Step 3 of Preparation 1 to give the title compound (43 g, 95%).
  • Step 4 To the compound of Step 4 (32 g, 0.02 mol) was added 6 N aqueous KOH solution (170 mL), the mixture was refluxed for 24 h and cooled to 0 °C. conc. Hydrochloric acid was slowly added thereto. The resulting white solid was precipitated and filtered. This solid was dissolved in ethyl acetate (1 L) and filtered. The filtrate was dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to give the the title compound as a white solid (25 g, 65%).
  • Step 7 The compound of Step 7 (5.00 g, 25.7 mmol) was reacted according to the same procedure as Step 5 of Preparation 1 to give the title compound (5.38 g, 88%) as a colorless liquid.
  • Step 9 To the solution of Step 9 compound (30.0 mg, 0.142 mmol) and NaHCO 3 (20 mg) in CH 2 Cl 2 (2 mL) was added Dess-Martin periodinane (121 mg, 0.286 mmol) while stirring at room temperature. The white turbid reaction solution was stirred for 2 h at room temperature, to which was added saturated NaHCO 3 (1 mL) to stop the reaction. The organic layer was separated, and the aqueous layer was extracted with CH 2 Cl 2 (3 ⁇ 5 mL). The organic layers were combined and washed with brine (5 mL). The organic layer was dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was filtered through a silica gel pad using Et 2 O (20 mL). The filtrate was concentrated under reduced pressure to give the pale yellow title compound (13 mg), which was then used in the next reaction without further purification.
  • Step 2 ( ⁇ )- ⁇ (1'S,3a'R,7a'R)-2,3,3a,4,7,7a-hexahydrospiro-[(1,3)dioxolane-2,2'-inden]-1’-yl ⁇ -methanol
  • Step 1 The compound of Step 1 was reacted according to the same procedures as Steps 3 to 9 ⁇ 7 steps ⁇ of Preparation 3 to give the title compound.
  • Step 2 The compound of Step 2 was reacted according to the same procedure as Step 10 of Preparation 3 to give the title compound.
  • the filtrate was concentrated under reduced pressure.
  • Step 4 compound 360 mg, 0.815 mmol
  • THF 2 mL
  • n -Bu 4 NF 2.45 mL, 1.0 M in THF, 2.45 mmol
  • saturated NaHCO 3 3 mL
  • the organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 ⁇ 10 mL).
  • the organic layers were combined, dried over anhydrous MgSO 4 and filtered.
  • Step 5 compound (228 mg, 0.696 mmol) was reacted according to the same procedure as Step 10 of Preparation 3 to give the pale yellow title compound (200 mg).
  • Step 1 ( ⁇ )-(1'R,3a'S,7a'R)-1'-[(t-butyldimethylsilyloxy)methyl]octahydrospiro-[(1,3)dioxolane-2,2'-inden]-6'-ol
  • Step 2 of Preparation 5 (1.63 g, 4.79 mmol) was reacted according to the same procedure as Step 3 of Preparation 5 to give the title compound (550 mg, 34%) as a colorless liquid which is more nonpolar than the isomer of Step 3 of Preparation 5.
  • Step 2 t-Butyl-( ⁇ )-(1'R,3a'S,7a'R)-1'-[(t-butyldimethylsilyloxy)methyl]octahydrospiro[[1,3]dioxolane-2,2'-inden]-6'-ylcarbamate
  • Step 1 compound was reacted according to the same procedure as Step 4 of Preparation 5 to give the title compound.
  • Step 2 compound was reacted according to the same procedure as Step 5 of Preparation 5 to give the title compound.
  • Step 3 compound was reacted according to the same procedure as Step 10 of Preparation 3 to give the title compound.
  • Step 1 ( ⁇ )-(1'R,3a'S,7a'R)-1'-(benzyloxymethyl)-1',3',3a',4',7',7a'-hexahydrospiro-[(1,3)dioxolane-2,2'-indene]
  • Step 2 ( ⁇ )-(2a'R,3'R,5a'S)-3'-(benzyloxymethyl)-octahydrospiro-[(1,3)dioxolane-2,4'-indeno(5,6-b)oxirane]
  • Step 6 compound (257 mg, 0.684 mmol) in CH 2 Cl 2 (10 mL) was stirred at room temperature, to which were added t -butyldimethylsilyl trifluoromethanesulfonate (314 ⁇ L, 1.37 mmol) and 2,6-rutidine (318 ⁇ L, 2.74 mmol).
  • NaHCO 3 5 mL was added to the reaction mixture to stop the reaction.
  • the organic layer was separated and the aqueous layer was extracted with CH 2 Cl 2 (3 ⁇ 10 mL).
  • the organic layers were combined, dried over anhydrous MgSO 4 and filtered.
  • Step 7 compound 300 mg, 0.613 mmol
  • methanol 3 mL
  • 20 wt% Pd(OH) 2 /C 30 mg
  • the resulting black turbid solution was treated to remove the air in the reaction vessel under reduced pressure condition, and the reaction mixture was heated to 50 °C under hydrogen gas of 1 atm.
  • Step 8 compound (100 mg, 0.250 mmol) was reacted according to the same procedure as Step 10 of Preparation 3 to give the yellow title compound (90 mg).
  • Step 5 compound of Preparation 7 (287 mg, 0.768 mmol) was reacted according to the same procedure as Step 6 of Preparation 7 to give the title alcohol compound (90 mg, 35%) as a colorless liquid which is more polar than the isomer of Step 6 of Preparation 7.
  • Step 1 compound was reacted according to the same procedure as Step 7 of Preparation 7 to give the title compound.
  • Step 2 compound was reacted according to the same procedure as Step 8 of Preparation 7 to give the title compound.
  • Step 3 compound was reacted according to the same procedure as Step 10 of Preparation 3 to give the title compound.
  • Step 1 ( ⁇ )-(1'R,3a'R,7a'R)-1-(benzyloxymethyl)-1',3',3a',4',7',7a'-hexahydrospiro[(1,3)dioxolane-2,2'-indene]
  • Step 2 ( ⁇ )-(1'R,3a'R,5'R,7a'R)-1-(benzyloxymethyl)-octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-ol
  • Step 1 compound (3.2 g, 10.65 mmol) was reacted according to the same procedures as Steps 2 and 3 of Preparation 5 ⁇ 2 step reaction ⁇ to give the title compound (2.2 g, 2 Step 65%).
  • Step 2 compound (700 mg, 2.19 mmol) was reacted according to the same procedure as Step 7 of Preparation 7 to give the title compound (890 mg, 93%).
  • Step 3 compound (890 mg, 2.05 mmol) was reacted according to the same procedure as Step 8 of Preparation 7 to give the title compound (600 mg, 85%).
  • Step 4 compound was reacted according to the same procedure as Step 10 of Preparation 3 to give the title compound.
  • Step 2 compound of Preparation 9 (1.3 g, 4.08 mmol) in benzene (8 mL) was stirred, during which PPh 3 (5.3 g, 20.41 mmol), 4-nitrobenzoic acid (3 g, 18.23 mmol) and diethylazodicarboxylate (3.2 mL, 20.41 mmol) were added.
  • the mixture was stirred for 30 min at room temperature, and H 2 O was added to the reaction vessel to stop the reaction.
  • the organic layer was separated from the reaction mixture, and the aqueous layer was extracted with Et 2 O.
  • the organic layers were combined and dried over anhydrous MgSO 4 .
  • Step 2 ( ⁇ )-(1'R,3a'R,5'S,7a'R)-5'-(t-butyl-dimethylsilyloxy)octahydrospiro[(1,3)dioxolane-2,2'-indene]-1'-carbaldehyde
  • Step 1 compound was reacted according to the same procedures as Steps 3-5 of Preparation 9 ⁇ 3 step reaction ⁇ to give the title compound.
  • Step 2 compound of Preparation 9 (300 mg, 0.942 mmol) was reacted according to the same procedure as Step 4 of Preparation 5 to give the title compound (240 mg, 3 Step Total Yield 70%).
  • Step 1 compound (240 mg, 0.57 mmol) was reacted according to the same procedure as Step 8 of Preparation 7 to give the title compound (100 mg, 75%).
  • Step 2 compound was reacted according to the same procedure as Step 10 of Preparation 3 to give the title compound.
  • Step 1 compound of Preparation 9 was reacted according to the same procedure as Step 5 of Preparation 7 to give the title compound.
  • Step 1 compound (2.0 g, 7.8 mmol) was reacted according to the same procedure as Step 6 of Preparation 7 to give the title compound (0.8 g, 40%) as a more polar isomer.
  • Step 2 compound (3.4 g, 13 mmol) was reacted according to the same procedure as Step 7 of Preparation 7 to give the title compound (5.0 g, 100%).
  • Step 3 compound was reacted according to the same procedures as Steps 2 and 3 of Preparation 5 ⁇ 2 step reaction ⁇ to give the title compound.
  • Step 4 compound (0.120 g, 0.307mmol), to which were added diisopropylethylamine (0.080 mL, 0.467 mmol), methoxymethyl chloride (0.035 mL, 0.467 mmol) and dimethylaminopyridine (0.004g, 0.031mmol) at 0 °C.
  • Step 5 compound (100 mg, 0.237 mmol) was reacted according to the same procedure as Step 8 of Preparation 7 to give the title compound (64 mg, 80%).
  • Step 6 compound (40 mg, 0.116 mmol) was reacted according to the same procedure as Step 10 of Preparation 3 to give the title compound (30 mg, 75%).
  • Step 2 of Preparation 12 The more nonpolar compound obtained in Step 2 of Preparation 12 (0.23 g, 11%) was reacted according to the same procedures as Steps 3-7 of Preparation 12 to give the title compound.
  • Step 9 compound of Preparation 3 was reacted according to the same procedure as Preparation 9 to give the title compound.
  • 6-Methylpyridin-3-ol (4 g, 36.7 mmol) was dissolved in CH 2 Cl 2 , to which was added pyridine (4.4 mL, 54.4 mmol, 1.5 equiv). At 0 °C, trifluoromethanesulfone anhydride (9.2 mL, 54.6 mmol, 1.5 equiv) was slowly added. After stirring for 1.5 h at 0 °C, methanol (1 mL) and saturated aqueous NaHCO 3 solution were added.
  • Step 1 bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]fumarate
  • Step 2 (-)-(1S,2S)-bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]cyclohex-4-ene-1,2-dicarboxylate
  • Step 1 compound (47 g, 0.12 mol) was added to anhydrous hexane (700 mL) and cooled to -40 °C.
  • Diisobutylaluminum chloride (240 mL, 25% solution) was added and stirred for 30 min.
  • 1,3-butadiene (28.5g).
  • the reaction solution was added to aqueous HCl solution, which was then extracted with ether, washed with NaHCO 3 solution and aqueous NaCl solution, dried over MgSO 4 and filtered.
  • the filtrate was concentrated under reduced pressure to give the title compound (46 g, 85%) as a gel.
  • Step 3 compound (0.17 mol) was reacted according to the same procedures as Steps 3-7 of Preparation 3 ⁇ 5 step reaction ⁇ to give the title compound.
  • Example 4 The same procedure as Example 4 was carried out to give the title compound (0.023g, 0.065mmol).
  • Example 13 compound was reacted according to the same procedure as Example 14 except for using N-methylamine instead of morpholine to give the title compound.
  • Example 13 compound was reacted according to the same procedure as Example 14 except for using N,N-dimethylamine instead of morpholine to give the title compound.
  • Example 17 ⁇ ( ⁇ )-(1S,2S,3aR,7aR)-1- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ octahydro-1H-inden-2-yl ⁇ (pyrrolidin-1-yl)methanone
  • Example 13 compound was reacted according to the same procedure as Example 14 except for using pyrrolidine instead of morpholine to give the title compound.
  • Example 18 ⁇ ( ⁇ )-(1S,2S,3aR,7aR)-1- ⁇ (E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl ⁇ octahydro-1H-inden-2-yl ⁇ (piperidin-1-yl)methanone
  • Example 13 compound was reacted according to the same procedure as Example 14 except for using piperidine instead of morpholine to give the title compound.
  • Example 13 compound was reacted according to the same procedure as Example 14 except for using N-methylpiperazine instead of morpholine to give the title compound.
  • Example 13 compound (100 mg, 0.274 mmol) was reacted according to the same procedure as Example 14 except for using ammonia water instead of morpholine to give the title compound (75 mg, 75%).
  • Example 13 compound was reacted according to the same procedure as Example 23 except for using ethanol instead of methanol to give the title compound.
  • Example 13 compound (20 mg, 0.055 mmol) was reacted according to the same procedure as Example 14 except for using 2-aminoethanol (0.007 mL, 0.109 mmol) instead of morpholine to give the title compound (20 mg, 90%).
  • Example 25 compound (20 mg, 0.049 mmol) was added to CH 2 Cl 2 (2 mL), and diethylaminosulfur trifluoride (0.007 mL, 0.054 mmol) and K 2 CO 3 (14 mg, 0.098 mmol) were added at -78 °C.
  • Example 13 compound was reacted according to the same procedure as Example 14 except for using hydroxylamine instead of morpholine to give the title compound.
  • Example 13 compound 200 mg, 0.547 mmol
  • diphenylphosphoyl azide (0.59 mL, 2.735 mmol)
  • NEt 3 (0.38 mL, 2.735 mmol
  • the reaction solution was concentrated under reduced pressure.
  • Example 41 The same procedure as Example 41 was carried out except for using ammonia water instead of dimethylamine to give the title compound.
  • Example 41 The same procedure as Example 41 was carried out except for using methylamine instead of dimethylamine to give the title compound.
  • Example 44 The same procedure as Example 44 was carried out except for using dimethylamine instead of methylamine to give the title compound.
  • Example 43 compound was reacted according to the same procedure as Example 48 to give the title compound.

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Abstract

The present invention relates to the new [6+5] fused bicycle derivatives, pharmaceutically acceptable salts or isomers thereof, processes for preparing the same, and pharmaceutical compositions comprising the same. The [6+5] fused bicycle derivatives can antagonize the thrombin receptor and thus may be effectively used for the treatment and prevention of thrombus, platelet aggregation, atherosclerosis, restenosis, blood coagulation, hypertension, arrhythmia, angina pectoris, heart failure, inflammation and cancer when used alone or with other cardiovascular agents.

Description

[6+5] FUSED BICYCLES AS A THROMBIN ANTAGONIST, PROCESS FOR PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE BICYCLES
The present invention relates to new [6+5] fused bicycles of the following formula (1)
Figure PCTKR2011004607-appb-I000001
in which, A, E, G, Het, R1 to R8 are as defined below, as a thrombin antagonist, pharmaceutically acceptable salts thereof, processes for preparing the same, and pharmaceutical compositions comprising the same. The compounds according to the present invention can be used as an antagonist for thrombin receptor known as a PAR-1 (protease receptor antagonist type 1) antagonist. Accordingly, the composition of the present invention may be effectively used for the treatment and prevention of thrombus, platelet aggregation, atherosclerosis, restenosis, blood coagulation, hypertension, arrhythmia, angina pectoris, heart failure, inflammation and cancer.
Nowadays, arterial thrombosis is the leading cause of death in developed countries, which is a disease acutely developed under the circumstance of chronic atherosclerotic blood vessel, resulting in myocardial infarction and stroke. Cardiovascular diseases caused by arterial thrombosis, etc. were revealed to be a cause of death, accounting for 36% of the whole deaths of 2.4 million in USA in 2004. In addition, it is assumed that 79 million corresponding to one third of the population of USA have more than one type of cardiovascular diseases, and 37 million corresponding to 47% of the above are estimated to be patients aged over 65 years. Thus, it may be found that deaths due to the cardiovascular diseases tend to increase according to the increase of age. Since 70% or more of the population aged over 60 years appear to have some cardiovascular diseases, it becomes more and more important to control the cardiovascular diseases according to the progress of the aging of population.
It is well known that platelet is very important in such arterial thrombosis and cardiovascular diseases. Thus, platelet becomes an important target among any other cells for the development of therapeutic agents. Use of antiplatelet drugs also tends to increase along with the recognition on the importance of platelet. Clopidogrel (Plavix) of Sanofi Aventis, the most widely used current antiplatelet drug, is an antagonist for an ADP receptor P2Y12, one of the various factors causing platelet aggregation. Although it is a blockbuster, it shows very different responses between patients, and its efficacy needs to be improved.
PAR-1 is a receptor that is activated via a mechanism in which the N-terminal amino acid sequence is cleaved and the newly generated N-terminal amino acid sequence interacts with PAR-1 itself. The receptors within the same group known up to now include PAR-2, PAR-3 and PAR-4 (Nature, 407:258-264, 2000). Among them, PAR-1 and PAR-4 exist in human platelets. PAR-1 is activated by a low concentration of thrombin and PAR-4 is activated by a high concentration of thrombin to participate in the platelet aggregation. Thrombin plays a key role in the physiological hemostasis to prevent the loss of blood by the cellular effect of vasoconstriction, platelet aggregation through PAR-1, etc. and by the humoral effect of activating fibrinogen in plasma to fibrin whereby causing the polymerization reaction of fibrin (J. Thromb. Haemost. 3(8): 1800-14, 2005). Direct thrombin inhibitors are known to frequently have the side effect of bleeding. However, in contrast to the direct thrombin inhibitors, the PAR-1 antagonist does not inhibit the humoral effect and thus is expected to have less side effect of bleeding (Mol. Pharmacol. 67:2-11, 2005).
As the drugs of the above group, SCH-530348 of Schering-Plough (J. Med. Chem, 51: 3061-64, 2008, WO2005118/ WO2003089428, 576/ WO1999026943) is under phase 3 clinical trial, and E-5555 of Eisai Co. (WO2006051648) is under phase 2 clinical trial.
Given the above-explained technical background, the present inventors extensively studied to find new compounds useful as an antagonist against PAR-1. As a result, we have discovered that the [6+5] fused bicycle derivatives of formula (1) meet such a purpose, and completed the present invention.
Thus, one object of the present invention is to provide the [6+5] fused bicycle derivatives of formula (1), pharmaceutically acceptable salts or isomers thereof.
Another object of the present invention is to provide a process for preparing the new compounds of formula (1).
Still another object of the present invention is to provide a pharmaceutical composition comprising as an active ingredient the [6+5] fused bicycle derivatives of formula (1), pharmaceutically acceptable salts or isomers thereof together with pharmaceutically acceptable carriers, which is used for the treatment and prevention of thrombus, platelet aggregation, atherosclerosis, restenosis, blood coagulation, hypertension, arrhythmia, angina pectoris, heart failure, inflammation and cancer.
First, the present invention relates to [6+5] fused bicycle derivatives of formula (1)
Figure PCTKR2011004607-appb-I000002
in which
Figure PCTKR2011004607-appb-I000003
denotes a double or single bond,
A, E and G independently of one another are selected from carbon, nitrogen and oxygen atoms, and the type of bond and the number of substituent are decided depending on the type of atom,
R1 and R2 independently of one another represent
hydrogen, halogen or cyano,
5- to 6-membered heteroaryl which has 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms and is optionally mono- or disubstituted by the substituents selected from oxo, C1-C4-alkyl, C1-C4-alkylsulfonyl and C1-C4-alkylcarbonyl,
saturated or partially unsaturated 5- to 6-membered heterocycle which has 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms and is optionally mono- or disubstituted by the substituents selected from oxo, C1-C4-alkyl, C1-C4-alkylsulfonyl and C1-C4-alkylcarbonyl,
(CH2)mRa, (CH2)mOC(O)Ra, (CH2)mORa, (CH2)mOC(S)Ra, (CH2)mOC(O)NRaRb, (CH2)mOC(S)NRaRb, (CH2)mOS(O)mRa, (CH2)mS(O)mRa, (CH2)mS(O)mNRaRb, (CH2)mOS(O)mNRaRb, C(O)NRaRb, (CH2)mC(O)ORa, (CH2)mC(O)Ra, O(CH2)mRa, NRaRb, N(Ra)C(O)Rb, N(Ra)C(O)NRaRb, (CH2)mN(Ra)C(O)ORb, or (CH2)mN(Ra)S(O)mRb, wherein m denotes a number of 0 to 2, Ra and Rb independently of one another represent hydrogen, halogen, hydroxy, C1-C4-alkyl, C3-C6-cycloalkyl, optionally halogen-substituted C6-C10-aryl, C1-C4-alkylcarbonyl, C1-C4-alkylsulfonyl, C1-C4-alkoxy-C1-C4-alkyl or hydroxy-C1-C4-alkyl, or represent 4- to 7-membered heteroaryl or heterocycle which contains 1 to 3 heteroatoms selected from nitrogen and oxygen atoms and is optionally substituted by C1-C4-alkyl, or Ra and Rb together with the atoms to which they are attached represent 4- to 7-membered heteroaryl or heterocycle which contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms and is optionally substituted by oxo or C1-C4-alkyl, or
[Corrected under Rule 26 08.07.2011]
R1 and R2 together represent oxo or hydroxyimino, or together with the atoms to which they are attached form a cycle B (
Figure WO-DOC-31
), wherein the cycle B represents 4- to 7-membered saturated heterocycle which contains 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms and is optionally mono- to trisubstituted by the substituents selected from oxo, C1-C4-alkyl, C1-C4-alkylsulfonyl and C1-C4-alkylcarbonyl,
R3 and R4 independently of one another represent hydrogen or C1-C4-alkyl, or
R3 and R4 together represent oxo,
R5 and R6 independently of one another represent hydrogen, halogen, cyano or amino, represent NRaRb, (CH2)mORa, O(CH2)mRa, (CH2)mC(O)ORa, (CH2)mOC(O)NRaRb, N(Ra)C(O)Rb, N(Ra)C(O)ORb or (CH2)mN(Ra)S(O)mRb (wherein m, Ra and Rb are as defined above), or represent 5- to 6-membered heteroaryl or heterocycle which contains 1 to 3 heteroatoms selected from nitrogen and oxygen atoms,
R5 and R6 together represent dioxolanyl, oxo or hydroxyimino,
R7 and R8 independently of one another represent hydrogen, halogen, O(CH2)mRa, NRaRb or N(Ra)C(O)ORb, wherein m, Ra and Rb each are as defined above,
R7 and R8 together represent dioxolanyl, and
Het represents monocyclic, bicyclic or tricyclic 5- to 14-membered heteroaryl or heterocycle which is optionally substituted by 1 to 4 R1 and contains 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms, wherein oxygen and sulfur atoms cannot exist adjacently, pharmaceutically acceptable salts or isomers thereof.
Figure PCTKR2011004607-appb-I000005
The substituent Het preferably represents 5- to 6-membered heteroaryl which is optionally substituted by C6-C10-aryl and contains 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur atoms, wherein the oxygen and sulfur atoms cannot exist adjacently and C6-C10-aryl may be optionally substituted by halogen. More preferably, Het represents (3-fluorophenyl)pyridine.
The most preferred compounds among the compounds of formula (1) according to the present invention are those wherein
Figure PCTKR2011004607-appb-I000006
R1 and R2 independently of one another represent
hydrogen, halogen or cyano,
5- to 6-membered heteroaryl which has 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms and is optionally mono- or disubstituted by the substituents selected from oxo, C1-C4-alkyl, C1-C4-alkylsulfonyl and C1-C4-alkylcarbonyl,
saturated or partially unsaturated 5- to 6-membered heterocycle which has 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms, and is optionally mono- or disubstituted by the substituents selected from oxo, C1-C4-alkyl, C1-C4-alkylsulfonyl and C1-C4-alkylcarbonyl,
(CH2)mRa, (CH2)mOC(O)Ra, (CH2)mORa, (CH2)mOC(S)Ra, (CH2)mOC(O)NRaRb, (CH2)mOC(S)NRaRb, (CH2)mOS(O)mRa, (CH2)mS(O)mRa, (CH2)mS(O)mNRaRb, (CH2)mOS(O)mNRaRb, C(O)NRaRb, (CH2)mC(O)ORa, (CH2)mC(O)Ra, O(CH2)mRa, NRaRb, N(Ra)C(O)Rb, N(Ra)C(O)NRaRb, (CH2)mN(Ra)C(O)ORb, or (CH2)mN(Ra)S(O)mRb, wherein m denotes a number of 0 to 2, Ra and Rb independently of one another represent hydrogen, halogen, hydroxy, C1-C4-alkyl, C3-C6-cycloalkyl, optionally halogen-substituted C6-C10-aryl, C1-C4-alkylcarbonyl, C1-C4-alkylsulfonyl, C1-C4-alkoxy-C1-C4-alkyl or hydroxy-C1-C4-alkyl, or represent 5- to 6-membered heteroaryl or heterocycle which contains 1 to 3 heteroatoms selected from nitrogen and oxygen atoms and is optionally substituted by C1-C4-alkyl, or Ra and Rb together with the atoms to which they are attached represent 5- or 6-membered heteroaryl or heterocycle which contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms and is optionally substituted by oxo or C1-C4-alkyl, or
R1 and R2 together represent oxo or hydroxyimino, or together with the atoms to which they are attached form a cycle B, wherein the cycle B is 5- to 6-membered saturated heterocycle which contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms and is optionally mono- or disubstituted by the substituents selected from oxo, C1-C4-alkyl, C1-C4-alkylsulfonyl and C1-C4-alkylcarbonyl,
R3 and R4 independently of one another represent hydrogen or C1-C4-alkyl, or
R3 and R4 together represent oxo,
R5 and R6 independently of one another represent hydrogen, halogen, cyano or amino, represent NRaRb, (CH2)mORa, O(CH2)mRa, (CH2)mC(O)ORa, (CH2)mOC(O)NRaRb, N(Ra)C(O)Rb, N(Ra)C(O)ORb or (CH2)mN(Ra)S(O)mRb (wherein m, Ra and Rb are as defined above), or represent 5- to 6-membered heteroaryl or heterocycle which contains 1 to 3 heteroatoms selected from nitrogen and oxygen atoms,
R5 and R6 together represent dioxolanyl, oxo or hydroxyimino,
R7 and R8 independently of one another represent hydrogen, halogen, ORa, NRaRb or N(Ra)C(O)ORb, wherein Ra and Rb each are as defined above, or
R7 and R8 together represent dioxolanyl, and
Het represents 6-membered heteroaryl which is optionally substituted by C6-C10-aryl and contains 1 or 2 nitrogen atoms, wherein C6-C10-aryl may be optionally substituted by halogen.
The present invention includes all the [6+5] fused bicycle derivatives of formula (1), pharmaceutically acceptable salts thereof, and furthermore includes possible solvates and hydrates that can be prepared therefrom.
The new [6+5] fused bicycle derivatives of formula (1) may exist as optically active isomers as well as racemic mixtures. The position of stereocenter that can exist in the structure of [6+5] fused bicycle according to the present invention may be depicted as the following formula 1A. In the formula 1A, * refers to the chiral center.
Figure PCTKR2011004607-appb-I000007
The representative compounds of formula (1) according to the present invention are selected from the following group:
<Example 1> (±)-5-(3-fluorophenyl)-2-{(E)-2-[(1'S,3a'R,7a'R)-octahydrospiro[(1,3)-dioxolane-2,2'-inden]-1'-yl]vinyl}pyridine;
<Example 2> (±)-5-(3-fluorophenyl)-2-{(E)-2-[(1'S,3a'S,7a'R)-octahydrospiro[(1,3)-dioxolane-2,2'-inden]-2-yl]vinyl}pyridine;
<Example 3> (±)-(1S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}hexahydro-1H-inden-2(3H)-one;
<Example 4> (±)-(1S,3aR,7aR, E)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}hexahydro-1H-inden-2(3H)-one oxime;
<Example 5> (±)-(1S,3aR,7aR, Z)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}hexahydro-1H-inden-2(3H)-one oxime;
<Example 6> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2(3H)-ol;
<Example 7> (±)-5-(3-fluorophenyl)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-methoxyoctahydro-1H-inden-1-yl]vinyl}pyridine;
<Example 8> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl acetate;
<Example 9> (±)-5-(3-fluorophenyl)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(benzyloxy)octahydro-1H-inden-1-yl]vinyl}pyridine;
<Example 10> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl methanesulfonate;
<Example 11> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl phenylcarbamate;
<Example 12> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl dimethylcarbamothioate;
<Example 13> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl carboxylic acid;
<Example 14> {(±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}(morpholin-4-yl)methanone;
<Example 15> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-N-methyloctahydro-1H-indene-2-carboxamide;
<Example 16> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-N,N-dimethyloctahydro-1H-indene-2-carboxamide;
<Example 17> {(±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}(pyrrolidin-1-yl)methanone;
<Example 18> {(±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}(piperidin-1-yl)methanone;
<Example 19> {(±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}(4-methylpiperazin-1-yl)methanone;
<Example 20> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-N-(methylsulfonyl)octahydro-1H-indene-2-carboxamide;
<Example 21> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-indene-2-carboxamide;
<Example 22> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-indene-2-carbonitrile;
<Example 23> (±)-(1S,2S,3aR,7aR)-methyl-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-indene-2-carboxylate;
<Example 24> (±)-(1S,2S,3aR,7aR)-ethyl-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-indene-2-carboxylate;
<Example 25> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-N-(2-hydroxyethyl)octahydro-1H-indene-2-carboxamide;
<Example 26> 2-{(±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-4,5-dihydrooxazole;
<Example 27> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-N-hydroxyoctahydro-1H-indene-2-carboxamide;
<Example 28> (±)-5-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-1,2,4-oxadiazole;
<Example 29> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-indene-2-amine;
<Example 30> (±)-methyl(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-ylcarbamate;
<Example 31> (±)-ethyl(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-ylcarbamate;
<Example 32> (±)-t-butyl-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-ylcarbamate;
<Example 33> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(1H-tetrazol-5-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 34> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(1-methyl-1H-tetrazol-5-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 35> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(2-methyl-2H-tetrazol-5-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 36> (±)-3-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-5-methyl-1,2,4-oxadiazole;
<Example 37> (±)-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methanol;
<Example 38> (±)-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl acetate;
<Example 39> (±)-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl methanesulfonate;
<Example 40> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(methoxymethyl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 41> (±)-O-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl dimethylcarbothiolate;
<Example 42> (±)-O-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl carbothiolate;
<Example 43> (±)-O-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl methylcarbothiolate;
<Example 44> (±)-1-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-3-methylurea;
<Example 45> (±)-3-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-1,1-dimethylurea;
<Example 46> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(4,5-dihydro-1H-imidazole-2-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 47> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methanesulfonamide;
<Example 48> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}acetamide;
<Example 49> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-N-methylacetamide;
<Example 50> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}cyclopropanecarboxamide;
<Example 51> (±)-O-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl acetyl(methyl)carbothiolate;
<Example 52> (±)-4-{[(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl]methyl}morpholine;
<Example 53> (±)-1-{{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl}-1H-imidazole;
<Example 54> (±)-N-{{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl}methanesulfonamide;
<Example 55> (±)-N-{{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl}-N-methylmethanesulfonamide;
<Example 56> (±)-N-{{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl}sultam;
<Example 57> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(pyrrolidin-1-ylmethyl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 58> (±)-1-{{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl}-1H-2-methylimidazole;
<Example 59> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(1H-imidazole-2-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 60> (±)-2-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-5-methyl-1,3,4-oxadiazole;
<Example 61> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-N-methylmethanesulfonamide;
<Example 62> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-ol;
<Example 63> (±)-(1S,2R,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-ol;
<Example 64> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-methoxy-2-methyloctahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 65> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-ylcarbamate;
<Example 66> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-indene-2-carboxylic acid;
<Example 67> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-indene-2-carboxamide;
<Example 68> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-indene-2-carbonitrile;
<Example 69> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-methyl-2-(1H-tetrazol-5-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 70> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-methyl-2-(1-methyl-1H-tetrazol-5-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 71> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-methyl-2-(2-methyl-2H-tetrazol-5-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 72> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-indene-2-amine;
<Example 73> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-yl}acetamide;
<Example 74> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-yl}methanesulfonamide;
<Example 75> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-isopropoxyoctahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 76> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro(indene-2,5'-oxazolidin)-2'-one;
<Example 77> (±)-(1S,2R,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro(indene-2,5'-oxazolidin)-2'-one;
<Example 78> (±)-2-{(E)-2-[(1'S,3a'R,7a'R)-1',3',3a',4',7',7a'-hexahydrospiro[(1,3)dioxolane-2,2'-indene]-1H-inden-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 79> (±)-(1S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-3a,4,7,7a-tetrahydro-1H-inden-2(3H)one;
<Example 80> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,3,3a,4,7,7a-hexahydro-1H-inden-2-ol;
<Example 81> (±)-2-{(E)-2-[(3a'R,4a'R,5'S,7a'R,8a'S)-2',2'-dimethyloctahydrospiro[(1,3)dioxolane-2,6'-indeno(5,6-d)(1,3)dioxol]-5'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 82> (±)-(3S,3aR,7aS)-3-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-octahydro-1H-isoindol-1-one;
<Example 83> (±)-(3S,3aR,7aS)-3-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-isoindol-1-one;
<Example 84> (±)-(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(N-(t)-butyloxycarbonyl)octahydro-1H-isoindole;
<Example 85> (±)-(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-isoindole;
<Example 86> (±)-(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(N-acetyl)octahydro-1H-isoindole;
<Example 87> (±)-1-{(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(methylsulfonyl)octahydro-1H-isoindole;
<Example 88> (±)-methyl-2-{(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-1H-isoindole-2-(3H,3aH,4H,5H,6H,7H,7aH)-yl}acetate;
<Example 89> (±)-ethyl-2-{(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-1H-isoindole-2-(3H,3aH,4H,5H,6H,7H,7aH)-yl}acetate;
<Example 90> (±)-2-{(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-1H-isoindole-2-(3H,3aH,4H,5H,6H,7H,7aH)-yl}acetic acid;
<Example 91> (±)-1-{(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-1H-isoindole-2-(3H,3aH,4H,5H,6H,7H,7aH)-yl}-2,2-dimethylpropan-1-one;
<Example 92> (±)-t-butyl (1S,2S)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,3-dihydro-1H-inden-2-ylcarbamate;
<Example 93> (±)-(1S,2S)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,3-dihydro-1H-indene-2-amine;
<Example 94> (±)-(1S,2S)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,3-dihydro-1H-indene-2-(N-acetyl)amine;
<Example 95> (±)-(1S,2S)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,3-dihydro-1H-indene-2-(N-methylsulfonyl)amine;
<Example 96> (±)-(1S,2S)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,3-dihydro-1H-indene-2-(N-methyl-N-methylsulfonyl)amine;
<Example 97> (±)-2-{(E)-2-[(1'S,3a'S,5'S,7a'R)-5'-fluorooctahydrospiro[(1,3)dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 98> (±)-2-{(E)-2-[(1'S,3a'S,5'R,7a'R)-5'-fluorooctahydrospiro[(1,3)dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 99> (±)-2-{(E)-2-[(1S,2S,3aR,5R,7aR)-2-methoxy-5-(methoxymethoxy)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 100> (±)-2-{(E)-2-[(1S,2S,3aR,5R,7aR)-2-methoxy-5-hydroxyoctahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 101> (±)-(1S,2S,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5-ylcarbamate;
<Example 102> (±)-2-{(E)-2-[(1'S,2'S,3a'S,7a'R)-2'-methoxyoctahydrospiro[(1,3)dioxolane-2,5'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 103> (±)-2-{(E)-2-[(1'S,2'S,3a'R,7a'R)-2'-methoxyoctahydrospiro[(1,3)dioxolane-2,5'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 104> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5(6H)-one;
<Example 105> (±)-(1S,2S,3aR,7aR,E)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5(6H)-one oxime;
<Example 106> (±)-(1S,2S,3aR,7aR,Z)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5(6H)-one oxime;
<Example 107> (±)-t-butyl-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5-ylcarbamate;
<Example 108> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-indene-5-amine;
<Example 109> (±)-ethyl (1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5-ylcarbamate;
<Example 110> (±)-N-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5-yl}methanesulfonamide;
<Example 111> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-methoxy-5-(1H-pyrrol-1-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 112> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-methoxy-5-(pyrrolidin-2-one-1-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 113> (±)-t-butyl-(1S,2S,3aR,6S,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-6-ylcarbamate;
<Example 114> (±)-t-butyl-(1S,2S,3aR,6R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-6-ylcarbamate;
<Example 115> (±)-t-butyl (1S,2S,3aR,5S,6S,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dimethoxyoctahydro-1H-inden-6-ylcarbamate;
<Example 116> (±)-(1S,2S,3aR,5S,6S,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dimethoxyoctahydro-1H-indene-6-amine;
<Example 117> (±)-(1S,2S,3aR,5S,6S,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dimethoxy-N,N-dimethyloctahydro-1H-indene-6-amine;
<Example 118> (±)-t-butyl (1S,2S,3aR,5R,6S,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-fluoro-2-methoxyoctahydro-1H-inden-6-ylcarbamate;
<Example 119> (±)-2-{(E)-2-[(1'S,3a'R,7a'R)-1',3',3a',4',7',7a'-hexahydrospiro[(1,3)dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 120> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(1H-1,2,4-triazol-1-yl)-2,3,3a,4,7,7a-hexahydro-1H-inden]-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 121> (±)-2-{(E)-2-[(1S,2R,3aR,7aR)-2-(1H-1,2,4-triazol-1-yl)-2,3,3a,4,7,7a-hexahydro-1H-inden]-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 122> (±)-2-{(E)-2-[(1'S,3a'R,5'R,7a'R)-5'-methoxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 123> (±)-2-{(E)-2-[(1'S,3a'R,5'S,7a'R)-5'-methoxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 124> (±)-2-{(E)-2-[(1'S,3a'R,5'R,7a'R)-5'-hydroxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 125> (±)-4-(1'S,3a'R,5'S,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-yl}morpholine;
<Example 126> (±)-2-{(E)-2-[(1'S,3a'R,5'S,7a'R)-5'-(1H-1,2,4-triazol-1-yl)octahydrospiro[(1,3)dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 127> (±)-4-{2-{(1'S,3a'R,5'R,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-yloxy}ethyl}morpholine;
<Example 128> (±)-2-{(E)-2-[(1'S,3a'R,5'S,7a'R)-5'-hydroxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 129> (±)-(1'S,3a'R,5'S,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-indene]-5'-carbonitrile;
<Example 130> (±)-(1'S,3a'R,5'R,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-indene]-5'-amine;
<Example 131> (±)-2-{(E)-2-[(1'S,3a'R,5'R,7a'R)-5'-(1H-pyrrol-1-yl)octahydrospiro[(1,3)dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 132> (±)-ethyl (1'S,3a'R,5'R,7a'R)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate;
<Example 133> (±)-(1S,2S,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-ol;
<Example 134> (±)-(1S,2S,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-yl methanesulfonate;
<Example 135> (±)-(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-indene-2-amine;
<Example 136> (±)-N-{(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-yl}methanesulfonamide;
<Example 137> (±)-N-{(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-hydroxyoctahydro-1H-inden-2-yl}methanesulfonamide;
<Example 138> (±)-2-{(E)-2-[(1S,2R,3aS,5R,7aR)-5-(methoxymethoxy)-2-(1H-pyrrol-1-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 139> (±)-1-{(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-yl}pyrrolidin-2-one;
<Example 140> (±)-{(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-yl}pivalamide;
<Example 141> (±)-1-{(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-yl}sultam;
<Example 142> (±)-(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-ol;
<Example 143> (±)-(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-yl methanesulfonate;
<Example 144> (±)-(1S,2S,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-indene-2-amine;
<Example 145> (±)-N-{(1S,2S,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-yl}methanesulfonamide;
<Example 146> (±)-t-butyl (1'S,3a'S,7a'R){1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro[(1,3)dioxolane-2,2'-inden]-6'-ylcarbamate;
<Example 147> (±)-t-butyl (1'S,3a'S,7a'R){1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate;
<Example 148> (±)-t-butyl (1S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-oxooctahydro-1H-inden]-6-ylcarbamate;
<Example 149> (±)-t-butyl (1S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-oxooctahydro-1H-inden]-5-ylcarbamate;
<Example 150> (±)-t-butyl (1S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxy-2-methyloctahydro-1H-inden]-6-ylcarbamate;
<Example 151> (±)-t-butyl (1S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxy-2-methyloctahydro-1H-inden]-5-ylcarbamate;
<Example 152> (±)-t-butyl (1'S,3a'R,7a'R){1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate;
<Example 153> (±)-t-butyl (1S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-oxooctahydro-1H-inden]-5-ylcarbamate;
<Example 154> (±)-t-butyl (1S,2S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxyoctahydro-1H-inden]-5-ylcarbamate;
<Example 155> (±)-t-butyl (1S,2R,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxyoctahydro-1H-inden]-5-ylcarbamate;
<Example 156> (±)-(1S,2S,3aS,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-2-yl methanesulfonate;
<Example 157> (±)-(1S,2R,3aS,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-2-yl methanesulfonate;
<Example 158> (±)-t-butyl (1S,2R,3aR,7aR)-2-amino-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-5-ylcarbamate;
<Example 159> (±)-t-butyl (1S,2R,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(methanesulfonamido)octahydro-1H-inden-5-ylcarbamate;
<Example 160> (±)-t-butyl (1S,2R,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(1H-1,2,3-triazol-1-yl)octahydro-1H-inden-5-ylcarbamate;
<Example 161> (±)-t-butyl (1S,2R,3aR,7aR)-2-(N-cyclopropylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-5-ylcarbamate;
<Example 162> (±)-t-butyl (1S,2R,3aS,7aR)-2-(N-cyclopropyl-N-methylsulfonamido)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-5-ylcarbamate;
<Example 163> (±)-1-{(1S,2R,3aS,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-sultam;
<Example 164> (±)-t-butyl (1S,2S,3aR,7aR)-2-amino-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-5-ylcarbamate;
<Example 165> (±)-t-butyl 1-{(1S,2S,3aS,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-sultam;
<Example 166> (±)-t-butyl (1S,2S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(2-oxooxazolidin-3-yl)-octahydro-1H-inden-5-ylcarbamate;
<Example 167> (±)-(1S,2S,3aS,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl dimethylsulfamate;
<Example 168> (±)-(1S,2S,3aS,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-ylsulfamate;
<Example 169> (±)-t-butyl (1S,2S,3aS,7aR)-2-cyano-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxyoctahydro-1H-inden-5-ylcarbamate;
<Example 170> (±)-t-butyl (1S,2R,3aS,7aR)-2-cyano-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxyoctahydro-1H-inden-5-ylcarbamate;
<Example 171> (±)-5-{(E)-(4aR,5S,7aR)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-methyloctahydrocyclopenta[c]pyran-6-ol;
<Example 172> (±)-2-{(E)-2-[(4aS,5S,7aR)-6-(methoxymethoxy)octahydrocyclopenta[c]pyran-7-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 173> (±)-t-butyl (1S,2R,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxyoctahydro-1H-inden-5-ylcarbamate;
<Example 174> (±)-(1S,2R,3aR,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-2-yl methanesulfonate;
<Example 175> (±)-(1S,2R,3aR,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-2-yl carbamate;
<Example 176> (±)-t-butyl (1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(methanesulfonamido)octahydro-1H-inden-5-ylcarbamate;
<Example 177> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(methanesulfonamido)octahydro-1H-inden-5-yl}formamide;
<Example 178> (±)-t-butyl (1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(formamido)octahydro-1H-inden-5-ylcarbamate;
<Example 179> (±)-t-butyl (1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(2-oxazolidin-3-yl)octahydro-1H-inden-5-ylcarbamate;
<Example 180> (±)-1-{(1S,2S,3aR,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-sultam;
<Example 181> (±)-(1S,2R,3aS,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-ylsulfamate;
<Example 182> (±)-t-butyl (1S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(hydroxyimino)octahydro-1H-inden]-5-ylcarbamate;
<Example 183> (±)-2-{(E)-2-[(1'S,3a'R,5'R,7a'R)-5'-hydroxyoctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 184> (±)-2-{(E)-2-[(1'S,3a'S,7a'R)-5'-oxooctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 185> (±)-methyl (1'S,3a'S,7a'R){1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate;
<Example 186> (±)-ethyl (1'S,3a'S,7a'R){1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate;
<Example 187> (±)-2-{(E)-2-[(1'S,3a'R,7a'R)-5',5'-difluorooctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 188> (±)-2-{(E)-2-[(1'S,3a'R,5'S,7a'R)-5'-hydroxyoctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 189> (±)-2-{(E)-2-[(1'S,3a'R,5'S,7a'R)-5'-fluorooctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 190> (±)-2-{(E)-2-[(1'S,3a'R,5'R,7a'R)-5'-fluorooctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 191> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}hexahydro-1H-inden-2(3H)-one;
<Example 192> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-ol;
<Example 193> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-yl carbamate;
<Example 194> (±)-(1S,2S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-ol;
<Example 195> (±)-(1S,2S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl methanesulfonate;
<Example 196> (±)-(1S,5R,3aR,7aR)-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-hydroxyoctahydro-1H-inden-2-one;
<Example 197> (±)-(1S,2S,5R,3aR,7aR)-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dihydroxyoctahydro-1H-indene-2-carbonitrile;
<Example 198> (±)-(1S,2R,5R,3aR,7aR)-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dihydroxyoctahydro-1H-indene-2-carbonitrile;
<Example 199> (±)-(1S,2S,5R,3aR,7aR)-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dihydroxyoctahydro-1H-indene-2-carboxamide;
<Example 200> (±)-(4aR,5S,7aS)-t-butyl-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-(methoxymethoxy)hexahydro-1H-cyclopenta[c]pyridine-2(3H)-carboxylate;
<Example 201> (±)-(1S,3aS,7aR)-5-(t-butyloxycarbonylamino)-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-yl methanesulfonate;
<Example 202> (±)-2-{(E)-2-[(1'S,3a'S,7a'R)-5',5'-difluorooctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 203> (±)-2-{(E)-2-[(1'S,3a'S,7a'R)-6',6'-difluorooctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
<Example 204> (±)-t-butyl(1S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2'-oxooctahydrospiro[indene-2,5'-oxazolidin]-5-ylcarbamate;
<Example 205> (±)-t-butyl (1'S,3a'S,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dioxooctahydrospiro[imidazolidine-4,2'-inden]-5'-ylcarbamate;
<Example 206> (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one;
<Example 207> (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-3'-methyloctahydrospiro[indene-2,5'-oxazolidin]-2'-one;
<Example 208> (±)-(1'S,3'aS,7a'R)-5',5'-difluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[imidazolidine-4,2'-inden]-2,5-dione;
<Example 209> (±)-(1'S,3'aS,7a'R)-5',5'-difluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[imidazolidine-4,2'-inden]-2-one;
<Example 210> (±)-(1'S,3a'S,7a'R)-5',5'-difluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-1,3-dimethyloctahydrospiro[imidazolidine-4,2'-inden]-2-one;
<Example 211> (±)-(1S,3aR,7aR)-6,6-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden]-2-ol;
<Example 212> (±)-(1S,2R,3aR,7aR)-6,6-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden]-2-yl carbamate;
<Example 213> (±)-(1S,2S,3aR,7aR)-6,6-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden]-2-yl carbamate;
<Example 214> (±)-N-{(1S,3aR,7aR)-6,6-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden]-2-yl}acetamide;
<Example 215> (±)-(1S,2R,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydrospiro-1H-inden]-2-ylcarbamate;
<Example 216> (±)-(1S,2S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydrospiro-1H-inden]-2-ylcarbamate;
<Example 217> (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one;
<Example 218> (±)-(1S,3aR,7aR)-6,6-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one;
<Example 219> (±)-N-{(1S,2R,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden]-2-yl}acetamide;
<Example 220> (±)-N-{(1S,2S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden]-2-yl}acetamide;
<Example 221> (±)-3-{(1S,2R,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-2-yl}oxazolidin-2-one;
<Example 222> (±)-N-{(1S,2R,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-2-yl}methanesulfonamide;
<Example 223> (±)-N-{(1S,2R,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-2-yl}-N-methylmethanesulfonamide;
<Example 224> (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiroindene-2,5'-oxathiazolidin-2',2'-dione;
<Example 225> (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,2'-morpholine]-5'-one;
<Example 226> (±)-(1S,3aR,7aR)-2-cyano-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl methanesulfonate;
<Example 227> (±)-N-{(1S,3aR,7aR)-2-cyano-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methanesulfonamide;
<Example 228> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro-[indene-2,4'-oxazolidin]-2'-one;
<Example 229> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-3'-methyloctahydrospiro-[indene-2,4'-oxazolidin]-2'-one;
<Example 230> (±)-(1'S,3a'R,7a'R)-5',5'-difluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-3H-spiro[furan-2,2'-inden]-5(4H)-one;
<Example 231> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2',2'-dimethyl-3'-(methylsulfonyl)octahydrospiro[indene-2,4'-oxazolidine]
<Example 232> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-3'-(methylsulfonyl)octahydrospiro[indene-2,4'-oxazolidine];
<Example 233> (±)-{(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(hydroxymethyl)octahydro-1H-inden-2-yl}methanesulfonamide;
<Example 234> (±)-{(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(fluoromethyl)octahydro-1H-inden-2-yl}methanesulfonamide;
<Example 235> (±)-(1S,3aS,5S,6S,7aR)-6-fluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-hydroxyoctahydrospiro[indene-2,5'-oxazolidin]-2'-one;
<Example 236> (±)-(1S,3aS,5S,6S,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5,6-dihydroxyoctahydrospiro[indene-2,5'-oxazolidin]-2'-one;
<Example 237> (±)-(1aR,2aR,3S,5aS,6aS)-3-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indeno-[5,6-b]oxirane-4,5'-oxazolidin]-2'-one;
<Example 238> (±)-(1aS,2aR,3S,5aS,6aR)-3-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indeno-[5,6-b]oxirane-4,5'-oxazolidin]-2'-one;
<Example 239> (±)-(1S,3aR,5R,6R,7aR)-5,6-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one;
<Example 240> (±)-(1'S,3a'S,5'S,6'S,7a'R)-6'-fluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-ol;
<Example 241> (±)-2-{(E)-2-{(3'S,3a'R,5'S,6'S,7a'S)-5'-fluoro-6'-methoxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-3'-yl}vinyl}-5-(3-fluorophenyl)pyridine;
<Example 242> (±)-(1'S,2S,3a'S,7a'R)-5',5'-difluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-3H-spiro[furan-2,2'-inden]-5(4H)-one;
<Example 243> (±)-(1'S,2R,3a'S,7a'R)-5',5'-difluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-3H-spiro[furan-2,2'-inden]-5(4H)-one;
<Example 244> (±)-(1'S,3a'R,5'S,6'S,7a'R)-6'-fluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-ol;
<Example 245> (±)-2-{(E)-2-{(3'S,3a'R,5'S,6'S,7a'R)-5'-fluoro-6'-methoxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-3'-yl}vinyl}-5-(3-fluorophenyl)pyridine;
<Example 246> (±)-(1'S,3a'R,6'S,7a'R)-6'-fluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'(1'H)-one;
<Example 247> (±)-2-{(E)-2-{(1'S,3a'S,5'R,6'S,7a'R)-5',6'-difluorooctahydrospiro[(1,3)dioxolane-2,2'-inden]-1'-yl}vinyl}-5-(3-fluorophenyl)pyridine;
<Example 248> (-)-(1R,2S,3aS,7aS)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one.
<Example 249> (-)-(1R,2R,3aS,7aS)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one;
<Example 250> (±)-5-(3-fluorophenyl)-2-{(E)-2-[(3a'R,4a'R,5'S,7a'S,8a'S)- octahydrospiro[(1,3)dioxolane-2,6'-indeno(5,6-d)(1,3)dioxol]-5'-yl]vinyl}pyridine;
<Example 251> (±)-5-(3-fluorophenyl)-2-{(E)-2-[(3a'S,4a'R,5'S,7a'S,8a'R)- octahydrospiro[(1,3)dioxolane-2,6'-indeno(5,6-d)(1,3)dioxol]-5'-yl]vinyl}pyridine;
<Example 252> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,4'-oxazolidin]-2'-thione;
<Example 253> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,4'-oxazolidin]-2'-imine;
<Example 254> (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(2-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one;
<Example 255> (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(2-methoxyphenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one;
<Example 256> (±)-(1S,3aR,7aR)-5,5-difluoro-1-[(E)-2-(5-hydroxypyridin-2-yl)vinyl]octahydrospiro[indene-2,5'-oxazolidin]-2'-one;
<Example 257> (±)-(1S,3aR,7aR)-1-{(E)-2-[5-(benzyloxy)pyridin-2-yl]vinyl} -5,5-difluorooctahydrospiro[indene-2,5'-oxazolidin]-2'-one;
<Example 258> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(2-morpholinoethoxy)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one;
<Example 259> (+)-(1S,2R,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one;
<Example 260> (+)-ethyl {(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxyoctahydrospiro-1H-inden-2-yl}methylcarbamate;
<Example 261> (+)-ethyl {(1S,3aR,7aR)-2,5,5-trifluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro-1H-inden-2-yl}methylcarbamate;
<Example 262> (±)-(4aR,5S,7aR)-t-butyl-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-hydroxy-6-methylhexahydro-1H-cyclopenta[c]pyridine-2(3H)-carboxylate;
<Example 263> (±)-(4aR,5S,7aR)-t-butyl 6-(carbamoyloxy)-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-methylhexahydro-1H-cyclopenta[c]pyridine-2(3H)-carboxylate;
<Example 264> (±)-(4aR,5S,7aR)-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-methyloctahydro-1H-cyclopenta[c]pyridin-6-yl carbamate;
<Example 265> (±)-(4aR,5S,7aR)-2-carbamoyl-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-methyloctahydro-1H-cyclopenta[c]pyridin-6-yl carbamate;
<Example 266> (±)-(4aR,5S,7aR)-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-formyl-6-methyloctahydro-1H-cyclopenta[c]pyridin-6-yl carbamate;
<Example 267> (±)-(4aR,5S,7aR)-t-butyl 5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5'-oxooctahydro-3'H-spiro(cyclopenta[c]pyridine-6,2'-furan)-2(1H)-carboxylate;
<Example 268> (±)-(4aR,5S,7aR)-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-methyloctahydrocyclopenta[c]pyran-6-yl carbamate;
<Example 269> (±)-t-butyl (1'S,3a'S,7a'R)-1'-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-oxodecahydro-3H-spiro(furan-2,2'-inden)-5'-yl carbamate; and
<Example 270> (±)-(1'S,3a'S,7a'R)-5'-amino-1'-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-3H-spiro(furan-2,2'-inden)-5(4H)-one.
The compounds of formula (1) of the present invention may be used in the form of a pharmaceutically acceptable salt. As the salts, acid addition salts formed by pharmaceutically acceptable free acids are useful. As the free acids, organic acids or inorganic acids may be used. The inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, phosphoric acid, etc., and the organic acids include citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, etc.
The addition salts according to the present invention may be prepared by a conventional method, for example, by dissolving the compounds of formula (1) in an excess aqueous acid solution and precipitating the resulting salts with water-miscible organic solvents such as methanol, ethanol, acetone or acetonitrile. The salts may also be prepared by heating the same amounts of the compound of formula (1) and acid in water or alcohol (e.g., glycol monomethylether) and then drying the mixture by evaporation, or suction-filtering the precipitated salts.
The compounds of the present invention may also be pharmaceutically acceptable metal salts formed by a base. The alkali metal salts or alkaline earth metal salts of the compounds of formula (1) may be prepared, for example, by dissolving the compounds of formula (1) in a solution of excess alkali metal hydroxide or alkaline earth metal hydroxide, filtering off the insoluble materials, evaporating the filtrate and drying. Sodium salt, potassium salt or calcium salt is pharmaceutically suitable. The corresponding silver salts may be obtained by reacting the alkali metal salts or alkaline earth metal salts with suitable silver salts (e.g., silver nitrate).
Each optical isomer of the compounds of formula (1) may be prepared by using the corresponding isomer as a starting material. Alternatively, the mixture of optical isomers may be used as a starting material to prepare the compound of formula (1) as a mixture of optical isomers, and the mixture may be subsequently separated into respective pure optical isomers. The separation of optical isomers may be carried out via the conventional column chromatography or recrystallization.
The present invention provides a process for preparing the [6+5] fused bicycle compounds of formula (1).
Specifically, the compounds of formula (1) can be prepared by reacting the compounds of formula (2) with the compounds of formula (3), or by reacting the compounds of formula (4) with the compounds of formula (5).
Figure PCTKR2011004607-appb-I000008
Figure PCTKR2011004607-appb-I000009
Figure PCTKR2011004607-appb-I000010
Figure PCTKR2011004607-appb-I000011
in which
A, E, G, Het, R1 to R8 are as defined above, and
X represents halogen.
An exemplified reaction, where Het is 3-(5-fluorophenyl)pyridine and X is bromo, is depicted in the following Reaction Scheme 1 along with the detailed reaction conditions.
Reaction Scheme 1
Figure PCTKR2011004607-appb-I000012
in which A, E, G, R1 to R8 are as defined above.
In the Reaction Scheme 1, the [6+5] fused bicycle compound (1) substituted by pyridine-vinyl can be prepared by Horner-Wadsworth-Emmons reaction of pyridin-2-yl methyl phosphonate with [6+5] fused bicycle (2) having an aldehyde group. For the Horner-Wadsworth-Emmons reaction, n-BuLi, lithium diisopropylamide, potassium t-butoxide, KHMDS, LiHMDS, etc. can be used as a base, and THF, diethylether, etc. are used as a solvent.
Also, the Stille reaction of [6+5] fused bicycle (4) having vinyl tin substituent with halo (preferably bromo or iodo) pyridine of formula (5) can give the compounds of formula (1b).
Hereinafter, the various and specific processes for preparing the compounds of formula (1) of the present invention using specific compounds are explained.
First, the process for preparing the compounds of formula (1) having an alcohol derivative substituent on the pentacycle is explained by the following Reaction Scheme 2.
Reaction Scheme 2
Figure PCTKR2011004607-appb-I000013
in which E, G, Ra, Rb and Het are as defined above.
The alcohol compounds (1c) can be prepared by treating the ketal compounds (1a) with an acid to give the ketone compounds (1b) and the subsequent reduction using NaBH4, etc., or by removing the protecting group from the alcohol compounds having t-butyldimethylsilyl or other suitable protecting group. Starting from the alcohol compounds of formula (1c), various alcohol derivatives exemplified in the examples are prepared using various reactions. Furthermore, derivatization of alcohols may be proceeded prior to the Horner-Wadsworth-Emmons reaction or the Stille reaction of Reaction Scheme 1.
The amine derived compounds of formula (1) are prepared as explained in the following Reaction Scheme 3.
Reaction Scheme 3
Figure PCTKR2011004607-appb-I000014
in which
E, G, Ra, Rb and Het are as defined above unless otherwise stated,
n denotes an integer of 1 or 2,
P represents a hydroxy protecting group.
The compounds of formula (1e) having a primary or secondary amine substituent on the pentacycle are prepared by reacting the ketone compounds (1b) with primary or secondary amines to give imines followed by a reductive amination reaction using a reducing agent such as NaCNBH3, NaBH(OAc)3, etc. Also, the compounds having a primary, secondary or tertiary amine substituent may be prepared starting from the alcohol compounds (Ic) via mesylates using a suitable base. Furthermore, the present specification provides a process for preparing the amine compounds (Ie) by treating the carboxylic acid-substituted compounds (Id) with a base such as diphenylphosphoryl azide, triethylamine, etc. to perform Curtius reaction and subsequent hydrolysis. Sulfonamides may be prepared from primary or secondary amine compounds, and the various cyclic compounds disclosed in the examples may be prepared using primary amines.
Processes for preparing the compounds of formula (1), wherein a spiro-ring is combined to the pentacycle or a tertiary alcohol and a tertiary amine groups are introduced into the pentacycle, are explained via the following Reaction Scheme 4.
Reaction Scheme 4
Figure PCTKR2011004607-appb-I000015
in which
E, G, Ra, Rb, Het and cycle B are as defined above.
The ketone compounds (Ib) are alkylated by alkyl lithium or alkyl magnesium bromide to give tertiary alcohol derivatives. Also, compounds such as cyanohydrin, aminonitrile, aminocarboxylate, aminoalcohol, etc. are prepared from ketone compounds, from which the various compounds including spirocycle compounds disclosed in the examples can be prepared. There is also a process for directly preparing the spirocycle compounds from the ketone-substituted compound (Ib).
Processes for preparing the compounds wherein the pentacycle is substituted by a heterocycle and the quarternary carbon compounds are explained via the following Reaction Scheme 5.
Reaction Scheme 5
Figure PCTKR2011004607-appb-I000016
in which
E, G, Ra, Het and the cycle B are as defined above.
The compounds having a heterocycle on the pentacycle may be prepared from the ester compounds (Ie) through a cyclization reaction. Also, the hydrogen ion of α-carbon of ester substituent may be removed by a base such as lithium diisopropylamide, NaH, LHMDS, etc. and then alkylated to give a quaternary carbon compound. Furthermore, quaternary carbon compounds having heterocyclic substituents are prepared through cyclization reactions staring from quaternary esters via amides and nitriles.
Processes for preparing compounds having substituents on the hexacycle are explained via the following Reaction Scheme 6.
Reaction Scheme 6
Figure PCTKR2011004607-appb-I000017
in which
A, R1, R2, R3 and R4 are as defined above, and
P represents a hydroxy-protecting group.
From the compounds having a double bond on the hexacycle, the compounds of formula (1) having various substituents on the hexacycle may be prepared.
As depicted in Reaction Schemes 2 to 5, aryl vinyl compounds are first prepared and the substituents on the pentacycle or hexacycle may be introduced. Otherwise, the substituents on the pentacycle or hexacycle are first introduced and the aryl vinyl compounds may be prepared according to the process of Reaction Scheme 1.
Processes for preparing the compounds having heteroatoms on the hexacycle may be explained via the following Reaction Scheme 7.
Reaction Scheme 7
Figure PCTKR2011004607-appb-I000018
in which
E and G are as defined above, and
P represents a hydroxy-protecting group.
The [6+5] fused bicycles containing heteroatoms may be prepared by Pauson -Khand reaction. After the preparation of bicycles, a substituent may be introduced to the pentacycle according to the processes of Reaction Schemes 2 to 5.
In the present invention, the compounds of formula (1) as prepared above are identified to confirm their molecular structures through infrared spectrometry, NMR, MS, liquid chromatography, X-ray crystallography, polarimetry, and comparisons between calculated and found elemental analysis of representative compounds.
The present invention further provides a pharmaceutical composition as an antagonist against PAR-1, which comprises the [6+5] fused bicycle derivatives of formula (1), pharmaceutically acceptable salts or isomers thereof as an active ingredient together with pharmaceutically acceptable carriers.
The composition of the present invention is particularly useful for the treatment and prevention of, but not limited to, thrombus, platelet aggregation, atherosclerosis, restenosis, blood coagulation, hypertension, arrhythmia, angina pectoris, heart failure, inflammation and cancer. Also, the composition may be used in the combined treatment with other cardiovascular agents.
The present invention still further provides a method for the treatment and/or prevention of thrombus, platelet aggregation, atherosclerosis, restenosis, blood coagulation, hypertension, arrhythmia, angina pectoris, heart failure, inflammation and cancer, characterized by using the [6+5] fused bicycle derivatives of formula (1), pharmaceutically acceptable salts or isomers thereof as an active ingredient.
The present invention still further provides a process for preparing the composition as an antagonist against PAR-1, characterized by mixing the [6+5] fused bicycle derivatives of formula (1), pharmaceutically acceptable salts or isomers thereof with pharmaceutically acceptable carriers.
As used herein, “pharmaceutical composition” means compositions comprising the active compounds of the present invention and other chemical components such as carriers, diluents, excipients, etc. Thus, pharmaceutically acceptable carriers, diluents, excipients or their combinations can be contained in said pharmaceutical composition, if necessary. A pharmaceutical composition facilitates the administration of the compound into a living organism. There are a number of techniques to administer the compound, and they include but are not limited to oral, injectable, aerosol, parenteral and topical administration.
As used herein, “carrier” means a substance that facilitates the incorporation of the compound into cells or tissues. For example, dimethylsulfoxide (DMSO) is a typical carrier that facilitates the introduction of various organic compounds into cells or tissues of living organisms.
As used herein, “diluent” is defined as a substance that is diluted in water, which dissolves the subject compound as well as stabilizes the biologically active form of the compound. The salts dissolved in a buffer solution are utilized as diluents in the art. A typically used buffer solution is phosphate-buffered saline which mimics the salt form of human solution. Buffer diluents rarely alter the biological activities of the compound, as the buffer salts can control the pH of solution at a low concentration.
As used herein, “pharmaceutically acceptable” is defined as a characteristic not to damage the biological activities and physical properties of the compound.
The compound of the present invention may be formulated into various forms of pharmaceutical administration depending on the purpose intended. In preparing the pharmaceutical compositions according to the present invention, the active component is mixed with various pharmaceutically acceptable carriers that can be selected according to the desired formulation. For example, the pharmaceutical compositions of the present invention can be formulated as an injectable preparation, oral preparation, etc., depending on the purpose intended.
The active compound of the present invention may be formulated by conventional methods of using pharmaceutically acceptable carriers and excipients known in the art and then charged in a unit dosage form or a multi-dose container.
The injection preparation may take such forms as solutions, suspensions or emulsions in oily or aqueous media, and may contain typical dispersing agents, suspending agents or stabilizing agents. For example, vegetable oils such as propylene glycol, polyethylene glycol or olive oil, injectable esters such as ethyl oleate, etc. may be used as the non-aqueous solvents or suspending media. Furthermore, the active ingredient can be used as a form of dry powder which is intended to be reconstructed by dissolving in sterilized pyrogen-free water prior to use.
The compound of the present invention may also be formulated as a suppository utilizing typical suppository bases such as witepsol, macrogol, tween 61, cacao oil, lauric oil, glycerol, cocoa butter or gelatin.
The solid preparations for oral administration may include capsules, tablets, pills, powders and granules, among which capsules and tablets are particularly advantageous. Preferably, tablets and pills are prepared as enteric coated forms. The solid preparations may be obtained by mixing the compound of the present invention with one or more inert diluents such as sucrose, lactose, starch, etc. and carriers such as lubricating agents (magnesium stearate, talc, etc.), disintegrating agents, binding agents, extenders, wetting agents, etc. As the liquid preparations for oral administration, suspensions, oral solutions, emulsions, syrups, etc. are selected, and various excipients, for example, wetting agents, sweeteners, flavouring agents, preservatives, etc. as well as the frequently used simple diluents such as water and liquid paraffin may be included therein.
If necessary, the compounds of the present invention or pharmaceutical compositions comprising the same may be administered in combination with other medicines, for example, other medicines for treating cardiovascular diseases.
The pharmaceutical compositions according to the present invention contain the active ingredient in an amount effective to achieve its intended purpose. More specifically, the therapeutically effective amount means the amount of the active compound effective to prolong the survival of the subject to be treated, or to prevent, alleviate or ameliorate the symptoms of the disease. A skilled artisan would be able to determine the therapeutically effective amount, particularly in light of the detailed description provided herein.
When the compound is formulated to a unit dosage form, the active compounds of the present invention are preferably contained in an amount of about 0.1 to 100 mg per unit dosage. The dosage of the compounds depends on the prescription of a physician, taking into account such factors as body weight or age of a patient, specific nature of the disease, severity of the disease, etc. However, dosage needed for the treatment of an adult is typically from about 0.1 to 100 mg per day, depending on the intensity and frequency of the administration. But for some patients a higher daily dosage may be desirable.
The present invention also provides a method for treating or preventing cardiovascular diseases using an effective amount of the compounds of the present invention. As used herein, “treatment” means the interruption, delay or amelioration of the progress of the disease when applied to a subject showing the onset of disease symptoms, and “prevention” means the interruption, delay or amelioration of the sign of the onset of disease when applied to a subject who does not show, but is at risk of, the onset of disease symptoms.
Hereinafter, the present invention will be more specifically explained with reference to the preparations and examples below. However, it should be understood that they are intended to illustrate the present invention but not in any manner to limit the scope of the present invention.
In the following preparations and examples, the symbol (±) is used to represent the relative stereochemistry. For example, the title of Preparation 1 “(±)-(1'R,3a'R,7a'R)-octahydrospiro [[1,3]dioxolane-2,2'-indene]-1'-carbaldehyde” substantially means that the final compound is obtained as a racemic mixture of (+)-(1'S,3a'S,7a'S)-octahydrospiro[[1,3]dioxolane-2,2'-indene]-1'-carbaldehyde and (-)-(1'R,3a'R,7a'R)-octahydrospiro[[1,3]dioxolane-2,2'-indene]-1'-carbaldehyde. The present specification indicates such situation in the manner of introducing a symbol (±) in front of the nomenclature. In the following Preparations and Examples, compounds having a symbol (±) in their nomenclatures are racemic mixtures in the same manner.
<Preparation 1> (±)-(1'R,3a'R,7a'R)-octahydrospiro[[1,3]dioxolane-2,2'-indene]-1'-carbaldehyde
Figure PCTKR2011004607-appb-I000019
(Step 1) (±)-(1R, 2S)-cyclohexan-1,2-diyl-dimethanol
LiAlH4 (5.7 g, 0.129 mol) was dissolved in anhydrous THF (60 mL) under nitrogen gas. cis-1,2-Cyclohexanedicarboxyl anhydride (5 g, 0.129 mol) dissolved in anhydrous THF (20 mL) was slowly added thereto while maintaining 0 ℃. After stirring under reflux for 2 h, the solution was cooled to 0 ℃. 2 N NaOH was added and the resulted solution was stirred for 1 h. The resulted solid was removed by filtration through celite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ether) to give the the title compound (18.5 g, 0.128 mol).
1H NMR (CDCl3, 300 MHz) δ1.38~1.56 (m, 8H), 1.94 (s, 2H), 3.35 (s, 2H), 3.55~3.60 (m, 2H), 3.73~3.79 (m, 2H)
(Step 2) (±)-(1R,2S)-cyclohexane-1,2-dimethanol bis(methanesulfonate)
The compound of Step 1 (18 g, 0.125 mol) was dissolved in anhydrous CH2Cl2 (100 mL). NEt3 (52 mL, 0.374 mol) and CH3SO2Cl (23 mL, 0.299 mol) were slowly added thereto while maintaining 0℃. After stirring for 2 h at room temperature, the reaction mixture was extracted with CH2Cl2 and washed twice with saturated aqueous NaCl solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (CH2Cl2:MeOH=20:1) to give the the title compound (9.5 g, 0.032 mol).
1H NMR (CDCl3, 300 MHz) δ 1.46~1.57 (m, 8H), 2.24 (d, J = 4.5 Hz, 2H), 3.03 (s, 6H), 4.16~4.29 (m, 4H).
(Step 3) (±)-2,2'-((1R,2S)-cyclohexan-1,2-diyl)diacetonitrile
The compound of Step 2 (14 g, 0.046 mol) was dissolved in DMSO (60 mL), KCN (11.5 g, 0.177 mol) was added, and the mixture was stirred for 12 h at 95 ℃. The mixture was extracted with CH2Cl2 and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethylacetate=3:1) to give the the title compound (7.3 g, 0.045 mol).
1H NMR (DMSO-d 6 , 300 MHz) δ1.20~1.46 (m, 5H), 1.98~2.31 (m, 2H), 2.48~2.50 (m, 2H), 3.37 (s, 2H).
(Step 4) (±)-(1R,3aR,7aR)-2-oxooctahydro-1H-indene-1-carbonitrile
At 0 ℃, to anhydrous THF (100 mL) were added sodium hydride (7.2 g, 0.180 mol) and N-methylaniline (19.5 mL, 0.180 mol). After stirring under reflux for 1 h, the compound of Step 3 (7.3 g, 0.045 mol) dissolved in anhydrous THF (50 mL) was added in portions, and the mixture was stirred under reflux for 3 h and then cooled to 0℃. The reaction mixture was extracted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and dissolved in boiling ethanol (100 mL). 6 N HCl (10 mL) was added and the mixture was stirred for 1 h. The solvent was distilled under reduced pressure. The residue was extracted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethylacetate=5:1) to give the the title compound (6.8 g, 0.041 mmol).
1H NMR (CDCl3, 200 MHz) δ1.01~1.14 (m, 1H), 1.23~1.39 (m, 2H), 1.57~1.97 (m, 5H), 2.25~2.50 (m, 2H), 2.56~2.72 (m, 2H), 3.22~3.41 (m, 1H).
(Step 5) (±)-(1'R,3a'R,7a'R)-octahydrospiro[[1,3]dioxolane-2,2'-indene]-1'-carbonitrile
The compound of Step 4 (3.0 g, 0.018 mol), ethylene glycol (12.5 mL, 0.046 mol) and para-toluenesulfonic acid (0.69 g, 0.003 mol) were dissolved in toluene (50 mL), and the mixture was stirred under reflux for 4 h using Dean-Stark apparatus. The reaction mixture was extracted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethylacetate=5:1) to give the the title compound (3.0 g, 0.014 mol).
1H NMR (CDCl3, 300 MHz) δ1.18~1.34 (m, 3H), 1.49~1.66 (m, 4H), 1.76~1.84 (m, 2H), 2.04~2.19 (m, 2H), 2.41~2.46 (m, 1H), 2.97~3.05 (m, 1H), 3.89~4.07 (m, 4H).
(Step 6) (±)-(1'R,3a'R,7a'R)-cis-octahydrospiro[[1,3]dioxolane-2,2'-indene]-1'-carbaldehyde
The compound of Step 5 (3 g, 0.014 mol) was dissolved in toluene, and iBu2AlH4(1.5 M toluene solution) (11.5 mL, 0.017 mol) was slowly added thereto at -78 ℃. The mixture was stirred for 2 h at room temperature. H2O (5 mL) was slowly added at 0 ℃, and the resulted solid was removed by filtration through celite. The filtrate was extracted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purifed by silica gel column chromatography (hexane:ethylacetate=5:1) to give the the title compound (4.2 g, 0.019 mmol).
1H NMR (CDCl3, 300 MHz) δ1.21~1.60 (m, 8H), 1.80 (m, 1H), 2.00~2.16 (m, 2H), 2.49~2.54 (m, 1H), 2.76~2.80 (m, 1H), 3.73~3.98 (m, 4H), 9.58 (d, J = 1.2 Hz, 1H).
<Preparation 2> (±)-(1'R,3a'S,7a'R)-octahydrospiro[[1,3]dioxolane-2,2'-indene]-1'-carbaldehyde
Figure PCTKR2011004607-appb-I000020
(Step 1) (±)-(1S, 2S)-cyclohexane-1,2-diyl-dimethanol
trans-1,2-Cyclohexane carboxyl anhydride (5 g, 0.032 mol) was reacted according to the same procedure as Step 1 of Preparation 1 to give the the title compound (4.8 g, 0.033 mol).
1H NMR (CDCl3, 300 MHz) δ0.96~1.16 (m, 2H), 1.19~1.43 (m, 4H), 1.59~1.75 (m, 4H), 3.47~3.61 (m, 4H), 4.19 (s, 1H).
(Step 2) (±)-(1S,2S)-cyclohexane-1,2-dimethanol bis(methanesulfonate)
The compound of Step 1 (4.9 g, 0.034 mol) was reacted according to the same procedure as Step 2 of Preparation 1 to give the the title compound (9.5 g, 0.032 mol).
1H NMR (CDCl3, 300 MHz) δ 1.26~1.29 (m, 4H), 1.71~1.82 (m, 6H), 3.02 (s, 6H), 4.19~4.32 (m, 4H).
(Step 3) (±)-2,2'-((1S,2S)-cyclohexane-1,2-diyl)diacetonitrile
The compound of Step 2 (9.5 g, 0.032 mol) was reacted according to the same procedure as Step 3 of Preparation 1 to give the the title compound (5.0 g, 0.030 mol).
1H NMR (CDCl3, 300 MHz) δ1.20~1.42 (m, 4H), 1.64~1.90 (m, 6H), 2.44~2.51 (m, 4H).
(Step 4) (±)-(1S,3aS,7aR)-2-oxooctahydro-1H-indene-1-carbonitrile
The compound of Step 3 (5.0 g, 0.030 mol) was reacted according to the same procedure as Step 4 of Preparation 1 to give the the title compound (4.3 g, 0.026 mol).
1H NMR (CDCl3, 300 MHz) δ0.19~2.07 (m, 10H), 2.17~2.22 (m, 1H), 2.50~2.58 (m, 1H), 2.90 (d, J = 12.9 Hz, 1H).
(Step 5) (±)-(1'S,3a'S,7a'R)-octahydrospiro[[1,3]dioxolane-2,2'-indene]-1'-carbonitrile
The compound of Step 4 (4.3 g, 0.026 mol) was reacted according to the same procedure as Step 5 of Preparation 1 to give the the title compound (5.0 g, 0.024 mol).
1H NMR (CDCl3, 300 MHz) δ1.03~1.28 (m, 2H), 1.30~1.39 (m, 3H), 1.56~1.77 (m, 2H), 1.79~1.88 (m, 3H), 2.04~2.13 (m, 2H), 2.52 (d, J = 1.2Hz, 1H), 3.89~3.93 (m, 1H), 4.01~4.14 (m, 3H).
(Step 6) (±)-(1'S,3a'S,7a'R)-octahydrospiro[[1,3]dioxolane-2,2'-indene]-1'-carbaldehyde
The compound of Step 5 (5.0 g, 0.024 mol) was reacted according to the same procedure as Step 6 of Preparation 1 to give the the title compound (5.0 g, 0.024 mol).
1H NMR (CDCl3, 300 MHz) δ1.09~1.48 (m, 5H), 1.55~1.64 (m, 1H), 1.71~1.91 (m, 4H), 1.98~2.05 (m, 1H), 2.45 ~2.50 (m, 1H), 4.10~3.70 (m, 4H), 9.62(d, J = 1.2 Hz, 1H).
<Preparation 3> (±)-(1'R,3a'S,7a'R)-1',3',3a',4',7',7a'-hexahydrospiro[[1,3]dioxolane-2,2'-indene]-1'-carbaldehyde
Figure PCTKR2011004607-appb-I000021
(Step 1) (±)-(1R,2R)-diethyl cyclohex-4-ene-1,2-dicarboxylate
Diethyl fumarate (53 g, 0.31 mol) was dissolved in anhydrous benzene (200 mL), and 1,3-butadiene (29 g) was added thereto, maintaining at 0 ℃. The reaction was carried out for 24 h in a pressurized vessel, maintaining at 50 ℃, and a residue was obtained by removing the solvent. The residue was distilled under vacuo (80-83 ℃ /0.5 mmHg) to give the the title compound (28 g, Yield 40%) as a white liquid.
1H NMR (CDCl3): δ 1.34 (t, 6H), 2.19 (m, 2H), 2.22 (m, 2H), 2.84 (m, 2H), 4.10 (q, 4H), 5.69 (d, 2H).
(Step 2) (±)-(1R,2R)-cyclohex-4-en-1,2-diyldimethanol
To dried THF (200 mL) was slowly added LiAlH4 (6 g, 0.16 mol), and the solution of Step 1 compound (28.6 g, 0.127 mol) in anhydrous THF (200 mL) was slowly added, maintaining at 0 ℃. The reaction solution was stirred under reflux for 12 h and then cooled to room temperature. Rochelle saturated solution (30 mL) was added, and refluxed for 4 h. The reaction solution was cooled to room temperature and filtered. The filtrate was distilled under reduced pressure, and the residue was distilled under reduced pressure (105-107 ℃/0.25 mmHg) to give the the title compound (15 g, 84%).
1H NMR (CDCl3): δ 1.9-1.21 (m, 6H), 3.54-3.58 (m, 2H), 3.6-3.7 (m, 2H), 4.0 (s, 2H), 5.63 (s, 2H).
(Step 3) (±)-(1R,2R)-cyclohex-4-ene-1,2-dimethanol bis(methanesulfonate)
The compound of Step 2 (25 g, 0.17 mol) was reacted according to the same procedure as Step 2 of Preparation 1 to give the the title compound (43 g, 85%).
1H NMR (CDCl3): δ 1.94-1.243 (m, 6H), 3.04 (s, 6H), 4.14-4.31 (m, 4H), 5.67 (s, 2H).
(Step 4) (±)-2,2'-((1S,2S)-cyclohex-4-en-1,2-diyl)diacetonitrile
The compound of Step 3 (65 g, 0.21 mol) was reacted according to the same procedure as Step 3 of Preparation 1 to give the the title compound (43 g, 95%).
1H NMR (CDCl3): δ 2.04-2.06 (m, 4H), 2.11-2.16 (m, 2H), 2.31-2.49 (m, 4H), 5.67 (s, 2H).
(Step 5) (±)-2,2-[(1R,2R)-cyclohex-4-en-1,2-diyl]-diacetic acid
To the compound of Step 4 (32 g, 0.02 mol) was added 6 N aqueous KOH solution (170 mL), the mixture was refluxed for 24 h and cooled to 0 ℃. conc. Hydrochloric acid was slowly added thereto. The resulting white solid was precipitated and filtered. This solid was dissolved in ethyl acetate (1 L) and filtered. The filtrate was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give the the title compound as a white solid (25 g, 65%).
mp 145-157℃
(Step 6) Dimethyl-(±)-[(1S,2S)-cyclohex-4-en-1,2-diyl]diacetate
In methanol (250 mL) was dissolved the compound of Step 5 (40 g, 0.2 mol). To the solution was added H2SO4 (15 mL), which was then stirred for 12 h while maintaining at 50 ℃. The reaction solution was concentrated under reduced pressure. The residue was slowly added to saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the the title compound (42 g, 92%) as a solid.
1H NMR (CDCl3): δ 1.78-1.85 (m, 2H), 2.16-2.31 (m, 8H), 3.7 (s, 6H), 5.60 (s, 2H).
(Step 7) (±)-(1S,3aS,7aR)-methyl-2-oxo-2,3,3a,4,7,7a-hexahydro-1H-indene-1-carboxylate
In anhydrous THF (100 mL) was dissolved the compound of Step 6 (10 g, 0.044 mol). NaH (3.6 g, 60%, 2 equiv) was slowly added thereto, and the mixture was refluxed for 6 h. The reaction solution was added to a small amount of 1N-HCl aqueous solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the the title compound (6.5 g, 76%) as a solid.
1H NMR (CDCl3): δ 1.56-1.09 (m, 4H), 2.32-2.43 (m, 3H), 2.56-2.64 (m, 1H), 2.98-2.93 (m, 1H), 3.76 (s, 3H), 5.75 (s, 2H).
(Step 8) (±)-(1'S,3a'S,7a'R)-methyl-2,3,3a,4,7,7a-hexahydrospiro-[(1,3)dioxolane-2,2'-indene]-1'-carboxylate
The compound of Step 7 (5.00 g, 25.7 mmol) was reacted according to the same procedure as Step 5 of Preparation 1 to give the the title compound (5.38 g, 88%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.56-1.92 (m, 4H), 2.08-2.16 (m, 2H), 2.23-2.33 (m, 2H), 2.67 (d, J = 11.4 Hz, 1H), 3.72 (s, 3H), 3.78-3.90 (m, 4H), 5.63 (m, 2H).
(Step 9) (±)-{(1'S,3a'S,7a'R)-2,3,3a,4,7,7a-hexahydrospiro-[(1,3)dioxolane-2,2'-inden]-1’-yl}-methanol
While the solution of LiAlH4 (1.29 g, 33.9 mmol) in THF (30 mL) was stirred at -30 ℃, the compound of Step 8 (5.38 g, 22.6 mmol) in THF (20 mL) was added thereto over 20 min using a syringe. After stirring for 1 h, the reaction was stopped by distilled water (5 mL) at 0 ℃. 2 N aqueous NaOH solution (50 mL) was added, and the mixture was stirred for 30 min. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 50 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1 - 2:1) to give the the title compound (4.09 g, 86%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.37 (dd, J= 12.8, 11.7 Hz, 1H), 1.57-1.86 (m, 5H), 2.09 (dd, J = 12.8, 6.02 Hz, 1H), 2.27 (m, 2H), 2.56 (m, 1H), 3.63 (m, 1H), 3.79-4.05 (m, 5H), 5.68 (s, 2H).
(Step 10) (±)-(1'R,3a'S,7a'R)-1',3',3a',4',7',7a'-hexahydrospiro[[1,3]dioxolane-2,2'-indene]-1'-carbaldehyde
To the solution of Step 9 compound (30.0 mg, 0.142 mmol) and NaHCO3 (20 mg) in CH2Cl2 (2 mL) was added Dess-Martin periodinane (121 mg, 0.286 mmol) while stirring at room temperature. The white turbid reaction solution was stirred for 2 h at room temperature, to which was added saturated NaHCO3 (1 mL) to stop the reaction. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The organic layers were combined and washed with brine (5 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was filtered through a silica gel pad using Et2O (20 mL). The filtrate was concentrated under reduced pressure to give the pale yellow title compound (13 mg), which was then used in the next reaction without further purification.
<Preparation 4> (±)-(1'R,3a'R,7a'R)-1',3',3a',4',7',7a'-hexahydrospiro[[1,3]dioxolane-2,2'-indene]-1'-carbaldehyde
Figure PCTKR2011004607-appb-I000022
(Step 1) (±)-(1R,2S)-cyclohex-4-en-1,2-diyldimethanol
cis-1,2,3,6-Tetrahydrophthalic anhydride was reacted according to the same procedure as Step 1 of Preparation 1 to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 2.00~2.15 (m, 6H), 3.54~3.58 (m, 2H), 3.67~3.72 (m, 2H), 4.06 (s, 2H), 5.61 (s, 2H).
(Step 2) (±)-{(1'S,3a'R,7a'R)-2,3,3a,4,7,7a-hexahydrospiro-[(1,3)dioxolane-2,2'-inden]-1’-yl}-methanol
The compound of Step 1 was reacted according to the same procedures as Steps 3 to 9―7 steps―of Preparation 3 to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 1.61~1.71 (m, 2H), 1.84~2.32 (m, 9H), 2.58~2.62 (m, 1H), 3.59~3.68 (m, 1H), 3.80~4.01 (m, 5H), 5.68(s, 2H).
(Step 3) (±)-(1'R,3a'R,7a'R)-1',3',3a',4',7',7a'-hexahydrospiro[[1,3]dioxolane-2,2'-indene]-1'-carbaldehyde
The compound of Step 2 was reacted according to the same procedure as Step 10 of Preparation 3 to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 1.25~1.91 (m, 6H), 2.00~2.25 (m, 4H), 2.74~2.78 (m, 1H), 3.28~3.33 (m, 3H), 3.89~3.97 (m, 4H), 4.07~4.13 (m, 1H), 9.77 (d, J = 2.1 Hz 1H).
<Preparation 5> (±)-t-Butyl-(1'R,3a'S,7a'R)-1'-formyloctahydrospiro-[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate
Figure PCTKR2011004607-appb-I000023
(Step 1) (±)-t-Butyl-{[(1'R,3a'S,7a'R)-trans-1',3',3a',4',7',7a'-hexahydrospiro-[(1,3)dioxolane-2,2'-inden]-1’-yl]methoxy}dimethylsilane
The Step 9 alcohol compound of Preparation 3 (1.43 g, 6.80 mmol) dissolved in DMF (10 mL) was stirred at room temperature, during which t-butyldimethylsilyl chloride (1.23 g, 8.16 mmol) and imidazole (926 mg, 13.6 mmol) were added thereto. After stirring for 3 h, distilled water (10 mL) was added to the reaction mixture to stop the reaction. The organic layer was separated, and the aqueous layer was extracted with Et2O (3 × 20 mL). The organic layers were combined and washed with brine (20 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 20:1) to give the title compound (2.03 g, 92%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 0.00 (s, 6H), 0.84 (s, 9H), 1.21-1.37 (m, 2H), 1.48-1.89 (m, 4H), 2.02 (dd, J = 12.7, 6.1 Hz, 1H), 2.17 (m, 1H), 2.32 (m, 1H), 3.52 (dd, J = 10.2, 6.9 Hz, 1H), 3.70 (dd, J = 10.2, 6.7 Hz, 1H), 3.76-3.94 (m, 4H), 5.62 (s, 2H).
(Step 2) (±)-t-Butyldimethyl{[(2a'R,3'R,5a'S)-octahydrospiro-[(1,3)dioxolane-2,4'-indeno(5,6-b)oxiran]-3'-yl]methoxy}silane
The solution of Step 1 compound (2.00 g, 6.61 mmol) in CH2Cl2 (20 mL) was stirred at room temperature, during which m-chloroperbenzoic acid (1.28 g, 7.39 mmol) was added thereto. After stirring for 2 h, saturated NaHCO3 (30 mL) was added to the reaction mixture, which was then stirred for 30 min. The the organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The organic layers were combined and washed with saturated aqueous sodium chloride solution (20 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to give the title compound (1.71 g, 81%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 0.00 (s, 6H), 0.84 (s, 9H), 1.05 (m, 1H), 1.19-1.76 (m, 6H), 1.89 (m, 1H), 2.28 (m, 1H), 3.10 (m, 2H), 3.47 (ddd, J = 10.0, 7.4, 2.4 Hz, 1H), 3.65 (ddd, J = 10.0, 6.4, 3.6 Hz, 1H), 3.70-3.91 (m, 4H).
(Step 3) (±)-(1'R,3a'S,7a'R)-1'-[(t-butyldimethylsilyloxy)methyl]octahydrospiro-[(1,3)dioxolane-2,2'-inden]-5'-ol
The solution of LiAlH4 (273 mg, 7.19 mmol) in THF (20 mL) was stirred at -30 ℃, during which the epoxide compound of Step 2 (1.63 g, 4.79 mmol) dissolved in THF (10 mL) was added over 20 min using a syringe. After stirring for 1 h, the reaction was stopped by distilled water (5 mL) at 0 ℃. 2 N aqueous NaOH solution (30 mL) was added and the mixture was stirred for 30 min. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 30 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (silica gel, hexanes:EtOAc = 10:1 - 4:1) to give the more polar title compound (930 mg, 57%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 0.00 (s, 6H), 0.84 (s, 9H), 1.21-1.51 (m, 5H), 1.60 (dd, J = 8.1, 3.0 Hz, 1H), 1.70 (m, 2H), 1.76 (d, J = 13.5 Hz, 1H), 1.88 (dd, J = 12.3, 5.0 Hz, 1H), 2.02 (d, J = 13.5 Hz, 1H), 3.50 (dd, J = 10.2, 6.0 Hz, 1H), 3.67 (dd, J = 10.2, 7.3 Hz, 1H), 3.73-3.92 (m, 4H), 4.06 (m, 1H).
(Step 4) t-Butyl (±)-(1'R,3a'S,7a'R)-1'-[(t-butyldimethylsilyloxy)methyl]octahydrospiro[[1,3]dioxolane-2,2'-inden]-5'-ylcarbamate
The solution of the alcohol compound of Step 3 (530 mg, 1.55 mmol) in CH2Cl2 (15 mL) was stirred at room temperature, during which pyridium chlorochromate (1.00 g, 4.64 mmol) was added. The resulting dark brown turbid solution was stirred for 3 h. To the reaction mixture was added a celite 545 (1 g) and stirred for 30 min. The reaction mixture was filtered through the celite 545 pad using CH2Cl2 (50 mL). The filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to give a ketone compound (470 mg) as a white solid, which was used in the next reaction without further purification.
The solution of the ketone compound (470 mg, 1.38 mmol) in methanol (2 mL) was stirred at room temperature, and NH4OAc (1.06 g, 13.8 mmol) and NaCNBH3 (106 mg, 1.66 mmol) were added thereto. The mixture was stirred for 2 h at room temperature, and then concentrated under reduced pressure. Distilled water (5 mL) was added to the concentrate, which was then extracted with ethyl acetate (5 × 10 mL). The organic layers were combined, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a pale yellow amine (430 mg), which was used in the next reaction without further purification.
The solution of the amine (430 mg) in CH2Cl2 (10 mL) was stirred at room temperature, during which t-butyloxycarbonyl dicarbonate (580 μL, 2.52 mmol) and NEt3 (351 μL, 2.52 mmol) were added. After stirring for 3 h, distilled water (3 mL) was added to the reaction mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The organic layers were combined and washed with brine (10 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 20:1) to give 365 mg of the title compound (3 Step Yield 59%) as a pale yellow liquid.
1H NMR (300 MHz, CDCl3) δ 0.00 (s, 6H), 0.84 (s, 9H), 0.90-1.42 (m, 6H), 1.39 (s, 9H), 1.68-2.01 (m, 4H), 2.11 (d, J = 11.7 Hz, 1H), 3.48 (m, 1H), 3.51 (dd, J = 10.2, 6.6 Hz, 1H), 3.66 (dd, J = 10.2, 6.9 Hz, 1H), 3.72-3.93 (m, 4H), 4.41 (d, J = 6.3 Hz, 1H).
(Step 5) t-Butyl-(±)-(1'R,3a'S,7a'R)-1'-(hydroxymethyl)octahydrospiro[[1,3]dioxolane-2,2'-inden]-5'-ylcarbamate
The solution of Step 4 compound (360 mg, 0.815 mmol) in THF (2 mL) was stirred at room temperature, to which was added n-Bu4NF (2.45 mL, 1.0 M in THF, 2.45 mmol). After stirring for 3 h, saturated NaHCO3 (3 mL) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound (228 g, 85%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 0.91 (m, 1H), 1.11-1.39 (m, 5H), 1.43 (s, 9H), 1.64-2.18 (m, 5H), 2.54 (br s, 1H), 3.64 (m, 2H), 3.78-4.04 (m, 5H), 4.44 (br s, 1H).
(Step 6) t-Butyl-(±)-(1'R,3a'S,7a'R)-1'-formyloctahydrospiro[[1,3]dioxolane-2,2'-inden]-5'-ylcarbamate
The Step 5 compound (228 mg, 0.696 mmol) was reacted according to the same procedure as Step 10 of Preparation 3 to give the pale yellow title compound (200 mg).
<Preparation 6> (±)-t-Butyl-(1'R,3a'S,7a'R)-1'-formyloctahydrospiro-[(1,3)dioxolane-2,2'-inden]-6'-ylcarbamate
Figure PCTKR2011004607-appb-I000024
(Step 1) (±)-(1'R,3a'S,7a'R)-1'-[(t-butyldimethylsilyloxy)methyl]octahydrospiro-[(1,3)dioxolane-2,2'-inden]-6'-ol
The compound of Step 2 of Preparation 5 (1.63 g, 4.79 mmol) was reacted according to the same procedure as Step 3 of Preparation 5 to give the title compound (550 mg, 34%) as a colorless liquid which is more nonpolar than the isomer of Step 3 of Preparation 5.
1H NMR (300 MHz, CDCl3) δ 0.00 (s, 6H), 0.84 (s, 9H), 1.21 (m, 1H), 1.45 (m, 2H), 1.68-1.94 (m, 8H), 3.52 (dd, J = 10.3, 6.4 Hz, 1H), 3.68 (dd, J = 10.3, 6.9 Hz, 1H), 3.72-3.94 (m, 4H), 4.07 (m, 1H).
(Step 2) t-Butyl-(±)-(1'R,3a'S,7a'R)-1'-[(t-butyldimethylsilyloxy)methyl]octahydrospiro[[1,3]dioxolane-2,2'-inden]-6'-ylcarbamate
The Step 1 compound was reacted according to the same procedure as Step 4 of Preparation 5 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 0.00 (s, 6H), 0.84 (s, 9H), 0.91-1.47 (m, 6H), 1.40 (s, 9H), 1.60-2.06 (m, 4H), 2.21 (d, J = 11.1 Hz, 1H), 3.47 (m, 1H), 3.50 (dd, J = 10.2, 6.5 Hz, 1H), 3.64 (dd, J = 10.2, 7.2 Hz, 1H), 3.72-3.94 (m, 4H), 4.43 (d, J = 7.5 Hz, 1H).
(Step 3) t-Butyl-(±)-(1'R,3a'S,7a'R)-1'-(hydroxymethyl)octahydrospiro[[1,3]dioxolane-2,2'-inden]-6'-ylcarbamate
The Step 2 compound was reacted according to the same procedure as Step 5 of Preparation 5 to give the title compound.
(Step 4) t-Butyl-(±)-(1'R,3a'S,7a'R)-1'-formyloctahydrospiro[[1,3]dioxolane-2,2'-inden]-6'-ylcarbamate
The Step 3 compound was reacted according to the same procedure as Step 10 of Preparation 3 to give the title compound.
<Preparation 7> (±)-t-Butyl-(1S,2R,3aS,7aR)-2-(t-butyldimethylsilyloxy)-1-formyloctahydro-1H-inden-5-ylcarbamate
Figure PCTKR2011004607-appb-I000025
(Step 1) (±)-(1'R,3a'S,7a'R)-1'-(benzyloxymethyl)-1',3',3a',4',7',7a'-hexahydrospiro-[(1,3)dioxolane-2,2'-indene]
The solution of the alcohol compound of Step 9 of Preparation 3 (4.02 mg, 19.1 mmol) in THF (50 mL) was stirred at room temperature, during which NaH (1.15 g, 28.7 mmol) was added in three portions. After the yellow suspension was stirred for 1 h, benzyl bromide (2.74 mL, 22.9 mmol) was added to the reaction mixture, which was then stirred for 12 h. Distilled water (20 mL) was added to the reaction mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 30 mL). The organic layers were combined and washed with saturated aqueous NH4Cl solution (30 mL) and brine (30 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 20:1) to give the title compound (4.94 g, 86%) as a pale yellow liquid.
1H NMR (300 MHz, CDCl3) δ 1.30-1.44 (m, 2H), 1.57-2.12 (m, 5H), 2.16-2.36 (m, 2H), 3.47 (dd, J = 9.6, 6.3 Hz, 1H), 3.60 (dd, J = 9.6, 6.9 Hz, 1H), 3.75-3.99 (m, 4H), 4.50 (s, 2H), 5.66 (s, 2H), 7.22-7.35 (m, 5H).
(Step 2) (±)-(2a'R,3'R,5a'S)-3'-(benzyloxymethyl)-octahydrospiro-[(1,3)dioxolane-2,4'-indeno(5,6-b)oxirane]
The olefin compound of Step 1 (4.87 g, 16.2 mmol) was reacted according to the same procedure as Step 2 of Preparation 5 to give the title compound (4.71 g, 92%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.06-1.75 (m, 5H), 1.83-2.04 (m, 2H), 2.14-2.50 (m, 2H), 3.14 (m, 2H), 3.38-3.58 (m, 2H), 3.75-3.97 (m, 4H), 4.53 (s, 2H), 7.26-7.37 (m, 5H).
(Step 3) (±)-(1'S,3a'S,5'R,7a'S)-1'-(benzyloxymethyl)-octahydrospiro-[(1,3)dioxolane-2,2'-inden]-5'-ol
The epoxide compound of Step 2 (4.71 g, 14.9 mmol) was reacted according to the same procedure as Step 3 of Preparation 5 to give the title compound (2.84 g, 60%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 1.32-1.67 (m, 7H), 1,82 (m, 1H), 1.89-1.98 (m, 2H), 2.04 (dd, J = 13.0, 2.0 Hz, 1H), 3.44 (dd, J = 9.3, 6.3 Hz, 1H), 3.58 (dd, J = 9.3, 7.2 Hz, 1H), 3.75-4.00 (m, 4H), 4.14 (m, 1H), 4.49 (s, 2H), 7.27-7.36 (m, 5H).
(Step 4) (±)-t-Butyl (1'R,3a'S,7a'R)-1'-(benzyloxymethyl)-octahydrospiro[[1,3]dioxolane-2,2'-inden]-5'-ylcarbamate
The alcohol compound of Step 3 (1.72 g, 5.40 mmol) was reacted according to the same procedure as Step 4 of Preparation 5 at room temperature to give the title compound (1.17 g, 3 Step Yield 46%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 0.81-1.29 (m, 3H), 1.33-1.58 (m, 2H), 1.43 (s, 9H), 1.77-2.17 (m, 6H), 3.44 (dd, J = 9.6, 6.0 Hz, 1H), 3.41 (m, 1H), 3.56 (dd, J = 9.6, 7.0 Hz, 1H), 3.75-4.01 (m, 4H), 4.37 (br s, 1H), 4.46 (s, 1H), 7.24-7.36 (m, 5H).
(Step 5) t-Butyl-(±)-(1R,3aS,7aR)-1-(benzyloxymethyl)-2-oxooctahydro-1H-inden-5-ylcarbamate
The solution of Step 4 acetal (364 mg, 0.872 mmol) in a solvent mixture of acetone:water (10:1, 5 mL) was stirred at room temperature, and p-toluenesulfonic acid (82.9 mg, 0.436 mmol) was added. After stirring for 5 h, saturated NaHCO3 (15 mL) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to give the title compound (287 mg, 88%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.06 (m, 1H), 1.25 (m, 2H), 1.44 (s, 9H), 1.63 (m, 4H), 2.36 (m, 2H), 3.61 (m, 1H), 3.62 (dd, J = 9.6, 4.5 Hz, 1H), 3.72 (dd, J = 9.6, 4.5 Hz, 1H), 4.44 (d, J = 12.0 Hz, 1H), 4.52 (d, J = 12.0 Hz, 1H), 4.57 (d, J = 9.3 Hz, 1H), 7.24-7.36 (m, 5H).
(Step 6) (±)-t-Butyl-(1R,2R,3aS,7aR)-1-(benzyloxymethyl)-2-hydroxyoctahydro-1H-inden-5-ylcarbamate
The solution of the Step 5 ketone compound (287 mg, 0.768 mmol) in methanol (10 mL) was stirred at room temperature, to which was added NaBH4 (145 mg, 3.84 mmol). After stirring for 2 h, the reaction mixture was concentrated under reduced pressure. To the concentrate was added distilled water (10 mL), which was then extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to give the title alcohol compound (167 mg, 65%) as a more nonpolar isomer.
1H NMR (300 MHz, CDCl3) δ 0.79-1.31 (m, 5H), 1.43 (s, 9H), 1.64-1.84 (m, 2H), 1.95-2.16 (m, 2H), 2.26 (m, 1H), 2.59 (d, J = 3.6 Hz, 1H), 3.45 (m, 1H), 3.64 (m, 2H), 4.41 (m, 2H), 4.46 (d, J = 12.0 Hz, 1H), 4.56 (d, J = 12.0 Hz, 1H), 7.26-7.38 (m, 5H).
(Step 7) (±)-t-Butyl-(1R,2R,3aS,7aR)-1-(benzyloxymethyl)-2-(t-butyldimethylsilyloxy)octahydro-1H-inden-5-ylcarbamate
The solution of Step 6 compound (257 mg, 0.684 mmol) in CH2Cl2 (10 mL) was stirred at room temperature, to which were added t-butyldimethylsilyl trifluoromethanesulfonate (314 μL, 1.37 mmol) and 2,6-rutidine (318 μL, 2.74 mmol). After stirring for 1 h, NaHCO3 (5 mL) was added to the reaction mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 20:1) to give the title compound (305 mg, 91%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 0.00 (s, 6H), 0.91 (s, 9H), 1.02-1.24 (m, 5H), 1.42 (s, 9H), 1.58-2.26 (m, 6H), 3.42 (dd, J = 8.7, 6.3 Hz, 1H), 3.47 (m, 1H), 3.66 (dd, J = 8.7, 7.2 Hz, 1H), 4.31 (m, 2H), 4.40 (d, J = 11.7 Hz, 1H), 4.50 (d, J = 11.7 Hz, 1H), 7.24-7.31 (m, 5H).
(Step 8) (±)-t-Butyl-(1R,2R,3aS,7aR)-2-(t-butyldimethylsilyloxy)-1-(hydroxymethyl)octahydro-1H-inden-5-ylcarbamate
The solution of Step 7 compound (300 mg, 0.613 mmol) in methanol (3 mL) was stirred at room temperature, to which was added 20 wt% Pd(OH)2/C (30 mg). The resulting black turbid solution was treated to remove the air in the reaction vessel under reduced pressure condition, and the reaction mixture was heated to 50 ℃ under hydrogen gas of 1 atm. After stirring for 6 h, the reaction mixture was filtered through a celite 545 pad using methanol (20 mL). The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to give the title compound (208 mg, 85%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 0.07 (s, 3H), 0.09 (s, 3H), 0.90 (s, 9H), 0.93-1.37 (m, 4H), 1.42 (s, 9H), 1.52 (m, 2H), 1.80-2.19 (m, 5H), 2.89 (br s, 1H), 3.48 (m, 1H), 3.58-3.94 (m, 2H), 4.43 (m, 2H).
(Step 9) (±)-t-Butyl-(1S,2R,3aS,7aR)-2-(t-butyldimethylsilyloxy)-1-formyloctahydro-1H-inden-5-ylcarbamate
The Step 8 compound (100 mg, 0.250 mmol) was reacted according to the same procedure as Step 10 of Preparation 3 to give the yellow title compound (90 mg).
<Preparation 8> (±)-t-Butyl-(1S,2S,3aS,7aR)-2-(t-butyldimethylsilyloxy)-1-formyloctahydro-1H-inden-5-ylcarbamate
Figure PCTKR2011004607-appb-I000026
(Step 1) (±)-t-Butyl-(1R,2S,3aS,7aR)-1-(benzyloxymethyl)-2-hydroxyoctahydro-1H-inden-5-ylcarbamate
The Step 5 compound of Preparation 7 (287 mg, 0.768 mmol) was reacted according to the same procedure as Step 6 of Preparation 7 to give the title alcohol compound (90 mg, 35%) as a colorless liquid which is more polar than the isomer of Step 6 of Preparation 7.
1H NMR (300 MHz, CDCl3) δ 0.79-1.32 (m, 4H), 1.43 (s, 9H), 1.52 (m, 1H), 1.62-1.82 (m, 4H), 1.925-2.16 (m, 3H), 3.36 (dd, J = 8.7, 8.7 Hz, 1H), 3.48 (m, 1H), 3.63 (dd, J = 8.7, 4.9 Hz, 1H), 4.15 (m, 1H), 4.37 (d, J = 8.1 Hz, 1H), 4.49 (d, J = 12.0 Hz, 1H), 4.55 (d, J = 12.0 Hz, 1H), 7.26-7.37 (m, 5H).
(Step 2) (±)-t-Butyl-(1R,2S,3aS,7aR)-1-(benzyloxymethyl)-2-(t-butyldimethylsilyloxy)octahydro-1H-inden-5-ylcarbamate
The Step 1 compound was reacted according to the same procedure as Step 7 of Preparation 7 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 0.01 (s, 6H), 0.86 (s, 9H), 0.94-1.42 (m, 5H), 1.45 (s, 9H), 1.57-2.15 (m, 6H), 3.50 (m, 3H), 4.13 (m, 1H), 4.37 (d, J = 8.1 Hz, 1H), 4.50 (s, 2H), 7.24-7.37 (m, 5H).
(Step 3) (±)-t-Butyl-(1R,2S,3aS,7aR)-2-(t-butyldimethylsilyloxy)-1-(hydroxymethyl)octahydro-1H-inden-5-ylcarbamate
The Step 2 compound was reacted according to the same procedure as Step 8 of Preparation 7 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 0.00 (s, 6H), 0.83 (s, 9H), 0.93-1.23 (m, 4H), 1.39 (s, 9H), 1.50-1.72 (m, 4H), 1.76-2.14 (m, 3H), 3.43 (m, 1H), 3.64 (m, 2H), 4.08 (m, 1H), 4.37 (d, J = 5.4 Hz, 1H).
(Step 4) (±)-t-Butyl-(1S,2S,3aS,7aR)-2-(t-butyldimethylsilyloxy)-1-formyloctahydro-1H-inden-5-ylcarbamate
The Step 3 compound was reacted according to the same procedure as Step 10 of Preparation 3 to give the title compound.
<Preparation 9> (±)-(1'R,3a'R,5'R,7a'R)-5'-(t-butyl-dimethylsilyloxy)octahydrospiro[(1,3)dioxolane-2,2'-indene]-1'-carbaldehyde
Figure PCTKR2011004607-appb-I000027
(Step 1) (±)-(1'R,3a'R,7a'R)-1-(benzyloxymethyl)-1',3',3a',4',7',7a'-hexahydrospiro[(1,3)dioxolane-2,2'-indene]
The solution of Step 2 compound of Preparation 4 (2.4 g, 11.41 mmol) in THF (15 mL) was cooled to 0 ℃ and stirred, during which NaH (547 mg, 13.69 mmol) was slowly added. After stirring for 1 h, benzyl bromide (1.6 mL, 13.69 mmol) and a catalytic amount of tetrabutylammonium iodide were added. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to give the title compound (3.1 g, 93%).
(Step 2) (±)-(1'R,3a'R,5'R,7a'R)-1-(benzyloxymethyl)-octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-ol
The Step 1 compound (3.2 g, 10.65 mmol) was reacted according to the same procedures as Steps 2 and 3 of Preparation 5―2 step reaction―to give the title compound (2.2 g, 2 Step 65%).
1H-NMR (300 MHz, CDCl3) δ 1.9 (m, 10H), 2.0 (m, 1H), 2.3 (m, 1H), 3.5 (m, 2H), 3.9 (m, 4H), 4.5 (s, 2H), 7.3 (m, 5H).
(Step 3) (±)-{(1'R,3a'R,5'R,7a'R)-1-(benzyloxymethyl)-octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-yloxy}(t-butyl)dimethylsilane
The Step 2 compound (700 mg, 2.19 mmol) was reacted according to the same procedure as Step 7 of Preparation 7 to give the title compound (890 mg, 93%).
1H-NMR (300 MHz, CDCl3) δ 0 (s, 6H), 0.8 (s, 9H), 1.6 (m, 4H), 2.3 (m, 2H), 3.4 (m, 2H), 3.9 (m, 4H), 4.45 (s, 2H), 7.3 (m, 5H).
(Step 4) (±)-{(1'R,3a'R,5'R,7a'R)-5-(t-butyldimethylsilyloxy)octahydrospiro[(1,3)dioxolane-2,2'-inden]-1’-yl}methanol
The Step 3 compound (890 mg, 2.05 mmol) was reacted according to the same procedure as Step 8 of Preparation 7 to give the title compound (600 mg, 85%).
(Step 5) (±)-(1'R,3a'R,5'R,7a'R)-5'-(t-butyl-dimethylsilyloxy)octahydrospiro[(1,3)dioxolane-2,2'-indene]-1'-carbaldehyde
The Step 4 compound was reacted according to the same procedure as Step 10 of Preparation 3 to give the title compound.
<Preparation 10> (±)-(1'R,3a'R,5'S,7a'R)-5'-(t-butyl-dimethylsilyloxy)octahydrospiro[(1,3)dioxolane-2,2'-indene]-1'-carbaldehyde
Figure PCTKR2011004607-appb-I000028
(Step 1) (±)-(1'R,3a'R,5'S,7a'R)-1-(benzyloxymethyl)-octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-ol
The solution of Step 2 compound of Preparation 9 (1.3 g, 4.08 mmol) in benzene (8 mL) was stirred, during which PPh3 (5.3 g, 20.41 mmol), 4-nitrobenzoic acid (3 g, 18.23 mmol) and diethylazodicarboxylate (3.2 mL, 20.41 mmol) were added. The mixture was stirred for 30 min at room temperature, and H2O was added to the reaction vessel to stop the reaction. The organic layer was separated from the reaction mixture, and the aqueous layer was extracted with Et2O. The organic layers were combined and dried over anhydrous MgSO4. The organic layer was filtered, the filtrate was concentrated under reduced pressure, and the concentrate in THF:H2O (10 mL) was stirred. The compound was stirred, adding NaOH (489 mg, 12.24 mmol) thereto. After stirring for 12 h, H2O was added to the reaction mixture, from which the organic layer was separated. The aqueous layer was extracted with Et2O. The organic layers were combined and dried over anhydrous MgSO4. The organic layer was filtered, the filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (hexane : ethyl acetate = 2:1) to give the title compound (1 g, 77%).
1H-NMR (300 MHz, CDCl3) δ1.24~1.29 (m, 4H), 1.37~2.02 (m, 5H), 1.96~2.02 (m, 2H), 2.26~2.32 (m, 1H), 3.36~3.61 (m, 3H), 3.75~3.85 (m, 5H), 3.93~3.97 (m, 1H), 4.16~4.23 (m, 1H), 4.50 (s, 2H), 7.25~7.36 (m, 5H).
(Step 2) (±)-(1'R,3a'R,5'S,7a'R)-5'-(t-butyl-dimethylsilyloxy)octahydrospiro[(1,3)dioxolane-2,2'-indene]-1'-carbaldehyde
The Step 1 compound was reacted according to the same procedures as Steps 3-5 of Preparation 9―3 step reaction―to give the title compound.
<Preparation 11> (±)-t-Butyl (1'R,3a'R,7a'R)-1'-formyloctahydrospiro-[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate
Figure PCTKR2011004607-appb-I000029
(Step 1) (±)-t-Butyl (1'R,3a'R,7a'R)-1'-(benzyloxymethyl)octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate
The Step 2 compound of Preparation 9 (300 mg, 0.942 mmol) was reacted according to the same procedure as Step 4 of Preparation 5 to give the title compound (240 mg, 3 Step Total Yield 70%).
1H-NMR (300 MHz, CDCl3) δ 1.2 (m, 3H), 1.4 (s, 8H), 1.7 (m, 4H), 2.1 (m, 1H), 2.3 (m, 1H), 3.4 (m, 2H), 3.9 (m, 4H), 4.5 (s, 2H), 7.3 (m, 5H).
(Step 2) (±)-t-Butyl (1'R,3a'R,7a'R)-1'-(hydroxymethyl)octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate
The Step 1 compound (240 mg, 0.57 mmol) was reacted according to the same procedure as Step 8 of Preparation 7 to give the title compound (100 mg, 75%).
(Step 3) (±)-t-Butyl (1'R,3a'R,7a'R)-1'-formyloctahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate
The Step 2 compound was reacted according to the same procedure as Step 10 of Preparation 3 to give the title compound.
<Preparation 12> (±)-(1S,2S,3aS,5R,7aR)-2-(t-butyl-dimethylsilyloxy)-5-(methoxymethoxy)octahydrospiro-1H-indene-1-carbaldehyde
Figure PCTKR2011004607-appb-I000030
(Step 1) (1R,3aR,7aR)-1-(benzyloxymethyl)-3a,4,7,7a-tetrahydro-1H-inden-2(3H)-one
The Step 1 compound of Preparation 9 was reacted according to the same procedure as Step 5 of Preparation 7 to give the title compound.
(Step 2) (1R,2S,3aR,7aR)-1-(benzyloxymethyl)-2,3,3a,4,7,7a-hexahydro-1H-inden-2-ol
The Step 1 compound (2.0 g, 7.8 mmol) was reacted according to the same procedure as Step 6 of Preparation 7 to give the title compound (0.8 g, 40%) as a more polar isomer.
1H-NMR (300 MHz, CDCl3) δ 1.36~1.44 (m, 1H), 1.71~1.76 (m, 1H), 1.84~2.19 (m, 7H), 2.48 (brs, 1H), 3.41 (t, 1H, J = 9.0Hz), 3.65~3.70 (m, 1H), 4.02~4.07 (m, 1H), 4.48~4.58 (m, 2H), 5.74~5.76 (m, 2H), 7.27~7.37 (m, 5H).
(Step 3) [(1R,2S,3aR,7aR)-1-(benzyloxymethyl)-2,3,3a,4,7,7a-hexahydro-1H-inden-2-yloxy](t-butyl)dimethylsilane
The Step 2 compound (3.4 g, 13 mmol) was reacted according to the same procedure as Step 7 of Preparation 7 to give the title compound (5.0 g, 100%).
1H-NMR (300 MHz, CDCl3) δ 0.04 (s, 6H), 0.85 (s, 9H), 1.36~1.40 (m, 1H), 1.76~2.16 (m, 8H), 3.49~3.50 (m, 2H), 4.03~4.08 (m, 1H), 4.50~4.51 (m, 2H), 5.72~5.73 (m, 2H), 7.25~7.35 (m, 5H).
(Step 4) (±)-(1R,2S,3aS,5R,7aR)-1-(benzyloxymethyl)-2-(t-butyl-dimethylsilyloxy)octahydro-1H-inden-5-ol
The Step 3 compound was reacted according to the same procedures as Steps 2 and 3 of Preparation 5―2 step reaction―to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 0.04 (s, 6H), 0.86 (s, 9H), 1.76~2.03 (m, 9H), 1.76~2.16 (m, 8H), 3.12 (brs, 2H), 3.42~3.48 (m, 2H), 3.89~3.92 (m, 1H), 4.48~4.49 (m, 2H), 7.27~7.34 (m, 5H).
(Step 5) (±)-[(1R,2S,3aS,5R,7aR)-1-(benzyloxymethyl)-5-(methoxymethoxy)octahydro-1H-inden-2-yloxy](t-butyl)dimethylsilane
In anhydrous CH2Cl2 (10 mL) was dissolved the Step 4 compound (0.120 g, 0.307mmol), to which were added diisopropylethylamine (0.080 mL, 0.467 mmol), methoxymethyl chloride (0.035 mL, 0.467 mmol) and dimethylaminopyridine (0.004g, 0.031mmol) at 0 ℃. After stirring for 3 h at room temperature, the mixture was extracted with CH2Cl2 and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 5:1) to give the title compound (0.100 g, 75%) .
1H-NMR (300 MHz, CDCl3) δ 0.04 (s, 6H), 0.86 (s, 9H), 1.26~2.05 (m, 10H), 2.12~2.19 (m, 1H), 3.34~3.50 (m, 5H), 3.68~3.81 (m, 1H), 3.96~4.09 (m, 1H), 4.51 (s, 2H), 4.61 (s, 2H), 7.27~7.38 (m, 5H).
(Step 6) (±)-[(1S,2S,3aS,5R,7aR)-2-(t-butyl-dimethylsilyloxy)-5-(methoxymethoxy)octahydro-1H-inden-1-yl]methanol
The Step 5 compound (100 mg, 0.237 mmol) was reacted according to the same procedure as Step 8 of Preparation 7 to give the title compound (64 mg, 80%).
1H-NMR (300 MHz, CDCl3) δ 0.05 (s, 6H), 0.88 (s, 9H), 1.26~1.87 (m, 9H), 1.93~2.01 (m, 1H), 2.08~2.18 (m, 1H), 3.38 (s, 3H), 3.62~3.64 (m, 2H), 3.77~3.81 (m, 1H), 3.96~4.02 (m, 1H), 4.28~4.30 (m, 1H), 4.68 (s, 2H).
(Step 7) (±)-(1S,2S,3aS,5R,7aR)-2-(t-butyl-dimethylsilyloxy)-5-(methoxymethoxy)octahydro-1H-indene-1-carbaldehyde
The Step 6 compound (40 mg, 0.116 mmol) was reacted according to the same procedure as Step 10 of Preparation 3 to give the title compound (30 mg, 75%).
1H-NMR (300 MHz, CDCl3) δ 0.04 (s, 6H), 0.88 (s, 9H), 1.25~1.62 (m, 4H), 1.67~1.86 (m, 3H), 2.02~2.20 (m, 3H), 2.60~2.62 (m, 1H), 3.37 (s, 3H), 3.78~3.80 (m, 1H), 4.50~4.67 (m, 1H), 4.69 (s, 2H), 9.71 (s, 1H).
<Preparation 13> (±)-(1S,2R,3aS,5R,7aR)-2-(t-butyl-dimethylsilyloxy)-5-(methoxymethoxy)octahydro-1H-indene-1-carbaldehyde
Figure PCTKR2011004607-appb-I000031
The more nonpolar compound obtained in Step 2 of Preparation 12 (0.23 g, 11%) was reacted according to the same procedures as Steps 3-7 of Preparation 12 to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 0.0 (s, 6H), 0.8 (s, 9H), 1.8 (m, 10H), 2.5 (m, 1H), 3.8 (m, 1H), 4.4 (m, 1H), 4.7 (s, 2H), 6.5 (d, 1H, J = 8.4 Hz), 6.8 (dd, 1H, J = 8.4, 8.4 Hz), 7.2 (m, 5H), 7.8 (d, 1H, J = 8.1 Hz), 8.8 (s, 1H).
<Preparation 14> (±)-(1'R,3a'S,7a'R)-5'-(t-butyl-dimethylsilyloxy)octahydrospiro[(1,3)dioxolane-2,2'-indene]-1'-carbaldehyde
Figure PCTKR2011004607-appb-I000032
The Step 9 compound of Preparation 3 was reacted according to the same procedure as Preparation 9 to give the title compound.
<Preparation 15> Diethyl [5-(3-fluorophenyl)pyridin-2-yl]methylphosphonate
Figure PCTKR2011004607-appb-I000033
(Step 1) 6-Methylpyridine-3-yl trifluoromethanesulfonate
6-Methylpyridin-3-ol (4 g, 36.7 mmol) was dissolved in CH2Cl2, to which was added pyridine (4.4 mL, 54.4 mmol, 1.5 equiv). At 0 ℃, trifluoromethanesulfone anhydride (9.2 mL, 54.6 mmol, 1.5 equiv) was slowly added. After stirring for 1.5 h at 0 ℃, methanol (1 mL) and saturated aqueous NaHCO3 solution were added. After the mixture was extracted with CH2Cl2, the solvent was removed and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1 ~ 4:1) to give the title compound (7 g, 79%).
(Step 2) 5-(3-Fluorophenyl)-2-methylpyridine
The Step 1 compound (6.2 g, 25.7 mmol), 3-fluorobenzeneboronic acid (4.3 g, 30.7 mmol), K2CO3 (10.7 g, 77.4 mmol) and Pd(PPh3)4 (297 mg, 0.26 mmol) were introduced into a 250 mL round-bottomed flask, to which was added a solvent mixture of toluene/ethanol/water (4/2/1) (60 mL). The mixture was heated to 120℃ for 22 h. After the mixture was cooled to room temperature, water was added. The mixture was extracted with ethyl acetate, dried over MgSO4 and filtered. The filtrate was distilled under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to give the title compound (4.3 g, Yield 97%).
1H-NMR (300 MHz, CDCl3) δ 2.62 (s, 3H), 7.04-7.47 (m, 5H), 7.76 (dd, J = 8.1Hz, 2.4Hz, 1H), 8.72 (d, J = 2.1Hz, 1H).
(Step 3) Diethyl [5-(3-fluorophenyl)pyridin-2-yl]methylphosphonate
In anhydrous THF (5 mL) was dissolved the Step 2 compound (0.9 g, 4.80 mmol), to which was added Li i Pr2NH (1.8 M in THF) (3.0 mL, 4.80 mmol) at -78 ℃. After stirring for 10 min, n-BuLi (1.6 M in THF) (6.0 mL, 9.61 mmol) and diethylchlorophosphonate (0.96 mL, 4.80 mmol) were slowly added. After stirring for 2 h, the mixture was extracted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (CH2Cl2:CH3OH=20:1) to give the title compound (0.55 g, 1.56 mmol).
1H-NMR (300 MHz, CDCl3) δ 1.29(t, J = 6.9 Hz, 7.2 Hz, 6H), 3.46 (d, J = 21.9 Hz, 2H), 4.09~4.16(m, 4H), 7.06~7.12(m, 1H), 7.24~7.49 (m, 4H), 7.82 (dd, J = 2.4 Hz, 2.4 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H).
<Preparation 16> (-)-(1'R,3a'R,7a'S)-methyl-2-oxo-2,3,3a,4,7,7a-hexahydro-1H-indene-1-carboxylate
Figure PCTKR2011004607-appb-I000034
(Step 1) bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]fumarate
Maleic anhydride (37.6 g, 0.384 mol) and (-)-menthol (120 g, 0.768 mol) were dissolved in benzene (400 mL). p-Toluenesulfonic acid (7.3 g) was added, which was then heated and refluxed overnight using Dean-Stark apparatus. The reaction solution was cooled to room temperature, and ether (500 mL) was added. The mixture was washed with NaHCO3 solution and aqueous NaCl solution. The filtrate was dried over MgSO4 and concentrated under reduced pressure to give 132 g of di-(-)-menthyl maleate as a solid. This compound (78.4 g) was dissolved in benzene (200 mL), morpholine (1.74 g) dissolved in benzene (20 mL) was added thereto in drops, and the mixture was refluxed for 12 h. After the reaction solution was cooled, ether (300 mL) was added. The mixture was washed with 2M aqueous HCl solution, NaHCO3 solution and aqueous NaCl solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (75 g) as a gel.
1H-NMR (300 MHz, CDCl3) δ δ 6.81 (s, vinyl H); IR (film) 1730 cm-1; [α ]D-102o (c 0.90, C6H6).
(Step 2) (-)-(1S,2S)-bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]cyclohex-4-ene-1,2-dicarboxylate
The Step 1 compound (47 g, 0.12 mol) was added to anhydrous hexane (700 mL) and cooled to -40 ℃. Diisobutylaluminum chloride (240 mL, 25% solution) was added and stirred for 30 min. To the reaction solution was added 1,3-butadiene (28.5g). The mixture was stirred for 4 h, maintaining the temperature, and then allowed to stand for 1 day at -15 ℃. The reaction solution was added to aqueous HCl solution, which was then extracted with ether, washed with NaHCO3 solution and aqueous NaCl solution, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (46 g, 85%) as a gel.
1H NMR (300 MHz, CDCl3) δ 2.10-2.50 (m, 4H), 2.84 (m, 2H), 5.68 (m, 2H); IR (CHCl3) 1730 cm-1;[α]D-30.2o (c 2.20, CHCl3).
(Step 3) (-)-(1S,2S)-cyclohex-4-en-1,2-diyldimethanol
LiAlH4 (6.5 g) was added to ether (200 mL) and maintained at 0 ℃. The Step 2 compound (44 g, 0.1 mol) dissolved in ether (200 mL) was added in drops thereto and stirred for 72 h. To the reaction solution were slowly added water (1 mL), 3M aqueous NaOH solution (1 mL) and water (3 mL), which was then stirred for 2 h, filtered and distilled under reduced pressure. The resulting residue in a gel phase was purified by silica gel column chromatography to give 8.4g (60%) of the title compound as a solid.
mp 63-65 ℃; [α]D+73o (c 1.75, CHCl3); 1H NMR (300 MHz, CDCl3): δ 1.70-1.90 (m, 4H), 2.01-2.05 (m, 2H), 3.57-3.72 (m, 2H), 3.73-3.76 (m, 2H), 5.68 (m, 2H).
(Step 4) (-)-(1R,3aR,7aS)-methyl-2-oxo-2,3,3a,4,7,7a-hexahydro-1H-indene-1-carboxylate
The Step 3 compound (0.17 mol) was reacted according to the same procedures as Steps 3-7 of Preparation 3―5 step reaction―to give the title compound.
1H NMR (CDCl3): δ 1.91-2.05 (m, 4H), 2.29-2.45 (m, 3H), 2.58-2.64 (m, 1H), 2.89-2.93 m, 1H), 3.76 (s, 3H), 5.75 (s, 2H).
Figure PCTKR2011004607-appb-I000035
<Example 1> (±)-5-(3-Fluorophenyl)-2-{(E)-2-[(1'S,3a'R,7a'R)-octahydrospiro[(1,3)-dioxolane-2,2'-inden]-1’-yl]vinyl}pyridine
The Preparation 15 compound (1.4 g, 4.56 mmol) was dissolved in anhydrous THF (15 mL), to which was slowly added n-BuLi (2.5M toluene solution, 1.8 mL) at 0 ℃. After stirring for 30 min, the Preparation 1 compound (0.5 g, 2.38 mmol) dissolved in THF (10 mL) was slowly added thereto. After stirring for 2 h at room temperature, the mixture was extracted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the title compound (0.450 g, 44%).
1H-NMR (300 MHz, CDCl3) δ 0.85~1.78 (m, 8H), 2.02~2.18 (m, 4H), 2.84~2.91 (m, 1H), 3.76~3.97 (m, 4H), 6.53~6.76 (m, 2H), 7.05~7.11 (m, 1H), 7.28~7.47 (m, 4H), 7.78 (m, 1H), 8.86 (d, J = 0.4 Hz, 1H).
<Example 2> (±)-5-(3-Fluorophenyl)-2-{(E)-2-[(1'S,3a'S,7a'R)-octahydrospiro[(1,3)-dioxolane-2,2'-inden]-2-yl]vinyl}pyridine
Figure PCTKR2011004607-appb-I000036
The Preparation 2 compound (0.024 mg, 0.114 mmol) was reacted according to the same procedure as Example 1 to give the title compound (0.008 mg, 0.021 mmol).
1H-NMR (300 MHz, CDCl3) δ 0.80~1.89 (m, 11H), 2.07~2.17 (m, 1H), 2.39 (t, J = 9.3Hz, 1H) 3.73~3.98 (m, 4H), 6.52~6.79 (m, 2H), 7.08 (m, 1H), 7.28~7.47 (m, 4H), 7.77~7.81 (m, 1H), 8.76 (d, J = 1.2Hz, 1H).
<Example 3> (±)-(1S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}hexahydro-1H-inden-2(3H)-one
The Example 1 compound (0.2g, 0.572mmol) was dissolved in acetone (2 mL) and H2O (2 mL), and p-toluenesulfonic acid (0.040 g, 0.211 mmol) was added. After stirring for 1 h at 50 ℃, the solvent was distilled under reduced pressure and the residue was diluted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the title compound (0.100 g, 0.298mmol).
1H-NMR (300 MHz, CDCl3) δ 1.11~1.79 (m, 8H), 2.20~2.28 (m, 1H), 2.34~2.54 (m, 2H), 3.34 (s, 1H), 6.82 ~7.11 (m, 3H), 7.24~7.46 (m, 4H), 7.89 (dd, J = 2.4 Hz, 1H), 8.73(d, J = 3.0Hz, 1H).
<Example 4> (±)-(1S,3aR,7aR, E)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}hexahydro-1H-inden-2(3H)-one oxime
The Example 3 compound (0.070 g, 0.208 mmol) was dissolved in ethanol (7 mL), and hydroxylammonium chloride (0.016 g, 0.295 mmol) and KOH (0.013 g, 0.229 mmol) were added. After stirring for 6 h at room temperature, the solvent was distilled under reduced pressure. The residue was diluted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the title compound (0.010 g, 0.028 mmol).
1H-NMR (300 MHz, CDCl3) δ 0.82~1.70 (m, 9H), 2.04~2.64 (m, 4H), 3.37~3.66 (m, 1H), 6.56~6.89 (m, 1H), 7.04~7.10 (m, 1H), 7.24~7.46 (m, 4H), 7.76~7.81 (m, 1H), 8.75 (s, 1H).
<Example 5> (±)-(1S,3aR,7aR, Z)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}hexahydro-1H-inden-2(3H)-one oxime
The same procedure as Example 4 was carried out to give the title compound (0.023g, 0.065mmol).
1H-NMR (300 MHz, CDCl3) δ 0.85~1.73 (m, 9H), 2.11~2.88 (m, 4H), 3.363~3.80 (m, 1H), 6.33~6.72 (m, 1H), 7.05~7.11 (m, 1H), 7.20~7.60 (m, 4H), 7.76~7.78 (m, 1H), 8.73 (s, 1H).
<Example 6> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2(3H)-ol
The Example 3 compound (0.040 g, 0.119 mmol) was dissolved in ethanol (5 mL) and NaBH4 (0.005 g, 0.131 mmol) was added. After stirring for 6 h at room temperature, the solvent was distilled under reduced pressure. The residue was diluted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the title compound (0.008 g, 0.023 mmol).
1H-NMR (300 MHz, CDCl3) δ 1.23~2.04m, 13H), 2.63~2.65m, 1H), 3.66~3.68m, 2H), 4.58t, J = 1.5 Hz, 1H), 5.77 (t, J = 7.5 Hz, 1H), 6.54~7.10 (m, 1H), 7.28 ~7.49 (m, 4H), 7.77 (dd, J = 2.4 Hz, 1H), 8.73 (d, J = 2.4 Hz, 1H).
<Example 7> (±)-5-(3-Fluorophenyl)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-methoxyoctahydro-1H-inden-1-yl]vinyl}pyridine
The Example 6 compound (0.034 g, 0.101 mmol) was dissolved in anhydrous THF (5 mL), and NaH (4.8 mg, 0.111 mmol) and CH3I (0.007 mL, 0.111 mmol) were added at 0 ℃. After stirring for 4 h at room temperature, ethyl acetate was added, which was then washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the title compound (0.010 g, 0.028 mmol).
1H-NMR (300 MHz, CDCl3) δ 1.40~1.67 (m, 9H), 1.84~2.17 (m, 3H), 2.72~2.80 (m, 1H), 3.33 (s, 3H), 3.75~3.81 (m, 1H), 6.55~6.79 (m, 2H), 7.05~7.11 (m, 1H), 7.28~7.47 (m, 4H), 7.79 (d, J = 2.4 Hz, 1H), 8.76 (d, J = 1.8Hz, 1H).
<Example 8> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl acetate
The Example 6 compound (0.015 g, 0.044 mmol) was dissolved in anhydrous CH2Cl2 (5 mL), and 4-dimethylaminopyridine (5 mg, 0.049 mmol) and acetic anhydride (0.005 mL, 0.049 mmol) were added. After stirring for 2 h at room temperature, ethyl acetate was added, which was then washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the title compound (0.006 g, 0.016 mmol).
1H-NMR (300 MHz, CDCl3) δ 1.25~1.69 (m, 9H), 1.89~2.00 (m, 1H), 2.05 (s, 4H), 2.31~2,41 (m, 1H), 2.84~2.92 (m, 1H), 5.04~5.10 (m, 1H), 6.5~6.70 (m, 2H), 7.05~7.11 (m, 1H), 7.28~7.47 (m, 4H), 7.80 (d, J = 2.4 Hz, 1H), 8.75 (d, J = 1.8 Hz, 1H).
<Example 9> (±)-5-(3-Fluorophenyl)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(benzyloxy)octahydro-1H-inden-1-yl]vinyl}pyridine
The Example 6 compound (0.015 g, 0.044 mmol) was dissolved in anhydrous DMF (5 mL), and NaH (2 mg, 0.049 mmol) and benzyl bromide (0.006 mL, 0.049 mmol) were added. After stirring for 3 h at room temperature, ethyl acetate was added, which was then washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4, filtered, concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=7:1) to give the title compound (0.007 g, 0.016 mmol).
1H-NMR (300 MHz, CDCl3) δ 0.83~1.83 (m, 9H), 2.17~2.40 (m, 3H), 2.62 (brs, 1H), 4.59 (s, 2H), 5.32~5.36 (m, 1H), 6.77~7.05 (m, 2H), 7.06~7.12 (m, 1H), 7.29~7.47 (m, 9H), 7.78~7.81 (m, 1H), 8.79 (d, J = 0.9 Hz, 1H).
<Example 10> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl methanesulfonate
The Example 6 compound (0.040 g, 0.118mmol) was dissolved in anhydrous CH2Cl2 (5 mL), and NEt3 (0.024 mL, 0.178 mmol) and CH3SO2Cl (0.011 mL, 0.142 mmol) were added. After stirring for 2 h at room temperature, ethyl acetate was added, which was then washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the title compound (0.012 g, 0.0029 mmol).
1H-NMR (300 MHz, CDCl3) δ 1.19~1.81 (m, 9H), 1.88~2.10 (m, 2H), 2.33~2.44 (m, 1H), 2.94~3.04 (m, 4H), 4.94~4.99 (m, 1H), 6.58~6.73 (m, 2H), 7.06~7.12 (m, 1H), 7.25~7.47 (m, 4H), 7.80~7.83 (m, 1H), 7.75 (s, 1H).
<Example 11> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl phenylcarbamate
The Example 6 compound (0.050 g, 0.148 mmol) and phenylisocyanate (0.019 mL, 0.163 mmol) were dissolved in petroleum ether (7 mL). After stirring for 3 h at 120 ℃, ethyl acetate was added, which was then washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the title compound (0.023 g, 0.050 mmol).
1H-NMR (300 MHz, CDCl3) δ 0.82~1.70 (m, 9H), 1.97~2.06 (m, 2H), 2.36~2.47 (m, 1H), 2.88~2.96 (m, 1H), 5.09~5.15 (m, 1H), 6.56~6.74 (m, 3H), 7.01~7.11 (m, 2H), 7.28~7.46 (m, 7H), 7.79 (dd, J = 2.4 Hz, 1H), 8.7 4(d, J = 2.4 Hz, 1H).
<Example 12> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl dimethylcarbamothioate
The Example 6 compound (0.040 g, 0.118mmol) was dissolved in anhydrous DMF (7 mL), and NaH (5 mg, 0.130 mmol) and dimethylaminothiocarbonyl chloride (0.016 mL, 0.130 mmol) were added at 0 ℃. After stirring for 3 h at room temperature, ethyl acetate was added, which was then washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=7:1) to give the title compound (0.028 g, 0.069 mmol).
1H-NMR (300 MHz, CDCl3) δ 1.23~1.72 (m, 9H), 1.90~2.07 (m, 2H), 2.44~2.54 (m, 1H), 2.97~3.13 (m, 1H), 3.29 (s, 3H), 3.34 (s, 3H), 5.59~5.65 (m, 1H), 6.54~6.72 (m, 2H), 7.05~7.11 (m, 1H), 7.25~7.47 (m, 4H), 7.81 (d, J = 2.4 Hz, 1H), 8.75 (s, 1H).
Figure PCTKR2011004607-appb-I000037
<Example 13> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl carboxylic acid
Isopropyl ester compound (100 mg, 0.245 mmol) was dissolved in methanol/water/THF (1:1:1, 9 mL), and NaOH (1.0 g, 25 mmol) was added at room temperature. After stirring for 24 h at room temperature, the mixture was concentrated under reduced pressure. The residue was acidified by 2 N aqueous HCl solution and extracted with ethyl acetate. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (78.4 mg, 78%).
1H-NMR (300 MHz, CDCl3) δ 1.05~1.80 (m, 15H), 1.85~2.23 (m, 3H), 2.63~2.80 (m, 1H), 3.05 (q, J = 8.7 Hz, 1H), 5.01 (m, J = 6.3 Hz, 1H), 6.54 (d, J = 15.6 Hz, 1H), 6.66 (dd, J = 8.1, 15.6 Hz, 1H), 7.07 (dd, J = 9.6 Hz, 1H), 7.20~7.50 (m, 4H), 7.79 (d, J = 5.7 Hz, 1H), 8.75 (s, H).
<Example 14> {(±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}(morpholin-4-yl)methanone
The Example 13 compound (20 mg, 0.055 mmol) was added to CH2Cl2 (2 mL), and (COCl)2 (0.009 mL, 0.11 mmol) and DMF (1~2 drops) were added thereto at 0 ℃. After stirring for 2 h at room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in anhydrous CH2Cl2 (2 mL). Morpholine was added at 0 ℃, and the mixture was stirred for 30 min at room temperature. Water was added to stop the reaction and the mixture was extracted with CH2Cl2. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate:dichloromethane = 2:1:1) to give the title compound (20 mg, 84%).
1H-NMR (300 MHz, CDCl3) δ 0.80~1.80 (m, 8H), 1.90~2.25 (m, 4H), 2.82~3.00 (m, 1H), 3.34 (q, J = 8.7 Hz, 1H), 3.40~3.80 (m, 8H), 6.56 (d, J = 15.3 Hz, 1H), 6.67 (dd, J = 8.7, 15.9 Hz, 1H), 7.08 (dd, J = 8.7 Hz, 1H), 7.20~7.50 (m, 4H), 7.79 (d, J = 8.4 Hz, 1H), 8.74 (s, 1H).
<Example 15> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-N-methyloctahydro-1H-indene-2-carboxamide
The Example 13 compound was reacted according to the same procedure as Example 14 except for using N-methylamine instead of morpholine to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 1.03~2.18 (m, 12H), 2.40~2.60 (m, 1H), 2.79 (d, J = 4.8 Hz, 3H), 3.00 (q, J = 9.6 Hz, 1H), 5.49 (brs, 1H), 6.54 (d, J = 15.6 Hz, 1H), 6.68 (dd, J = 8.7, 15.3 Hz, 1H), 7.09 (dd, J = 7.2 Hz, 1H), 7.20~7.50 (m, 4H), 7.81 (dd, J = 2.1, 8.1 Hz, 1H), 8.74 (d, J = 1.5 Hz, 1H).
<Example 16> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-N,N-dimethyloctahydro-1H-indene-2-carboxamide
The Example 13 compound was reacted according to the same procedure as Example 14 except for using N,N-dimethylamine instead of morpholine to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 1.10~1.80 (m, 10H), 1.88~2.30 (m, 3H), 2.95 (s, 3H), 3.00 (s, 3H), 3.37 (q, J = 8.7 Hz, 1H), 6.55 (d, J = 15.3 Hz, 1H), 6.68 (dd, J = 8.4, 15.3 Hz, 1H), 7.07 (dd, J = 8.7 Hz, 1H), 7.20~7.50 (m, 4H), 7.78 (dd, J = 2.4, 8.1 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H).
<Example 17> {(±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}(pyrrolidin-1-yl)methanone
The Example 13 compound was reacted according to the same procedure as Example 14 except for using pyrrolidine instead of morpholine to give the title compound.
1H NMR (CDCl3, 200 MHz) δ 1.00~2.50 (m, 16H), 2.80~3.00 (m, 1H), 3.32 (q, J = 9.0 Hz, 1H), 3.30~3.60 (m, 4H), 6.55 (d, J = 15.3 Hz, 1H), 6.69 (dd, J = 9.0, 15.3 Hz, 1H), 7.08 (dd, J = 8.4 Hz, 1H), 7.20~7.50 (m, 4H), 7.79 (d, J = 8.1 Hz, 1H), 8.75 (s, 1H).
<Example 18> {(±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}(piperidin-1-yl)methanone
The Example 13 compound was reacted according to the same procedure as Example 14 except for using piperidine instead of morpholine to give the title compound.
1H NMR (CDCl3, 200 MHz) δ 0.60~2.30 (m, 18H), 2.88~3.05 (m, 1H), 3.25~3.70 (m, 5H), 6.55 (d, J = 15.6 Hz, 1H), 6.68 (dd, J = 8.7, 15.6 Hz, 1H), 7.08 (dd, J = 8.4 Hz, 1H), 7.20~7.50 (m, 4H), 7.78 (dd, J = 1.8, 8.1 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H).
<Example 19> {(±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}(4-methylpiperazin-1-yl)methanone
The Example 13 compound was reacted according to the same procedure as Example 14 except for using N-methylpiperazine instead of morpholine to give the title compound.
1H NMR (CDCl3, 200 MHz) δ 0.60~2.50 (m, 14H), 2.25 (s, 3H), 2.86~3.40 (m, 1H), 3.36 (q, J = 8.4 Hz, 1H), 3.42~3.76 (m, 4H), 6.55 (d, J = 15.3 Hz, 1H), 6.68 (dd, J = 8.7, 15.6 Hz, 1H), 7.08 (dd, J = 9.0 Hz, 1H), 7.20~7.50 (m, 4H), 7.79(dd, J = 2.1, 8.1 Hz, 1H), 8.74 (d, J = 1.5 Hz, 1H).
<Example 20> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-N-(methylsulfonyl)octahydro-1H-indene-2-carboxamide
The Example 13 compound (50 mg, 0.137 mmol) was added to CH2Cl2 (5 mL), and methanesulfonamide (26 mg, 0.274 mmol), 4-N,N-dimethylaminopyridine (1.7 mg, 0.014 mmol) and 1-[3-(dimethylamino)propyl]-2-ethylcarbodiimide (32 mg, 0.164 mmol) were added thereto in the order at room temperature. After stirring for 2 h at room temperature, water was added to stop the reaction. The mixture was extracted with CH2Cl2. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate = 4:1) to give the title compound (34 mg, 56%).
1H-NMR (300 MHz, CDCl3) δ 1.10~1.80 (m, 9H), 1.85~2.30 (m, 3H), 2.70~2.88 (m, 1H), 3.07 (q, J = 9.0 Hz, 1H), 6.54 (d, J = 15.6 Hz, 1H), 6.66 (dd, J = 8.1, 15.3 Hz, 1H), 7.08 (dd, J = 8.4 Hz, 1H), 7.20~7.50 (m, 4H), 7.79 (dd, J = 2.7, 8.4 Hz, 1H), 8.75 (d, J = 2.1 Hz, 1H).
<Example 21> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-indene-2-carboxamide
The Example 13 compound (100 mg, 0.274 mmol) was reacted according to the same procedure as Example 14 except for using ammonia water instead of morpholine to give the title compound (75 mg, 75%).
1H-NMR (300 MHz, CDCl3) δ 1.10~2.25 (m, 12H), 2.55~2.73 (m, 1H), 2.82~3.00 (m, 1H), 3.00 (q, J = 9.0 Hz, 1H), 5.54 (brs, 1H), 5.66 (brs, 1H), 6.58 (d, J = 15.6 Hz, 1H), 6.71 (dd, J =8.7, 15.3 Hz, 1H), 7.06 (dd, J = 8.4 Hz, 1H), 7.20~7.50 (m, 4H), 7.80 (dd, J = 2.7, 8.4 Hz, 1H), 8.75 (d, J = 2.1 Hz, 1H).
<Example 22> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-indene-2-carbonitrile
The Example 21 compound (50 mg, 0.137 mmol) was added to CH2Cl2 (5 mL), and DMSO (0.017 mL, 0.233 mmol) and (COCl)2 (0.015 mL, 0.178 mmol) were added thereto at -78 ℃. After stirring for 15 min at -78 ℃, NEt3 (0.025 mL, 0.178 mmol) was added. After stirring for 1 h at -78 ℃, water was added to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to give the title compound (41 mg, 88%).
1H-NMR (300 MHz, CDCl3) δ 1.10~1.75 (m, 8H), 1.75~1.86 (m, 1H), 1.86~2.00 (m, 1H), 2.05~2.23 (m, 1H), 2.23~2.40 (m, 1H), 2.68~2.83 (m, 1H), 3.06 (q, J = 9.3 Hz, 1H), 6.60 (d, J = 15.6 Hz, 1H), 6.68 (d, J = 15.3 Hz, 1H), 7.10 (dd, J = 8.1 Hz, 1H), 7.20~7.50 (m, 4H), 7.83 (dd, J = 2.1, 7.8 Hz, 1H), 8.77 (d, J = 2.1 Hz, 1H)
<Example 23> (±)-(1S,2S,3aR,7aR)-methyl-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-indene-2-carboxylate
The Example 13 compound (100mg, 0.274 mmol) was dissolved in methanol (5 mL), and 4 drops of conc. hydrochloric acid was added thereto. After stirring for 6 h at room temperature, aqueous NaHCO3 solution was added to stop the reaction. The mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to give the title compound (97 mg, 93%).
1H-NMR (300 MHz, CDCl3) δ 1.10~1.80 (m, 9H), 1.86~2.32 (m, 3H), 2.70~2.86 (m, 1H), 3.07 (q, J = 9.0 Hz, 1H), 3.68 (s, 3H), 6.54 (d, J = 15.3 Hz, 1H), 6.68 (dd, J = 8.7, 15.6 Hz, 1H), 7.09 (dd, J = 8.4 Hz, 1H), 7.20~7.50 (m, 4H), 7.81 (d, J = 8.1 Hz, 1H), 8.76 (s, 1H).
<Example 24> (±)-(1S,2S,3aR,7aR)-ethyl-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-indene-2-carboxylate
The Example 13 compound was reacted according to the same procedure as Example 23 except for using ethanol instead of methanol to give the title compound.
1H-NMR (300 MHz, CDCl3) δ1.23 (t, J = 7.2 Hz, 3H), 1.25~1.80 (m, 9H), 1.85~2.25 (m, 3H), 2.70~2.85(m, 1H), 3.06 (q, J = 9.0 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 6.54(d, J = 15.6 Hz, 1H), 6.66 (dd, J = 8.1, 15.3 Hz, 1H), 7.08 (dd, J = 8.4 Hz, 1H), 7.20~7.50 (m, 4H), 7.79 (dd, J = 2.4, 8.4 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H).
<Example 25> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-N-(2-hydroxyethyl)octahydro-1H-indene-2-carboxamide
The Example 13 compound (20 mg, 0.055 mmol) was reacted according to the same procedure as Example 14 except for using 2-aminoethanol (0.007 mL, 0.109 mmol) instead of morpholine to give the title compound (20 mg, 90%).
1H-NMR (300 MHz, CDCl3) δ 1.15~2.20 (m, 12H), 2.42~2.60 (m, 1H), 2.88~3.06 (m, 1H), 3.20~3.38 (m, 1H), 3.43~3.60 (m, 1H), 3.60~3.80 (m, 2H), 6.12 (brt, 1H), 6.50~6.66 (m, 2H), 7.09 (dd, J = 9.3Hz, 1H), 7.20~7.50 (m, 4H), 7.81 (dd, J = 2.4, 8.4 Hz, 1H), 8.72 (d, J = 2.1 Hz, 1H).
<Example 26> 2-{(±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-4,5-dihydrooxazole
The Example 25 compound (20 mg, 0.049 mmol) was added to CH2Cl2 (2 mL), and diethylaminosulfur trifluoride (0.007 mL, 0.054 mmol) and K2CO3 (14 mg, 0.098 mmol) were added at -78 ℃. The reaction mixture was slowly warmed to room temperature and stirred for further 4 h. Water was added to stop the reaction, and the mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound (17 mg, 89%).
1H-NMR (300 MHz, CDCl3) δ 1.05~1.80 (m, 9H), 1.80~2.27 (m, 3H), 2.70~2.85 (m, 1H), 3.0 (m, 1H), 3.05 (q, J = 9.3 Hz, 1H), 3.83 (t, J = 9.3 Hz, 2H), 4.24 (t, J = 9.3 Hz, H), 6.63 (d, J = 15.6 Hz, 1H), 6.66 (dd, J = 7.8, 15.3 Hz, 1H), 7.06 (dd, J = 8.1 Hz, 1H), 7.20~7.50 (m, 4H), 7.79 (d, J = 5.7 Hz, 1H), 8.75 (s, 1H).
<Example 27> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-N-hydroxyoctahydro-1H-indene-2-carboxamide
The Example 13 compound was reacted according to the same procedure as Example 14 except for using hydroxylamine instead of morpholine to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 1.00~2.25 (m, 12H), 2.43~2.65 (m, 1H), 2.95 (q, J = 9.6 Hz, 1H), 6.44(d, J = 15.6 Hz, 1H), 6.55 (dd, J = 8.4, 15.3 Hz, 1H), 7.07 (dd, J = 8.4 Hz, 1H), 7.10~7.50 (m, 4H), 7.74 (dd, J = 2.1, 7.8 Hz, 1H), 8.66 (d, J = 1.8 Hz, 1H), 9.37 (brs, 1H).
<Example 28> (±)-5-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-1,2,4-oxadiazole
The Example 21 compound (20 mg, 0.055 mmol) was added to dimethylformamide dimethylacetal (2 mL), which was refluxed for 3 h. After concentration under reduced pressure, the residue was dissolved in dioxane (2 mL), to which were added hydroxylamine hydrochloride (11 mg, 0.164 mmol), 2N NaOH (5 drops) and acetic acid (7 drops). After heating under reflux for 4 h, the mixture was concentrated under reduced pressure. To the residue was added aqueous NaHCO3 solution, which was then extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1 → 2:1) to give the title compound (13 mg, 59%).
1H-NMR (300 MHz, CDCl3) δ 1.10~2.23 (m, 12H), 2.60~2.80( m, 1H), 2.96 (m, J = 9.3 Hz, 1H), 6.60 (d, J = 15.3 Hz, 1H), 6.68 (dd, J = 8.4, 15.3 Hz, 1H), 7.07 (dd, J = 8.7 Hz, 1H), 7.20~7.50 (m, 4H), 7.69 (d, J = 9.6 Hz, 1H), 7.76 (dd, J = 2.4, 8.1 Hz, 1H), 8.55~8.75 (m, 2H), 9.42 (brs, 1H).
<Example 29> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-indene-2-amine
The Example 13 compound (200 mg, 0.547 mmol), diphenylphosphoyl azide (0.59 mL, 2.735 mmol) and NEt3 (0.38 mL, 2.735 mmol) were added to benzene (5 mL), and the mixture was heated under reflux for 1 h. After consumption of the starting material was confirmed by thin layer chromatography, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane = 5:1:2) to give an isocyanate. This isocyanate (30 mg) and NaOH (3 equiv) were added to a solvent mixture of H2O/acetonitrile (1:1, 2 mL), which was then stirred for 2 h at room temperature. The mixture was concentrated under reduced pressure and purified by column chromatography (hexane:ethyl acetate:dichloromethane = 5:1:2 → dichloromethane:methanol = 10:1) to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 1.10~2.10 (m, 12H), 2.25~2.45 (m, 1H), 2.46 (brs, 2H), 3.21 (q, J = 7.5 Hz, 1H), 6.50~6.70 (m, 2H), 7.02~7.14 (m, 1H), 7.20~7.30 (m, 1H), 7.30~7.48 (m, 3H), 7.79 (dd, J = 2.4, 8.1 Hz, 1H), 8.74 (d, J = 2.1Hz, 1H).
<Example 30> (±)-Methyl(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-ylcarbamate
The Example 13 compound (30 mg, 0.082 mmol), diphenylphosphoryl azide (3 equiv) and NEt3 (3.5 equiv) were added to benzene (2 mL), which was then heated under reflux for 1 h. After consumption of the starting material was confirmed by thin layer chromatography, methanol (0.5 mL) was added at room temperature and heated under reflux again. After 16 h, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane = 7:1:2 → 5:1:2) to give the title compound (32 mg, 100%).
1H-NMR (300 MHz, CDCl3) δ 1.20~1.80 (m, 9H), 1.82~1.98 (m, 1H), 1.98~2.13 (m, 1H), 2.33~2.65 (m, 2H), 3.62 (s, 3H), 3.85~4.05 (m, 1H), 4.65~4.88 (brs, 1H), 6.54 (d, J = 15.9 Hz, 1H), 6.62 (dd, J = 7.8, 15.9 Hz, 1H), 7.03~7.15 (m, 1H), 7.24~7.31 (m, 1H), 7.32~7.48 (m, 3H), 7.80 (dd, J = 2.4, 8.2 Hz, 1H), 8.75 (d, J = 2.3 Hz, 1H).
<Example 31> (±)-Ethyl(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-ylcarbamate
The isocyanate (30 mg) obtained as an intermediate in Example 29 and Cs2CO3 (3 equiv) were added to ethanol (2 mL) and stirred for 2 h at room temperature. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane = 5:1:2) to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 1.20 (t, J = 7.1 Hz, 3H), 1.20~1.77 (m, 9H), 1.85~1.97 (m, 1H), 1.97~2.11 (m, 1H), 2.33~2.61 (m, 2H), 3.84~4.04 (m, 1H), 4.06 (q, J = 7.1 Hz, 2H), 4.64~4.81 (brs, 1H), 6.54 (d, J = 15.6 Hz, 1H), 6.63 (dd, J = 7.6, 15.7 Hz, 1H), 7.03~7.13 (m, 1H), 7.22~7.32 (m, 1H), 7.32~7.50 (m, 3H), 7.80 (dd, J = 2.4, 8.2 Hz, 1H), 8.75 (d, J = 1.8 Hz, 1H).
<Example 32> (±)-t-Butyl-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-ylcarbamate
The Example 29 compound (23 mg, 0.07 mmol) was dissolved in anhydrous THF (1.5 mL), and di-t-butyl dicarbonate (0.02 mL, 0.08 mmol) and NEt3 (0.01 mL, 0.07 mmol) were added thereto. After stirring for 1.5 h, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane = 7:1:2) to give the title compound (25 mg, 0.06 mmol, Yield 82%).
1H-NMR (300 MHz, CDCl3) δ 1.56-1.83 (m, 8H), 1.65-1.62 (m, 2H), 2.03-1.89 (m, 2H), 2.50-2.37 (m, 2H), 3.94-3.89 (m, 1H), 4.62 (brs, 1H), 6.66-6.52 (m, 2H), 7.11-7.04 (m, 1H), 7.30-7.25 (m, 1H), 7.47-7.34 (m, 3H), 7.79 (dd, J = 2.4, 8.1 Hz, 1H), 8.75 (d, J = 1.8 Hz, 1H).
<Example 33> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(1H-tetrazol-5-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Example 22 compound (20 mg, 0.058 mmol) was dissolved in toluene (2 mL), and n-Bu3SnCl (0.049 mL, 0.182 mmol) and NaN3 (12 mg, 0.182 mmol) were added thereto. After reflux for 48 h, the mixture was cooled to room temperature and extracted with 1 N aqueous NaOH solution. The aqueous layer was acidified by 6 N HCl and extracted with ethyl acetate. The organic layer was dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1 → 1:1) to give the title compound (17 mg, 74%).
1H-NMR (300 MHz, DMSO-d6) δ= 1.10~2.60 (m, 12H), 2.80~3.60 (m, 2H), 6.42 (d, J = 15.9 Hz, 1H), 6.70 (dd, J = 8.4, 15.3 Hz, 1H), 7.23 (dd, J = 7.8 Hz, 1H), 7.40~7.67 (m, 4H), 8.04 (dd, J = 2.1, 8.4 Hz, 1H), 8.81 (d, J = 2.4 Hz, 1H).
<Example 34> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(1-methyl-1H-tetrazol-5-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Example 33 compound (15 mg, 0.038 mmol) was added to DMF (1 mL), and K2CO3 (10 mg, 0.075 mmol) and iodomethane (0.005 mL, 0.075 mmol) were added thereto. After stirring for 5 h, water was added and the mixture was extracted CH2Cl2. The organic layer was dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1 → 2:1) to give the title compound (6 mg, 40%).
1H-NMR (300 MHz, CDCl3) δ 1.10~1.85 (m, 8H), 1.85~2.53 (m, 4H), 3.16~3.29 (m, 1H), 3.38 (m, J = 8.7 Hz, 1H), 6.47 (d, J = 15.6 Hz, 1H), 6.73 (dd, J = 9.0, 15.3 Hz, 1H), 7.09 (dd, J = 8.4 Hz, 1H), 7.14~7.50 (m, 4H), 7.79 (d, J = 8.4 Hz, 1H), 8.74 (s, 1H).
<Example 35> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(2-methyl-2H-tetrazol-5-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
The same procedure as Example 34 was carried out to give the title compound (4 mg, 27%).
1H-NMR (300 MHz, CDCl3) δ 1.10~1.85 (m, 8H), 1.85~2.55 (m, 4H), 3.20 (m, J = 9.3 Hz, 1H), 3.35~3.50 (m, 1H), 4.29 (s, 3H), 6.47 (d, J = 15.6 Hz, 1H), 6.68 (dd, J = 8.7, 15.3 Hz, 1H), 7.07 (dd, J = 7.5 Hz, 1H), 7.20~7.50 (m, 4H), 7.77 (dd, J = 2.1, 8.4 Hz, 1H), 8.73 (d, J = 2.1 Hz, 1H).
<Example 36> (±)-3-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-5-methyl-1,2,4-oxadiazole
Figure PCTKR2011004607-appb-I000038
The Example 22 compound (20 mg, 0.058 mmol) was added to ethanol (8 mL), and hydroxylamine hydrochloride (8 mg, 0.115 mmol) and KOH (6 mg, 0.115 mmol) were added thereto. After reflux for 6 h, the mixture was cooled to room temperature. Water was added, which was then extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated under reduced pressure. To the residue was added dimethylformamide dimethylacetal (2 mL), which was then heated under reflux for 2 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to give the title compound (7 mg, 30%).
1H-NMR (300 MHz, CDCl3) δ 1.10~2.25 (m, 12H), 2.60~2.85 (m, 1H), 3.07 (m, J = 9.0 Hz, 1H), 6.58(d, J = 15.6 Hz, 1H), 6.68 (dd, J = 8.7, 15.6 Hz, 1H), 7.09 (dd, J = 9.9 Hz, 1H), 7.20~7.50 (m, 4H), 7.81 (dd, J = 2.1, 7.8 Hz, 1H), 7.87 (brs, 1H), 8.75 (d, J = 2.1 Hz, 1H).
<Example 37> (±)-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methanol
The Example 23 compound (97 mg, 0.256 mmol) was dissolved in THF (10 mL), and NaBH4 (97 mg, 2.56 mmol) was added thereto at room temperature. After stirring for 30 min, water (2 mL) was added. After stirring for 5 h at room temperature, aqueous NaHCO3 solution was added, which was then extracted with ethylacetate. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1 → 2:1) to give the title compound (76 mg, 84%).
1H-NMR (300 MHz, CDCl3) δ 1.10~1.70 (m, 10H), 1.83~2.21(m, 3H), 2.50 (q, J = 8.7 Hz, 1H), 3.60 (dd, J = 5.1, 16.2 Hz, 1H), 3.73 (dd, J = 5.1, 10.5 Hz, 1H), 6.53 (d, J = 15.6 Hz, 1H), 6.66 (dd, J = 8.7, 15.6 Hz, 1H), 7.08 (dd, J = 8.1 Hz, 1H), 7.20~7.50 (m, 4H), 7.79 (dd, J = 2.4, 8.4 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H).
<Example 38> (±)-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl acetate
The Example 37 compound (15 mg, 0.043 mmol) was added to CH2Cl2 (2 mL), and NEt3 (3 drops), dimethylaminopyridine (2 crystals) and acetic anhydride (2 drops) were added in the order at 0 ℃. The mixture was stirred for 1 h at room temperature, and water (2~3 drops) was added thereto. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to give the title compound (12 mg, 70%).
1H-NMR (300 MHz, CDCl3) δ 1.00~2.15 (m, 12H), 2.01 (s, 3H), 2.15~2.32 (m, 1H), 2.50 (q, J = 9.0Hz, 1H), 4.03 (dd, J = 6.6, 10.5 Hz, 1H), 4.18 (dd, J = 6.0, 10.8 Hz, 1H), 6.49 (d, J = 15.6 Hz, 1H), 6.62 (dd, J = 8.7, 15.6 Hz, 1H), 7.08 (dd, J = 8.4 Hz, 1H), 7.20~7.50 (m, 4H), 7.79 (dd, J = 2.4, 8.1 Hz, 1H), 8.75 (d, J = 1.8 Hz, 1H).
<Example 39> (±)-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl methanesulfonate
The Example 37 compound (5 mg, 0.014 mmol) was dissolved in CH2Cl2 (2 mL), and NEt3 (2 drops), dimethylaminopyridine (1 crystal) and methanesulfonyl chloride (1 drop) were added in the order at 0 ℃. The mixture was stirred for 1 h at room temperature, and water (2~3 drops) was added thereto. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to give the title compound (3 mg, 50%).
1H-NMR (300 MHz, CDCl3) δ 1.10~1.70 (m, 9H), 1.82~2.40 (m, 4H), 2.53 (q, J = 8.7 Hz, 1H), 2.99 (s, 3H), 4.20 (dd, J = 6.6, 9.3 Hz, 1H), 4.29 (dd, J = 4.8, 9.3 Hz, 1H), 6.53 (d, J = 15.3 Hz, 1H), 6.62 (dd, J = 8.7, 16.2 Hz, 1H), 7.09 (dd, J = 8.1 Hz, 1H), 7.20~7.50 (m, 4H), 7.81 (dd, J = 2.4, 8.1 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H).
<Example 40> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(methoxymethyl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Example 37 compound (7 mg, 0.020 mmol) was added to THF/DMF (1:1, 2 mL), and K2CO3 (8 mg, 0.060 mmol) and iodomethane (0.004 mL, 0.006 mmol) were added thereto. After stirring for 2 h at 50 ℃, water was added, which was then extracted with CH2Cl2. The organic layer was dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to give the title compound (5 mg, 71%).
1H-NMR (300 MHz, CDCl3) δ 1.10~1.75 (m, 10H), 1.80~2.25 (m, 3H), 2.43 (q, J = 9.0 Hz, 1H), 3.29 (dd, J = 7.5, 9.0 Hz, 1H), 3.33 (s, 3H), 3.47 (dd, J = 4.5, 9.0 Hz, 1H), 6.49 (d, J = 15.6 Hz, 1H), 6.63 (dd, J = 8.7, 15.6 Hz, 1H), 7.08 (dd, J = 8.4 Hz, 1H), 7.20~7.50 (m, 4H), 7.79 (dd, J = 2.4, 8.4 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H).
Figure PCTKR2011004607-appb-I000039
<Example 41> (±)-O-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl dimethylcarbothiolate
The Example 39 compound (20 mg, 0.057 mmol) was dissolved in CH2Cl2 (3 mL), and dimethylaminopyridine (1 mg, 0.006 mmol) and 1,1-thiocarbonyl diimidazole (11 mg, 0.063 mmol) were added thereto. After stirring for 4 h at room temperature, the mixture was filtered through a silica gel pad. The filtrate was washed with ethyl acetate. The filtrate was distilled under reduced pressure and the residue was dissolved in THF (1 mL) again, to which was added dimethylamine (2 M THF solution, 1 mL). After 30 min, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to give the title compound (19 mg, 76%).
1H-NMR (300 MHz, CDCl3) δ 1.10~1.77 (m, 9H), 1.82~2.20 (m, 3H), 2.28~2.45 (m, 1H), 2.56 (q, J = 9.0 Hz, 1H), 3.01 (s, 3H), 3.31 (s, 3H), 4.38~4.56 (m, 2H), 6.49 (d, J = 15.6 Hz, 1H), 6.65 (dd, J = 9.0, 15.6 Hz, 1H), 7.08 (dd, J = 8.7 Hz, 1H), 7.20~7.50 (m, 4H), 7.79 (dd, J = 2.1, 8.1 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H).
<Example 42> (±)-O-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl carbothiolate
The same procedure as Example 41 was carried out except for using ammonia water instead of dimethylamine to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 1.10~1.80 (m, 9H), 1.82~2.20 (m, 3H), 2.23~2.43 (m, 1H), 2.55 (q, J = 8.7 Hz, 1H), 4.38~4.54 (m, 2H), 6.18 (brs, 1H), 6.36 (brs, 1H), 6.52 (d, J = 15.6 Hz, 1H), 6.61 (dd, J = 7.8, 15.3 Hz, 1H), 7.08 (dd, J = 8.4 Hz, 1H), 7.20~7.50 (m, 4H), 7.80 (dd, J = 2.4, 8.1 Hz, 1H), 8.73 (d, J = 2.4 Hz, 1H).
<Example 43> (±)-O-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl methylcarbothiolate
The same procedure as Example 41 was carried out except for using methylamine instead of dimethylamine to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 0.88~2.20 (m, 12H), 2.22~2.47 (m, 1H), 2.47~2.66 (m, 1H), 2.78, 3.04 (d, J = 5.1 Hz, 3H), 4.46 (dd, J = 1.2, 6.6 Hz, 1.3H), 4.52 (dd, J = 2.7, 6.6 Hz, 0.7H), 6.35 (brs, 1H), 6.43~6.72 (m, 2H), 7.08 (dd, J = 8.7 Hz, 1H), 7.20~7.50 (m, 4H), 7.75~7.85 (m, 1H), 8.74 (d, J = 1.8 Hz, 1H).
Figure PCTKR2011004607-appb-I000040
<Example 44> (±)-1-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-3-methylurea
The Example 13 compound (20 mg, 0.055mmol), diphenylphosphoryl azide (0.035 mL, 0.164 mmol) and NEt3 (0.028 mL, 0.164 mmol) were added to benzene (2 mL), which was then heated under reflux for 2 h. After consumption of the starting material was confirmed by thin layer chromatography, methylamine was added at 0 ℃. After the mixture was further heated under reflux for 2 h, it was cooled to room temperature. Water was added, and the mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1 → 1:4) to give the title compound(18 mg, 82%).
1H-NMR (300 MHz, CDCl3) δ 1.15~2.18 (m, 9H), 2.36~2.60 (m, 2H), 2.73, 2.80 (d, J = 4.8 Hz, 3H), 3.84~4.04 (m, 1H), 4.26~4.42 (m, 1H), 4.53 (d, J = 4.5 Hz, 1H), 6.55 (d, J = 15.6 Hz, 1H), 6.64 (dd, J = 8.1, 15.9 Hz, 1H), 7.09 (dd, J = 8.4 Hz, 1H), 7.20~7.50 (m, 4H), 7.80 (dd, J = 2.4, 8.1 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H).
<Example 45> (±)-3-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-1,1-dimethylurea
The same procedure as Example 44 was carried out except for using dimethylamine instead of methylamine to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 1.18-1.66 (m, 9H), 1.91-1.95 (m, 1H), 2.44-2.60 (m, 2H), 2.87 (s, 6H), 4.05-4.15 (m, 1H), 4.43 (d, J = 6.9 Hz, 1H), 6.54-6.66 (m, 2H), 7.05-7.11 (m, 1H), 7.26-7.29 (m, 1H), 7.34-7.37 (m, 1H), 7.40-7.47 (m, 2H), 7.80 (dd, J = 2.4, 8.1 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H).
<Example 46> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(4,5-dihydro-1H-imidazole-2-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000041
(COCl)2 (0.014 mL, 0.171 mmol) was dissolved in CH2Cl2 (2 mL), and DMSO (0.022 mL, 0.312 mmol) was slowly added thereto at -78 ℃. After 5 min, the Example 37 compound (50 mg, 0.142 mmol) dissolved in CH2Cl2 (1 mL) was slowly added thereto. After 10 min, NEt3 (0.099 mL, 0.710 mmol) was added. Water was added, and the mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4. The filtrate was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (8 mL), and ethylenediamine (0.005 mL, 0.078 mmol) and N-bromosuccinimide (14 mg, 0.078 mmol) were added thereto. After stirring for 16 h at room temperature, aqueous NaHCO3 solution was added, which was then extracted with CH2Cl2. The organic layer was dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (dichloromethane:methanol = 10:1) to give the title compound (39 mg, 71%).
1H-NMR (300 MHz, CDCl3) δ 1.10~2.50 (m, 12H), 2.70 (q, J = 9.3 Hz, 1H), 2.91 (q, J = 9.0 Hz, 1H), 3.58 (s, 4H), 6.59 (d, J = 15.6 Hz, 1H), 6.70 (dd, J = 8.4, 15.3 Hz, 1H), 7.09 (dd, J = 8.4 Hz, 1H), 7.20~7.50 (m, 4H), 7.81 (dd, J = 2.1, 7.8 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H).
Figure PCTKR2011004607-appb-I000042
<Example 47> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methanesulfonamide
The Example 29 compound (53 mg, 0.16 mmol) was dissolved in anhydrous CH2Cl2, and methanesulfonyl chloride (0.02 mL, 0.24 mmol) and dimethylaminopyridine (2 mg, 0.02 mmol) were added thereto. The mixture was stirred for 2 h at room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane =3:1:2) to give the title compound (41 mg, Yield 62%).
1H-NMR (300 MHz, CDCl3) δ 1.22-1.67 (m, 8H), 1.89-2.05 (m, 2H), 2.43-2.58 (m, 2H), 2.92 (s, 3H), 3.74 (q, J = 7.8 Hz, 1H), 4.37 (d, J = 8.1 Hz, 1H), 6.57-6.69 (m, 2H), 7.06-7.13 (m, 1H), 7.25-7.30 (m, 1H), 7.34-7.37 (m, 2H), 7.41-7.48 (m, 1H), 7.81 (d, J = 2.4, 8.1 Hz, 1H), 8.76 (d, J = 2.1 Hz, 1H).
<Example 48> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}acetamide
The Example 29 compound (10 mg, 0.030 mmol) was dissolved in CH2Cl2 (2 mL), and NEt3 (0.008 mL, 0.059 mmol) and acetic anhydride (0.004 mL, 0.039 mmol) were added thereto at 0 ℃. After stirring for 1 h at room temperature, water was added, which was then extracted with CH2Cl2. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound (7 mg, 64%).
1H-NMR (300 MHz, CDCl3) δ 1.05~2.20 (m, 11H), 1.95 (s, 3H), 2.35~2.65 (m, 2H), 4.15~4.35 (m, 1H), 5.74 (d, J = 8.1 Hz, 1H), 6.53~6.70 (m, 2H), 7.08 (dd, J = 8.4 Hz, 1H), 7.20~7.50 (m, 4H), 7.80(dd, J = 2.4, 8.1 Hz, 1H), 8.74 (d, J = 1.8 Hz, 1H),
<Example 49> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-N-methylacetamide
The Example 48 compound was dissolved in THF (3 mL), and NaH (60% in oil, 4 mg, 0.100 mmol) and iodomethane (0.006 mL, 0.100 mmol) were added thereto. After stirring for 16 h at room temperature, water was added, which was then extracted with CH2Cl2. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1 → 1:1) to give the title compound (10 mg, 50%).
1H-NMR (300 MHz, CDCl3) δ 0.80~2.30 (m, 10H), 2.09(s, 3H), 2.70~2.90 (m, 2H), 2.95 (s, 3H), 4.11 (q, J = 9.0 Hz, 1H), 5.02 (q, J = 10.5 Hz, 1H), 6.40~6.66 (m, 2H), 7.09 (dd, J = 8.1 Hz, 1H), 7.20~7.50 (m, 4H), 7.73~7.86 (m, 1H), 8.74 (d, J = 2.4 Hz, 1H).
<Example 50> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}cyclopropanecarboxamide
The Example 29 compound (3 mg, 0.009 mmol) was dissolved in CH2Cl2 (2 mL), and NEt3 (0.002 mL, 0.018 mmol) and cyclopropanecarbonyl chloride (0.001 mL, 0.012 mmol) were added thereto at 0 ℃. After stirring for 1 h at room temperature, water was added, which was then extracted with CH2Cl2. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1 → 2:1) to give the title compound (2.7 mg, 75%).
1H-NMR (300 MHz, CDCl3) δ 0.60~2.20 (m, 16H), 2.40~2.66 (m, 2H), 4.10~4.30 (m, 1H), 5.70 (d, J = 7.5 Hz, 1H), 6.50~6.70 (m, 2H), 7.09 (dd, J = 8.1 Hz, 1H), 7.20~7.50 (m, 4H), 7.80 (dd, J = 2.4, 8.1 Hz, 1H), 8.74 (d, J = 1.8 Hz, 1H).
<Example 51> (±)-O-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl acetyl(methyl)carbothiolate
Figure PCTKR2011004607-appb-I000043
The Example 43 compound was reacted according to the same procedure as Example 48 to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 1.00~1.80 (m, 9H), 1.85~2.60 (m, 5H), 2.47 (s, 3H), 3.46 (s, 3H), 4.45 (dd, J = 9.0, 10.5 Hz, 1H), 4.65 (dd, J = 5.1, 10.8 Hz, 1H), 6.51 (d, J = 15.3 Hz, 1H), 6.65 (dd, J = 8.7, 15.6 Hz, 1H), 7.09 (dd, J = 8.4 Hz, 1H), 7.20~7.50 (m, 4H), 7.81 (dd, J = 2.4, 8.1 Hz, 1H), 8.75 (d, J = 2.1 Hz, 1H).
Figure PCTKR2011004607-appb-I000044
<Example 52> (±)-4-{[(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl]methyl}morpholine
The Example 39 compound (13 mg, 0.03 mmol) was dissolved in CH3CN (1.5 mL). Morpholine (0.005 mL, 0.06 mmol) and K2CO3 (0.008 mg, 0.06 mmol) were added thereto and refluxed for 48 h. After the mixture was cooled to room temperature, it was concentrated under reduced pressure to remove the organic solvent. The residue was purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane =3:1:2) to give the title compound (12 mg, Yield 95%).
1H-NMR (300 MHz, CDCl3) δ 0.86-1.68 (m, 7H), 1.88-1.92 (m, 1H), 1.88-2.07 (m, 4H), 2.29-2.52 (m, 8H), 3.66 (t, J = 4.8 Hz, 4H), 6.58-6.66 (m, 1H), 7.06-7.11 (m, 1H), 7.29-7.37 (m, 3H), 7.40-7.47 (m, 1H), 7.80 (dd, J = 2.4, 8.4 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H).
<Example 53> (±)-1-{{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl}-1H-imidazole
The same procedure as Example 52 was carried out except for using imidazole instead of morpholine to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 0.80~2.20 (m, 12H), 2.20~2.40 (m, 1H), 2.41 (q, J = 9.6 Hz, 1H), 3.88 (dd, J = 8.4, 13.8 Hz, 1H), 4.07 (dd, J = 5.4, 13.8 Hz, 1H), 6.44 (d, J = 15.6 Hz, 1H), 6.56 (dd, J = 8.7, 15.6 Hz, 1H), 6.92 (s, 1H), 7.01 (s, 1H), 7.09 (dd, J = 8.4 Hz, 1H), 7.20~7.50 (m, 4H), 7.50 (s, 1H), 7.81 (dd, J = 2.1, 8.1 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H).
<Example 54> (±)-N-{{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl}methanesulfonamide
The same procedure as Example 52 was carried out except for using methanesulfonamide instead of morpholine to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 1.05~1.73 (m, 9H), 1.85~2.23 (m, 3H), 2.44 (q, J = 9.0 Hz, 1H), 2.94 (s, 3H), 3.08~3.34 (m, 2H), 4.25 (t, J = 6.6 Hz, 1H), 6.54 (d, J = 15.6 Hz, 1H), 6.63 (dd, J = 8.1, 15.6 Hz, 1H), 7.09 (dd, J = 8.4 Hz, 1H), 7.20~7.50 (m, 4H), 7.80 (dd, J = 2.1, 8.1 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H).
<Example 55> (±)-N-{{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl}-N-methylmethanesulfonamide
The same procedure as Example 52 was carried out except for using N-methylmethanesulfonamide instead of morpholine to give the title compound.
1H NMR (CDCl3, 200 MHz) δ1.12~1.75 (m, 9H), 1.86~2.28 (m, 3H), 2.45 (q, J = 9.0 Hz, 1H), 2.76 (s, 3H), 2.79 (s, 3H), 3.13 (dd, J = 6.3, 12.9 Hz, 1H), 3.21 (dd, J = 9.0, 12.6 Hz, 1H), 6.53 (d, J = 15.6 Hz, 1H), 6.64 (dd, J = 8.7, 15.6 Hz, 1H), 7.09 (dd, J = 8.4 Hz, 1H), 7.20~7.50 (m, 4H), 7.80 (dd, J = 2.4, 8.1 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H).
<Example 56> (±)-N-{{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl}sultam
The same procedure as Example 52 was carried out except for using sultam instead of morpholine to give the title compound.
1H NMR (CDCl3, 200 MHz) δ1.10~1.80 (m, 9H), 1.82~2.35 (m, 6H), 2.46 (q, J = 8.4 Hz, 1H), 2.96~3.28 (m, 6H), 6.53 (d, J = 15.3 Hz, 1H), 6.64 (dd, J = 8.7, 15.6 Hz, 1H), 7.09 (dd, J = 8.4 Hz, 1H), 7.20~7.50 (m, 4H), 7.80 (dd, J = 2.7, 8.4 Hz, 1H), 8.75 (d, J = 2.1 Hz, 1H).
<Example 57> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(pyrrolidin-1-ylmethyl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
The same procedure as Example 52 was carried out except for using pyrrolidine instead of morpholine to give the title compound.
1H NMR (CDCl3, 200 MHz) δ1.10~2.20 (m, 16H), 2.31 (q, J = 8.7 Hz, 1H), 2.38~2.63 (m, 7H), 6.49 (d, J = 15.3 Hz, 1H), 6.62(dd, J = 8.7, 15.6 Hz, 1H), 7.08 (dd, J = 8.4 Hz, 1H), 7.20~7.50 (m, 4H), 7.79 (dd, J = 2.4, 8.4 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H).
<Example 58> (±)-1-{{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl}-1H-2-methylimidazole
The same procedure as Example 52 was carried out except for using 2-methylimidazole instead of morpholine to give the title compound.
1H NMR (CDCl3, 200 MHz) δ 1.15-1.64 (m, 11H), 1.90-2.05 (m, 3H), 2.43-2.48 (m, 5H), 3.77 (dd, J = 9.0, 13.8 Hz, 1H), 3.98 (dd, J = 5.7, 13.8 Hz, 1H), 6.42 (d, J = 15.6 Hz, 1H), 6.50-6.58 (m, 1H), 6.84 (d, J = 5.1 Hz, 2H), 7.06-7.12 (m, 1H), 7.28-7.30 (m, 2H), 7.36 (m, 1H), 7.41-7.48 (m, 1H), 7.80 (dd, J = 2.4, 8.1 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H).
<Example 59> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(1H-imidazole-2-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000045
The Example 46 compound (10 mg, 0.026 mmol) was dissolved in DMSO (1 mL). Di(acetoxy)iodobenzene (9 mg, 0.028 mmol) and K2CO3 (4 mg, 0.028 mmol) were added thereto and stirred for 16 h at room temperature. Aqueous NaHCO3 solution was added, which was then extracted with ethyl acetate. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title compound (5 mg, 50%).
1H-NMR (300 MHz, CDCl3) δ 1.00~2.43 (m, 12H), 2.96 (q, J = 9.3 Hz, 1H), 3.17 (q, J = 9.6 Hz, 1H), 6.50 (d, J = 15.6 Hz, 1H), 6.77 (dd, J = 9.3, 15.3 Hz, 1H), 6.95 (brs, 1H), 7.10(dd, J = 8.1 Hz, 1H), 7.20~7.50 (m, 6H), 7.81 (dd, J = 2.1, 7.8 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H).
<Example 60> (±)-2-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-5-methyl-1,3,4-oxadiazole
Figure PCTKR2011004607-appb-I000046
The Example 13 compound (10 mg, 0.027 mmol) was added to CH2Cl2 (2 mL). (COCl)2 (0.005 mL, 0.055 mmol) and DMF (1 drop) were added thereto at 0 ℃. After stirring for 2 h at room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in anhydrous CH2Cl2 (2 mL) again. Hydrazine (0.004 mL, 0.082 mmol) was added at 0 ℃ and stirred for 30 min at room temperature. Water was added to stop the reaction, which was then extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was added to ethanol (5 mL), to which were added acetic anhydride (0.006 mL, 0.052 mmol) and NEt3 (0.007 mL, 0.052 mmol). After the mixture was heated under reflux for 16 h, water was added to stop the reaction. The mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give carbohydrazide, which was then dissolved in polyphosphoric acid (0.2 mL) and heated for 1 h at 120 ℃. Aqueous NaHCO3 solution was carefully added, which was then extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1 → 2:1) to give the title compound (2 mg, 26%).
1H-NMR (300 MHz, CDCl3) δ 1.00~2.45 (m, 12H), 2.50 (s, 3H), 3.18 (q, J = 9.3 Hz, 1H), 3.25~3.40 (m, 1H), 6.54 (d, J = 15.6 Hz, 1H), 6.69 (dd, J = 8.4, 15.6 Hz, 1H), 7.08 (dd, J = 9.0 Hz, 1H), 7.20~7.50 (m, 4H), 7.79 (dd, J = 2.1, 8.1 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H).
<Example 61> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-N-methylmethanesulfonamide
Figure PCTKR2011004607-appb-I000047
The Example 47 compound (24 mg, 0.06 mmol) was dissolved in acetone (2 mL), to which were added K2CO3 (16 mg, 0.12 mmol) and iodomethane (0.006 mL, 0.09 mmol). After heating under reflux for 2 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane = 5:1:2) to give the title compound (3.2 mg, Yield 13%).
1H-NMR (300 MHz, CDCl3) δ 1.22-1.68 (m, 8H), 1.87-1.93 (m, 1H), 2.06 (m, 1H), 2.21 (m, 1H), 2.76 (s, 3H), 2.78-2.86 (m, 2H), 3.90 (s, 3H), 4.25-4.35 (m, 1H), 7.06-7.12 (m, 1H), 7.27 (m, 1H), 7.35-7.48 (m, 3H), 7.80 (dd, J = 2.4, 8.4 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H).
Figure PCTKR2011004607-appb-I000048
<Example 62> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-ol
(Step 1) (±)-(1R,3aR,7aR)-1-[(t-butyldimethylsilyloxy)methyl]hexahydro-1H-inden-2(3H)-one
In anhydrous DMF (50 mL) was dissolved (±)-(1R,3aR,7aR)-1-(hydroxymethyl)hexahydro-1H-inden-2(3H)-one (3.0 g, 0.018 mol). t-Butylchlorodimethylsilane (4.03 g, 0.027 mol) and imidazole (2.67 g, 0.039 mol) were added thereto, stirred for 2 h at room temperature, extracted with CH2Cl2 and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the title compound (4.5 g, 0.016 mol).
1H-NMR (300 MHz, CDCl3) δ 0.01(s, 6H), 0.83 (s, 9H), 1.00~1.31 (m, 3H), 1.50~1.76 (m, 5H), 2.02~2.22 (m, 4H), 2.44~2.47 (m, 2H), 3.63~3.94 (m, 2H).
(Step 2) (±)-(1R,3aR,7aR)-1-[(t-butyldimethylsilyloxy)methyl]-2-methyloctahydro-1H-inden-2-ol
The Step 1 compound (0.5 g, 1.77 mmol) was dissolved in anhydrous ether (20 mL), and methyl lithium (1.6 M ether solution, 1.77 mL 2.83 mmol) was added at -20 ℃. The mixture was stirred for 1 h, extracted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate = 30:1) to give the title compound (0.180 g, 0.603 mmol).
1H-NMR (300 MHz, CDCl3) δ 0.08 (s, 6H), 0.96 (s, 9H), 1.25~2.17 (m, 15H), 3.34 (s, 1H), 3.72~3.90 (m, 2H).
(Step 3) (±)-(1R,3aR,7aR)-1-(hydroxymethyl)-2-methyloctahydro-1H-inden-2-ol
The Step 2 compound (0.18 g, 0.603 mmol) was dissolved in anhydrous THF (10 mL), and tetrabutylammonium fluoride (1.0 M THF solution, 2.83 mmol) was added at -40 ℃. The mixture was stirred for 2 h at room temperature, extracted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (CH2Cl2:MeOH = 20:1) to give the title compound (0.110 g, 0.543 mmol).
1H-NMR (300 MHz, CDCl3) δ 1.22 (s, 3H), 1.24~2.07 (m, 12H), 3.55~3.70 (m, 2H), 4.86 (s, 2H).
(Step 4) (±)-(1S,3aR,7aR)-2-hydroxy-2-methyloctahydro-1H-indene-1-carbaldehyde
The Step 3 compound (0.1 g, 0.543 mmol) was reacted according to the same procedure as Step 10 of Preparation 3 to give the title compound (0.070 g, Yield 71%).
1H-NMR (300 MHz, CDCl3) δ 1.18~1.76 (m, 13H), 1.87~2.03 (m, 2H), 2.35~2.42 (m, 2H), 2.88 (dd, 1H, J = 1.5, 1.8 Hz), 9.77 (s, 1H).
(Step 5) (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-ol
The Preparation 15 compound and the Step 4 compound (0.070 mg, 0.384 mmol) were reacted according to the same procedure as Example 1 to give the title compound (40 mg, Yield 29%) as a more nonpolar isomer.
1H-NMR (300 MHz, CDCl3) δ 1.12~1.34 (m, 3H), 1.37 (s, 3H), 1.42~1.62 (m, 5H), 1.81~2.54 (m, 5H), 6.57~6.78 (m, 2H), 7.04~7.10 (m, 1H), 7.23~7.46 (m, 4H), 7.89 (dd, J = 2.4 Hz, 1H), 8.73 (d, J = 2.4 Hz, 1H).
<Example 63> (±)-(1S,2R,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-ol
The same procedure as Example 62 was carried out to give the title compound (15 mg, Yield 11%) as a more polar isomer.
1H-NMR (300 MHz, CDCl3) δ 1.28 (s, 3H), 1.35~1.74 (m, 10H), 1.91~2.08 (m, 3H), 2.82~2.89 (m, 1H), 6.55~6.70 (m, 2H), 7.05~7.11 (m, 1H), 7.25~7.47 (m, 4H), 7.81 (d, 1H, J=28 Hz), 8.76 (s, 1H).
<Example 64> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-methoxy-2-methyloctahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Example 62 compound (0.024 g, 0.068 mmol) was dissolved in anhydrous DMF (50 mL) and NaH (0.003 g, 0.082 mmol) and CH3I (0.0046 mL, 0.075 mmol) were added thereto at 0 ℃. The mixture was stirred for 12 h at room temperature, extracted with CH2Cl2 and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography(hexane:ethyl acetate=10:1) to give the title compound (1.00 mg 0.003mmol).
1H-NMR (300 MHz, CDCl3) δ 1.10~1.63 (m, 9H), 1.28 (s, 3H), 2.04~2.49( m, 4H), 3.16 (s, 3H), 6.50~6.80 (m, 2H), 7.07~7.10 (m, 1H), 7.24~7.48 (m, 4H), 7.79 (dd, 1H, J = 2.4, 2.1 Hz), 8.75(d, J = 2.4 Hz, 1H)
<Example 65> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-ylcarbamate
The Example 62 compound (0.05 g, 0.142 mmol) was dissolved in anhydrous THF (5 mL), to which was added trichloroacetyl isocyanate (0.033 mL, 0.284 mmol). The mixture was stirred for 2 h at room temperature, from which volatile substances were removed under reduced pressure. Methanol (2 mL), H2O (0.1 mL) and K2CO3 (0.038 g, 0.245 mmol) were added thereto. After completion of the reaction, the mixture was extracted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to give the title compound (0.052 g, 0.132 mmol).
1H-NMR (300 MHz, CDCl3) δ 1.10~1.63 (m, 9H), 1.64 (s, 3H), 2.04~2.79 (m, 4H), 4.74 (s, 2H), 6.52~6.83 (m, 2H), 7.04~7.11 (m, 1H), 7.24~7.47 (m, 4H), 7.80 (dd, 1H, J = 2.4 Hz), 8.76 (d, J = 1.8 Hz, 1H).
Figure PCTKR2011004607-appb-I000049
<Example 66> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-indene-2-carboxylic acid
Diisopropylamine (0.077mL, 0.550 mmol) was dissolved in THF (2 mL) and n-BuLi (2.5 M hexane solution, 0.2 mL, 0.500 mmol) was added at 0 ℃ to prepare lithium diisopropylamide. After 20 min, a solution of the Example 23 compound (95 mg, 0.250mmol) in THF (2 mL) was slowly added in drops to the lithium diisopropylamide solution at -78 ℃. After the reaction temperature was raised to 0 ℃, iodomethane (0.031 mL, 0.500 mmol) was added. After stirring for 3 h at 0 ℃, water was added, and the mixture was extracted with ether. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in methanol (4 mL). 6N NaOH solution (4 mL) was added. The mixture was heated for 5 h at 70 ℃ and cooled to room temperature. The reaction mixture was concentrated under reduced pressure, acidified by diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 7:1 → 4:1) to give the title compound (87 mg, 96%).
1H-NMR (300 MHz, CDCl3) δ 1.00~2.40 (m, 13H), 2.75~2.94 (m, 1H), 3.06~3.26 (m, 1H), 3.38~3.54 (m, 1H), 6.52~6.82 (m, 2H), 7.08 (dd, J = 8.4 Hz, 1H), 7.20~7.50 (m, 4H), 7.84 (dd, J = 2.7, 8.1 Hz, 1H), 8.84 (d, J = 1.8 Hz, 1H).
<Example 67> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-indene-2-carboxamide
The Example 66 compound (45 mg, 0.119 mmol) was added to CH2Cl2 (3 mL), and (COCl)2 (0.020 mL, 0.237 mmol) and DMF (0.009 mL, 0.118 mmol) were added thereto at 0 ℃. The mixture was stirred for 2 h at room temperature and concentrated under reduced pressure. The residue was dissolved in THF (2 mL) again. Ammonia water (1 mL) was added at 0 ℃, which was then stirred for 2 h at room temperature and extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1 → 100% ethyl acetate) to give the title compound (40 mg, 89%).
1H-NMR (300 MHz, CDCl3) δ 1.10~2.30 (m, 12H), 1.31 (s, 3H), 3.16 (dd, J = 9.9, 11.1 Hz, 1H), 5.24 (brs, 1H), 5.64 (brs, 1H), 6.62 (d, J = 15.6 Hz, 1H), 6.78 (dd, J = 9.6, 15.6 Hz, 1H), 7.09 (dd, J = 8.7 Hz, 1H), 7.20~7.50 (m, 4H), 7.81 (dd, J = 2.4, 8.1 Hz, 1H), 8.77 (d, J = 2.4 Hz, 1H).
<Example 68> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-indene-2-carbonitrile
The Example 67 compound (40 mg, 0.106 mmol) was reacted according to the same procedure as Example 22 to give the title compound (33 mg, 87%).
1H-NMR (300 MHz, CDCl3) δ 1.10~2.20 (m, 12H), 1.37 (s, 3H), 3.10~3.27 (m, 1H), 6.60~6.78 (m, 2H), 7.10 (dd, J = 8.1 Hz, 1H), 7.20~7.50 (m, 4H), 7.82 (dd, J = 2.1, 7.8 Hz, 1H), 8.78 (d, J = 2.1 Hz, 1H).
<Example 69> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-methyl-2-(1H-tetrazol-5-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Example 68 compound (30 mg, 0.083 mmol) was reacted according to the same procedure as Example 33 to give the title compound (20 mg, 60%).
1H-NMR (300 MHz, CDCl3) δ= 0.80~2.42 (m, 11H), 2.52 (d, J = 13.5 Hz, 1H), 3.03 (t, J = 9.0 Hz, 1H), 6.48 (d, J = 15.6 Hz, 1H), 6.76 (dd, J = 9.9, 15.6 Hz, 1H), 7.11 (dd, J = 7.8 Hz, 1H), 7.20~7.60 (m, 4H), 7.85 (dd, J = 2.1, 7.8 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H).
<Example 70> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-methyl-2-(1-methyl-1H-tetrazol-5-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Example 69 compound (15 mg, 0.037 mmol) was reacted according to the same procedure as Example 34 to give the title compound (2 mg, 13%).
1H-NMR (300 MHz, CDCl3) δ= 1.10~2.35 (m, 12H), 1.45 (s, 3H), 3.82 (dd, J = 8.1, 10.8 Hz, 1H), 6.79 (d, J = 15.6 Hz, 1H), 6.88 (dd, J = 8.4, 15.6 Hz, 1H), 7.09 (dd, J = 8.4 Hz, 1H), 7.20~7.50 (m, 4H), 7.80 (dd, J = 2.4, 8.1 Hz, 1H), 8.76 (d, J = 2.1 Hz, 1H).
<Example 71> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-methyl-2-(2-methyl-2H-tetrazol-5-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Example 69 compound (15 mg, 0.037 mmol) was reacted according to the same procedure as Example 34 to give the title compound (9 mg, 58%).
1H-NMR (300 MHz, CDCl3) δ 1.10~1.80 (m, 8H), 1.48 (s, 3H), 2.00~2.40 (m, 4H), 3.43 (dd, J = 9.6, 11.1 Hz, 1H), 4.30 (s, 3H), 6.47 (d, J = 15.6 Hz, 1H), 6.73 (dd, J = 9.3, 15.6 Hz, 1H), 7.08 (dd, J = 8.4Hz, 1H), 7.20~7.50 (m, 4H), 7.77 (dd, J = 2.4, 8.4 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H).
<Example 72> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-indene-2-amine
The Example 66 compound (20 mg, 0.053 mmol) was reacted according to the same procedure as Example 29 to give the title compound (15 mg, 83%).
1H-NMR (300 MHz, CDCl3) δ 0.80~2.15 (m, 15H), 2.68 (t, J = 6.9 Hz, 1H), 6.55~6.73 (m, 2H), 7.07 (dd, J = 8.4 Hz, 1H), 7.13~7.50 (m, 4H), 7.77 (dd, J = 2.4, 8.1 Hz, 1H), 8.73 (d, J = 2.1 Hz, 1H).
<Example 73> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-yl}acetamide
The Example 72 compound (11 mg, 0.031 mmol) was reacted according to the same procedure as Example 48 to give the title compound (10 mg, 81%).
1H-NMR (300 MHz, CDCl3) δ 1.00~2.20 (m, 12H), 1.34 (s, 3H), 1.94 (s, 3H), 3.02 (t, J = 9.6 Hz, 1H), 5.43 (brs, 1H), 6.58 (d, J = 15.6 Hz, 1H), 6.71 (dd, J = 9.3, 15.6 Hz, 1H), 7.09 (dd, J = 8.1 Hz, 1H), 7.20~7.50 (m, 4H), 7.82 (dd, J = 2.4, 8.1 Hz, 1H), 8.77 (d, J = 2.4 Hz, 1H).
<Example 74> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-yl}methanesulfonamide
The Example 72 compound (15 mg, 0.043 mmol) was reacted according to the same procedure as Example 47 to give the title compound (10 mg, 56%).
1H-NMR (300 MHz, CDCl3) δ 1.10~2.20 (m, 12H), 1.45 (s, 3H), 2.77 (t, J = 10.5 Hz, 1H), 3.04 (s, 3H), 4.49 (brs, 1H), 6.63(d, J = 15.6 Hz, 1H), 6.76 (dd, J = 9.0, 15.6 Hz, 1H), 7.11 (dd, J = 8.1 Hz, 1H), 7.20~7.50 (m, 4H), 7.90 (dd, J = 2.4, 8.1 Hz, 1H), 8.81 (d, J = 2.4 Hz, 1H).
<Example 75> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-isopropoxyoctahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000050
(Step 1) (±)-(1R,2S,3aR,7aR)-1-(benzyloxymethyl)-2-isopropoxyoctahydro-1H-indene
Inden-2-ol compound (300 mg, 1.152 mmol) was dissolved in CH2Cl2 (4 mL), and isopropyl trichloroacetimidate (707 mg, 3.456 mmol) and trifluoromethanesulfonic acid (0.005 mL, 0.058 mmol) were added thereto at 0 ℃. After stirring for 16 h at room temperature, aqueous NaHCO3 solution was added, which was then extracted with CH2Cl2. The organic layer was dried over MgSO4 and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate =10:1) to give the title compound (70 mg, 20%).
1H-NMR (300 MHz, CDCl3) δ 1.11 (t, J = 6.0 Hz, 6H), 1.18~2.06 (m, 13H), 3.40 (dd, J = 5.7, 9.3 Hz, 1H), 3.47 (dd, J = 5.7, 9.3 Hz, 1H), 3.61 (m, J = 6.3 Hz, 1H), 3.75~3.86 (m, 1H), 4.52 (s, 2H), 7.20~7.40 (m, 5H).
(Step 2) (±)-(1R,2S,3aR,7aR)-1-(hydroxymethyl)-2-isopropoxyoctahydro-1H-indene
The Step 1 compound (70 mg, 0.231 mmol) was dissolved in ethanol (5 mL). 10% Pd/C (10 mg) was added, and the mixture was stirred for 16 h at room temperature under the pressure of hydrogen balloon. The mixture was filtered through a celite pad, and the Pd/C cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate =2:1) to give the title compound (49 mg, 100%).
1H-NMR (300 MHz, CD3OD) δ 1.12 (d, J = 6.0 Hz, 6H), 1.20~2.06 (m, 13H), 3.44~3.60 (m, 2H), 3.67 (m, J = 6.3 Hz, 1H), 3.76~3.88 (m, 1H).
(Step 3) (±)-(1S,2S,3aR,7aR)-2-isopropoxyoctahydro-1H-indene-1-carbaldehyde
The Step 2 compound (24 mg, 0.113 mmol) was reacted according to the same procedure as Step 10 of Preparation 3 to give the title compound (24 mg, 100%).
1H-NMR (300 MHz, CDCl3) δ 0.80~1.80 (m, 15H), 1.80~2.25 (m, 3H), 2.60~2.80 (m, 1H), 3.50~3.70 (m, 1H), 4.20~4.38 (m, 1H), 9.73 (d, J = 2.4 Hz, 1H).
(Step 4) (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-isopropoxyoctahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Step 3 compound (24 mg, 0.113 mmol) was reacted according to the same procedure as Example 1 to give the title compound (15 mg, 35%).
1H-NMR (300 MHz, CDCl3) δ 1.05~1.73 (m, 9H), 1.12 (d, J = 6.2 Hz, 3H), 1.13 (d, J = 6.2 Hz, 3H), 1.77~1.89 (m, 1H), 1.89~2.05 (m, 1H), 2.06~2.20 (m, 1H), 2.65~2.78 (m, 1H), 3.64 (m, J = 6.2 Hz, 1H), 3.87~3.97 (m, 1H), 6.57 (d, J = 15.6 Hz, 1H), 6.72 (dd, J = 8.8, 15.6 Hz, 1H), 7.08(dd, J = 8.3 Hz, 1H), 7.23~7.50 (m, 4H), 7.80 (dd, J = 2.4, 8.2 Hz, 1H), 8.76 (d, J = 2.3Hz, 1H).
<Example 76> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro(indene-2,5'-oxazolidin)-2’-one
Figure PCTKR2011004607-appb-I000051
(Step 1) (±)-(1S,2S,3aR,7aR)-2'-oxo-octahydrospiro(indene-2,5'-oxazolidine)-1-carbaldehyde
(±)-(1R,2S,3aR,7aR)-2'-oxo-octahydrospiro(indene-2,5'-oxazolidine)-1-methanol compound (70 mg, 0.311 mmol) was reacted according to the same procedure as Step 10 of Preparation 3 to give the title compound (69 mg, 100%).
1H-NMR (300 MHz, CDCl3) δ 0.97~2.80 (m, 13H), 3.62 (d, J = 8.9 Hz, 1H), 3.77 (d, J = 8.9 Hz, 1Hz), 5.37 (brs, 0.66H), 9.71(d, J = 3.3 Hz, 1H).
(Step 2) (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro(indene-2,5'-oxazolidin)-2’-one
The Step 1 compound (69 mg, 0.311mmol) was reacted according to the same procedure as Example 1 to give the title compound (40 mg, 33%).
1H-NMR (300 MHz, CDCl3) δ 0.80~2.40 (m, 12H), 2.50~2.65 (m, 1H), 3.54 (d, J = 8.5 Hz, 1H), 3.60 (d, J = 8.5 Hz,1H), 5.08 (brs, 1H), 6.52~6.78 (m, 2H), 7.09 (dd, J = 8.3 Hz, 1H), 7.23~7.56 (m, 4H), 7.78~7.85 (m, 1H), 8.72~8.78 (m, 1H).
<Example 77> (±)-(1S,2R,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro(indene-2,5'-oxazolidin)-2’-one
Figure PCTKR2011004607-appb-I000052
(Step 1) (±)-(1S,2R,3aR,7aR)-2'-oxo-octahydrospiro(indene-2,5'-oxazolidine)-1-carbaldehyde
(±)-(1R,2R,3aR,7aR)-2'-oxo-octahydrospiro(indene-2,5'-oxazolidine)-1-methanol compound (62 mg, 0.275 mmol) was reacted according to the same procedure as Step 10 of Preparation 3 to give the title compound (61 mg, 100%).
1H-NMR (300 MHz, CDCl3) δ 1.00~2.43 (m, 12H), 3.28 (dd, J = 1.7, 9.5 Hz, 1H), 3.46 (d, J = 9.7 Hz, 1H), 3.61 (d, J = 9.7 Hz, 1H), 5.90 (brs, 1H), 9.89 (d, J = 1.9 Hz, 1H).
(Step 2) (±)-(1S,2R,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro(indene-2,5'-oxazolidin)-2’-one
The Step 1 compound (61 mg, 0.275 mmol) was reacted according to the same procedure as Example 1 to give the title compound (55 mg, 51%).
1H-NMR (300 MHz, CDCl3) δ 1.10~2.20 (m, 12H), 3.11 (dd, J = 8.5, 11.0 Hz, 1H), 3.33 (d, J = 9.0 Hz, 1H), 3.77 (d, J = 8.9 Hz, 1H), 5.28 (brs, 1H), 6.62 (d, J = 15.5 Hz, 1H), 6.72 (dd, J = 8.4, 15.5 Hz, 1H), 7.09 (dd, J = 8.3 Hz, 1H), 7.23~7.50 (m, 4H), 7.81 (dd, J = 2.4, 8.1 Hz, 1H), 8.76 (d, J = 2.3 Hz, 1H).
<Example 78> (±)-2-{(E)-2-[(1'S,3a'R,7a'R)-1',3',3a',4',7',7a'-hexahydrospiro[(1,3)dioxolane-2,2'-indene]-1H-inden-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000053
The Preparation 4 compound (144 mg, 0.68 mmol) was reacted according to the same procedure as Example 1 to give the title compound (119 mg, 46%).
1H-NMR (300 MHz, CDCl3) δ 1.80 (d, J = 12.6 Hz, 1H), 1.92-2.04 (m, 2H), 2.13-2.21 (m, 5H), 2.61 (t, J = 9.6 Hz, 1H), 3.77-3.97 (m, 4H), 5.71 (dd, J = 10.2, 19.8 Hz, 2H), 6.56 (d, J = 15.9 Hz, 1H), 6.78 (dd, J =9.6, 15.9 Hz, 1H), 7.04-7.10 (m, 1H),7.27 (d, J = 9.6 Hz, 1H), 7.34-7.46 (m, 5H), 7.78 (dd, J = 2.1, 8.1 Hz, 1H), 8.77 (d, J = 2.1 Hz, 1H).
<Example 79> (±)-(1S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-3a,4,7,7a-tetrahydro-1H-inden-2(3H)one
Figure PCTKR2011004607-appb-I000054
The Example 78 compound (93 mg, 0.25 mmol) was reacted according to the same procedure as Example 3 to give the title compound (12 mg, 14%).
1H-NMR (300 MHz, CDCl3) δ 1.94-2.03 (m, 2H), 2.22-2.34 (m, 2H), 2.37-2.52 (m, 2H), 2.57-2.66 (m, 1 H), 2.77-2.86 (m, 1H), 3.04 (brs,1H), 5.68-5.76 (m, 2H), 6.82 (d, J = 15.9 Hz, 1H), 6.93 (d, J = 15.9 Hz, 1H), 7.06-7.12 (m, 1H), 7.25-7.30 (m, 1H), 7.32-7.37 (m, 2H), 7.40-7.47 (m, 1H), 7.80 (dd, J = 2.4, 8.1 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H).
<Example 80> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,3,3a,4,7,7a-hexahydro-1H-inden-2-ol
Figure PCTKR2011004607-appb-I000055
The Example 79 compound (8 mg, 0.02 mmol) was reacted according to the same procedure as Example 6 to give the title compound (2 mg, 30%).
1H-NMR (300 MHz, CDCl3) δ 1.39-1.49 (m, 2H), 1.79-1.96 (m, 3H), 2.12-2.33 (m, 3H), 2.54-2.57 (m, 1H), 3.64 (s, 1H), 3.95-4.02 (m, 1H), 6.81 (d, J = 15.6 Hz, 1H), 7.05 (m, 1H), 7.29 (d, J = 15.6 Hz, 1H), 7.36-7.44 (m, 4H), 7.89 (dd, J = 2.4, 8.1 Hz, 1H), 8.72 (d, J = 2.4 Hz, 1H).
<Example 81> (±)-2-{(E)-2-[(3a'R,4a'R,5'S,7a'R,8a'S)-2',2'-dimethyloctahydrospiro[(1,3)dioxolane-2,6'-indeno(5,6-d)(1,3)dioxol]-5'-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000056
(Step 1) (±)-(1'R,3a'R,5'S,6'R,7a'R)-5',6'-dihydroxyoctahydrospiro[(1,3)dioxolane-2,2'-indene]-1'-carbonitrile
(1'R,3a'R,7a'R)-1',3',3a',4',7',7a'-hexahydrospiro[[1,3]dioxolane-2,2'-indene]-1'-carbonitrile (502 mg, 2.45 mmol) was dissolved in t-butanol (2.5 mL) and water (2.5 mL). N-methylmorpholine (344 mg, 2.94 mmol) and OsO4 (2.5 wt butanol solution) (0.04 mL, 0.12 mmol) were added in the order. After 10.5 h, the mixture was concentrated under reduced pressure to remove t-BuOH, extracted with ethyl acetate and washed with aqueous NaHCO3 solution. The organic layer was dried over MgSO4 and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane=1:1:2) to give the title compound (499 mg, Yield 85%).
1H-NMR (300 MHz, CDCl3) δ 1.46-2.04 (m, 5H), 2.21 (dd, J = 7.8, 14.4 Hz, 1H), 2.40-2.51 (m, 1H), 2.60 (m, 1H), 2.87 (d, J = 11.1 Hz, 1H), 3.75-3.81 (m, 1H), 3.92-3.97 (m, 2H), 3.99-4.07 (m, 2H), 4.12-4.19 (m, 1H).
(Step 2) (±)-(3a'R,4a'R,5'R,7a'R,8a'S)-2',2'-dimethyloctahydrospiro[(1,3)dioxolane-2,6'-indeno(5,6-d)(1,3)dioxole]-5'-carbonitrile
The Step 1 compound (254 mg, 1.00 mmol) was dissolved in acetone (15 mL), and 2,2-dimethoxypropane (0.38 mL, 3.00 mmol) and p-toluenesulfonic acid (0.02 mg, 0.10 mmol) were added thereto. The mixture was stirred for 70 min at room temperature. After consumption of the starting material was confirmed by thin layer chromatography, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane = 7:1:2) to give the title compound (248 mg, Yield 88%).
1H-NMR (300 MHz, CDCl3) δ 1.32 (s, 3H), 1.20-1.35 (m, 2H), 1.46 (s, 3H), 1.53 (dd, J = 9.6, 13.5 Hz, 1H), 1.93 (ddd, J = 2.7, 5.4, 14.4 Hz, 1H), 2.08 (dd, J = 8.4, 13.5 Hz, 1H), 2.22 (ddd, J = 2.7, 5.4, 14.1 Hz, 1H), 2.48-2.75 (m, 3H), 3.96-4.05 (m, 2H), 4.13-4.29 (m, 2H), 4.35-4.44 (m, 2H).
(Step 3) (±)-(3a'R,4a'R,5'R,7a'R,8a'S)-2',2'-dimethyloctahydrospiro[[1,3]dioxolane-2,6'-indeno(5,6-d)(1,3)dioxole]-5'-carbaldehyde
The Step 2 compound (204 mg, 0.73 mmol) was reacted according to the same procedure as Step 6 of Preparation 1 to give the title compound (144 mg, 70%) as a white solid.
(Step 4) (±)-2-{(E)-2-[(3a'R,4a'R,5'S,7a'R,8a'S)-2',2'-dimethyloctahydrospiro[(1,3)dioxolane-2,6'-indeno(5,6-d)(1,3)dioxol]-5'-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Step 3 compound (1444 mg, 0.51 mmol) was reacted according to the same procedure as Example 1 to give the title compound (167 mg, 73%) as a white solid.
1H-NMR (300 MHz, CDCl3) δ 1.23-1.36 (m, 8H), 1.53-1.60 (m, 1H), 1.82-1.92 (m, 1H), 2.04-2.17 (m, 2H), 2.42-2.53 (m, 3H), 3.89-3.99 (m, 4H), 4.40-4.51 (m, 2H), 6.59 (d, J = 15.9, 1H), 6.74 (m,1H), 7.07-7.25 (m, 1H), 7.28 (m, 1H), 7.35-7.44 (m, 3H), 7.79 (dd, J = 2.4, 8.2 Hz, 1H), 8.76 (d, J = 2.0 Hz, 1H).
<Example 82> (±)-(3S,3aR,7aS)-3-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-octahydro-1H-isoindol-1-one
Figure PCTKR2011004607-appb-I000057
(Step 1) (±)-(3S,3aR,7aS)-3-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(4-methoxybenzyl)octahydro-1H-isoindol-1-one
(±)-(1S,3aS,7aS)-2-(4-methoxybenzyl)-3-oxooctahydro-1H-isoindole-1-carbaldehyde (205 mg, 0.71 mmol) was reacted according to the same procedure as Example 1 to give the title compound (260 mg, Yield 80%).
1H-NMR (300 MHz, CDCl3) δ 1.20-1.28 (m, 4H), 1.32 (m, 1H), 1.47 (m, 1H), 1.58-1.65 (m, 1H), 1.90-1.95 (m, 1H), 2.20 (m, 1H), 2.68 (m, 1H), 3.68 (s, 3H), 4.89 (d, J = 14.4 Hz, 1H), 5.01-5.08 (m, 1H), 5.73-5.80 (m, 1H), 6.50-6.68 (m, 3H), 6.86 (d, J = 8.7 Hz, 1H), 7.03 (d, J = 8.7 Hz, 1H), 7.07-7.14 (m, 1H), 7.19 (d, J = 8.7 Hz, 1H), 7.28-7.32 (m, 2H), 7.37 (d, J = 7.8 Hz, 1H), 7.42-7.49 (m, 1H), 7.81 (dd, J = 2.4, 8.4 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H).
(Step 2) (±)-(3S,3aR,7aS)-3-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-octahydro-1H-isoindol-1-one
The Step 1 compound (120 mg, 0.26 mmol) was dissolved in acetonitrile (3 mL), and water (1.5 mL) was added. At 0 ℃, Ce4NH4(NO3)5 (360 mg, 0.65 mmol) was added and stirred. After 10 min, the mixture was reacted at room temperature. After 24 h, the mixture was concentrated under reduced pressure to remove the organic solvent and extracted with ethyl acetate. The organic layer was dried over MgSO4. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane =1:1:2) to give the title compound (32 mg, 0.09 mmol, Yield 36%).
1H-NMR (300 MHz, CDCl3) δ 1.28-1.92 (m, 8H), 2.29-2.35 (m, 1H), 2.59 (t, J = 6.3 Hz, 1H), 4.00 (m, 1H), 5.89 (brs, 1H), 6.67 (d, J = 15.6 Hz, 1H), 6.79 (dd, J = 6.0, 15.6 Hz, 1H), 7.10 (dd, J = 2.4, 8.4 Hz, 1H), 7.30-7.38 (m, 3H), 7.41-7.48 (m, 1H), 7.83 (dd, J = 2.4, 8.1 Hz, 1H), 8.78 (d, J = 2.4 Hz, 1H).
<Example 83> (±)-(3S,3aR,7aS)-3-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-isoindol-1-one
Figure PCTKR2011004607-appb-I000058
The Example 82 compound (6.7 mg, 0.02 mmol) was dissolved in THF (1 mL) and treated with excess NaH. After 5 min, CH3I (0.02 mL, 2.3 mmol) was added and stirred for 1.5 h. The mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane =1:1:2) to give the title compound (7 mg, Yield 100%).
1H-NMR (300 MHz, CDCl3) δ 1.33-2.07 (m, 8H), 2.23 (m, 1H), 2.67 (m, 1H), 2.87 (s, 3H),3.75 (m, 1H), 6.58-6.73 (m, 2H), 7.08-7.13 (m, 1H), 7.30-7.49 (m, 4H), 7.84-7.90 (m, 1H), 8.79 (s, 1H).
<Example 84> (±)-(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(N-(t)-butyloxycarbonyl)octahydro-1H-isoindole
Figure PCTKR2011004607-appb-I000059
(±)-(1R,3aS,7aR)-t-butyl 1-formylhexahydro-1H-isoindole-2(3H)-carboxylate was reacted according to the same procedure as Example 1 to give the title compound.
<Example 85> (±)-(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-isoindole
Figure PCTKR2011004607-appb-I000060
The Example 84 compound (520 mg, 1.23 mmol) was dissolved in CH2Cl2 (3 mL), and trifluoroacetic acid (1 mL, 13.5 mmol) was added at 0 ℃. After stirring for 7 h at room temperature, aqueous NaHCO3 solution was added, which was then extracted with CH2Cl2. The organic layer was dried over MgSO4 and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2:CH3OH = 10:1) to give the title compound (320 mg, 81%).
1H-NMR (300 MHz, CD3OD) δ 1.13~1.88 (m, 9H), 2.22~2.35 (m, 1H), 2.36~2.53 (m, 1H), 3.07 (dd, J = 2.7, 11.4 Hz, 1H), 3.42 (dd, J = 6.6, 11.4 Hz, 1H), 4.21 (t, J = 9.6 Hz, 1H), 6.72 (dd, J = 8.7, 15.6 Hz, 1H), 6.90 (d, J = 15.6 Hz, 1H), 7.10~7.23 (m, 1H), 7.40~7.56 (m, 3H), 7.61 (d, J = 8.4 Hz, 1H), 8.08(dd, J = 2.7, 8.4 Hz, 1H), 8.81 (d, J = 2.1 Hz, 1H).
<Example 86> (±)-(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(N-acetyl)octahydro-1H-isoindole
Figure PCTKR2011004607-appb-I000061
The Example 85 compound (20 mg, 0.062 mmol) was reacted according to the same procedure as Example 48 to give the title compound (18 mg, 80%).
1H-NMR (300 MHz, CDCl3) δ 1.20~2.20 (m, 9H), 2.12 (s, 3H), 2.36~2.63 (m, 1H), 3.35~3.66 (m, 2H), 4.48~4.58 (m, 1H), 6.52, 6.56 (d, J = 15.6 Hz, 1H), 6.80 (dd, J = 5.7, 15.6 Hz, 1H), 7.02~7.15 (m, 1H), 7.20~7.55 (m, 4H), 7.83 (dd, J = 2.1, 8.1Hz, 1H), 8.77 (d, J = 2.4 Hz, 1H).
<Example 87> (±)-1-{(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(methylsulfonyl)octahydro-1H-isoindole
Figure PCTKR2011004607-appb-I000062
The Example 85 compound (20 mg, 0.062 mmol) was reacted according to the same procedure as Example 47 to give the title compound (16.4 mg, 66%).
1H-NMR (300 MHz, CDCl3) δ 1.10~1.80 (m, 7H), 2.08~2.24 (m, 1H), 2.36~2.53 (m, 1H), 2.93 (s, 3H), 3.00~3.55 (brs, 2H), 3.48 (dd, J = 1.5, 6.6 Hz, 2H), 4.28 (dd, J = 4.8, 6.3 Hz, 1H), 6.76 (d, J = 15.6 Hz, 1H), 6.84 (dd, J = 6.6, 15.6 Hz, 1H), 7.13 (dd, J = 7.5 Hz, 1H), 7.20~7.55 (m, 4H), 7.97 (dd, J = 2.4, 8.1 Hz, 1H), 8.87 (d, J = 2.4 Hz, 1H).
<Example 88> (±)-Methyl-2-{(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-1H-isoindole-2-(3H,3aH,4H,5H,6H,7H,7aH)-yl}acetate
Figure PCTKR2011004607-appb-I000063
The Example 85 compound (20 mg, 0.062 mmol) was dissolved in THF (3 mL). NaH (60% in oil, 5 mg, 0.124 mmol) was added at 0 ℃, which was then stirred for 5 min. Methylbromoacetate (0.012 mL, 0.124 mmol) was added, which was then stirred for 2 h at room temperature. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4 and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to give the title compound (18 mg, 73%).
1H-NMR (300 MHz, CDCl3) δ 1.15~1.80 (m, 8H), 2.02~2.16 (m, 1H), 2.16~2.32 (m, 1H), 2.50 (dd, J = 4.5, 9.3 Hz, 1H), 3.37 (d, J = 16.8 Hz, 1H), 3.45 (d, J = 9.0 Hz, 1H), 3.47 (d, J = 9.3 Hz, 1H), 3.60 (d, J = 17.1 Hz, 1H), 3.69 (s, 3H), 6.52 (dd, J = 8.1, 15.9 Hz, 1H), 6.66 (d, J = 15.9 Hz, 1H), 7.09 (dd, J = 8.4 Hz, 1H), 7.40~7.56 (m, 4H), 7.81 (dd, J = 2.4, 8.1 Hz, 1H), 8.76 (d, J = 1.8 Hz, 1H).
<Example 89> (±)-Ethyl-2-{(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-1H-isoindole-2-(3H,3aH,4H,5H,6H,7H,7aH)-yl}acetate
Figure PCTKR2011004607-appb-I000064
The same procedure as Example 88 was carried out except for using ethyl bromoacetate instead of methyl bromoacetate to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 1.25 (t, J = 6.9 Hz, 3H), 1.30~1.75 (m, 8H), 2.20~2.15 (m, 1H), 2.15~2.32 (m, 1H), 2.52 (dd, J = 4.8, 9.3 Hz, 1H), 3.37 (d, J = 17.1 Hz, 1H), 3.42~3.53 (m, 2H), 3.58 (d, J = 17.1 Hz, 2H), 4.15 (dq, J = 1.8, 7.2 Hz, 2H), 6.52 (dd, J = 7.8, 15.6 Hz, 1H), 6.66 (d, J = 15.6 Hz, 1H), 7.08 (dd, J = 8.4 Hz, 1H), 7.20~7.55 (m, 4H), 7.81 (dd, J = 2.4, 8.1 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H).
<Example 90> (±)-2-{(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-1H-isoindole-2-(3H,3aH,4H,5H,6H,7H,7aH)-yl}acetic acid
Figure PCTKR2011004607-appb-I000065
The Example 89 compound (15 mg, 0.037 mmol) was dissolved in methanol/water (3:1, 4 mL), to which was added 2 N NaOH (2 mL). After stirring for 3 h at room temperature, the mixture was concentrated under reduced pressure. The residue was acidified by diluted aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer was dried over MgSO4 and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2:CH3OH = 10:1) to give the title compound (10 mg, 71%).
1H-NMR (300 MHz, CDCl3) δ 0.80~2.10 (m, 8H), 2.25~2.47 (m, 1H), 2.47~2.64 (m, 1H), 2.76~2.90 (m, 1H), 2.90~3.43 (brs, 1H), 3.49 (d, J = 15.3 Hz, 1H), 3.70~3.88 (m, 2H), 3.96~4.13 (m, 1H), 6.77 (d, J = 15.9 Hz, 1H), 6.93 (dd, J = 9.3, 15.9 Hz, 1H), 7.09 (dd, J = 8.4 Hz, 1H), 7.20~7.56 (m, 3H), 7.64 (d, J = 8.1 Hz, 1H), 7.81 (dd, J = 2.1, 8.1 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H).
<Example 91> (±)-1-{(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-1H-isoindole-2-(3H,3aH,4H,5H,6H,7H,7aH)-yl}-2,2-dimethylpropan-1-one
Figure PCTKR2011004607-appb-I000066
The Example 85 compound (20 mg, 0.062 mmol) was dissolved in CH2Cl2 (3 mL), and NEt3 (0.017 mL, 0.124 mmol), dimethylaminopyridine (1 mg, 0.006 mmol) and pivaloyl chloride (0.015 mL, 0.124 mmol) were added in the order. After stirring for 1 h at room temperature, water was added and the mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound (20 mg, 80%).
1H-NMR (300 MHz, CDCl3) δ 0.80~1.80 (m, 17H), 1.94~2.10 (m, 1H), 2.32~2.48 (m, 1H), 3.60~3.76 (m, 2H), 4.62 (t, J = 5.4 Hz, 1H), 6.61 (d, J = 15.6 Hz, 1H), 6.80 (dd, J = 5.7, 15.9 Hz, 1H), 7.11 (dd, J = 8.4 Hz, 1H), 7.20~7.55 (m, 4H), 7.93(d, J = 8.4 Hz, 1H), 8.85 (s, 1H).
<Example 92> (±)-t-Butyl (1S,2S)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,3-dihydro-1H-inden-2-ylcarbamate
Figure PCTKR2011004607-appb-I000067
(Step 1) (±)-t-Butyl (1S,2S)-1-[(E)-2-(tributylstanyl)vinyl]-2,3-dihydro-1H-inden-2-ylcarbamate
t-Butyl (1S,2S)-1-ethynyl-2,3-dihydro-1H-inden-2-yl carbamate (880 mg, 3.42 mmol) and tributyltin hydride (1.09 mL, 4.10 mmol) were dissolved in anhydrous THF (11 mL). Bis(triphenylphosphine)palladium(II) chloride (480 mg, 0.68 mmol) was added at 0 ℃ and stirred for 1 h. After consumption of the starting material was confirmed by thin layer chromatography, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane = 10:1:2) to give the title compound (1.456 g, 78%).
1H-NMR (300 MHz, CDCl3) δ 0.70~1.00 (m, 9H), 1.10~1.40 (m, 12H), 1.40~1.65 (m, 6H), 1.45 (s, 9H), 2.70 (dd, J = 7.5, 15.6 Hz, 1H), 3.35 (dd, J = 7.2, 15.9 Hz, 1H), 3.55 (t, J = 6.6 Hz, 1H), 4.05~4.30 (m, 1H), 4.78 (brs, 1H), 5.85~6.20 (m, 2H), 7.03~7.26 (m, 4H).
(Step 2) (±)-t-Butyl (1S,2S)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,3-dihydro-1H-inden-2-ylcarbamate
The Step 1 compound (1.456 g, 2.655 mmol) was dissolved in toluene (13 mL). 2-Bromo-5-(3-fluorophenyl)-pyridine (669 mg, 2.655 mmol) and Pd(PPh3)4 (307 mg, 0.266 mmol) were added thereto and stirred for 16 h at 100 ℃. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane = 10:1:2) to give the title compound (500 mg, 44%).
1H-NMR (300 MHz, CDCl3) δ 1.43 (s, 9H), 2.80 (dd, J = 7.5, 15.6 Hz, 1H), 3.43 (dd, J = 6.9, 15.6 Hz, 1H), 3.82 (t, J = 7.2 Hz, 1H), 4.21~4.40 (m, 1H), 4.85 (brs, 1H), 6.66 (d, J = 15.9 Hz, 1H), 6.81 (dd, J = 8.4, 15.6 Hz, 1H), 7.07 (dd, J = 7.2 Hz, 1H), 7.15~7.33 (m, 5H), 7.33~7.50 (m, 3H), 7.82 (dd, J = 2.4, 8.1 Hz, 1H), 8.76 (d, J = 2.1 Hz, 1H).
<Example 93> (±)-(1S,2S)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,3-dihydro-1H-indene-2-amine
Figure PCTKR2011004607-appb-I000068
The Example 92 compound (300 mg, 0.697 mmol) was reacted according to the same procedure as Example 85 to give the title compound (145 mg, 63%).
1H-NMR (300 MHz, CDCl3) δ 1.75 (brs, 2H), 2.70~2.85 (m, 1H), 3.20~3.35 (m, 1H), 3.56~3.73 (m, 2H), 6.70~6.88 (m, 2H), 7.03~7.50 (m, 9H), 7.83 (dd, J = 2.4, 8.1 Hz, 1H), 8.78 (d, J = 2.4 Hz, 1H).
<Example 94> (±)-(1S,2S)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,3-dihydro-1H-indene-2-(N-acetyl)amine
Figure PCTKR2011004607-appb-I000069
The Example 93 compound (22 mg, 0.067 mmol) was reacted according to the same procedure as Example 48 to give the title compound (23 mg, 85%).
1H-NMR (300 MHz, CDCl3) δ 2.95 (dd, J = 8.1, 15.6 Hz, 1H), 3.00 (s, 3H), 3.49 (dd, J = 7.2, 15.6 Hz, 1H), 3.88 (t, J = 7.8 Hz, 1H), 4.14 (m, 1H), 4.69 (d, J = 8.1 Hz, 1H), 6.74 (d, J = 15.3 Hz, 1H), 6.83 (dd, J = 8.1, 15.9 Hz, 1H), 7.08 (dd, J = 8.1 Hz, 1H), 7.15~7.50 (m, 8H), 7.84 (dd, J = 2.7, 8.4 Hz, 1H), 8.78 (d, J = 2.4 Hz, 1H).
<Example 95> (±)-(1S,2S)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,3-dihydro-1H-indene-2-(N-methylsulfonyl)amine
Figure PCTKR2011004607-appb-I000070
The Example 93 compound (22 mg, 0.067 mmol) was reacted according to the same procedure as Example 47 to give the title compound (23 mg, 85%).
1H-NMR (300 MHz, CDCl3) δ 2.95 (dd, J = 8.1, 15.6 Hz, 1H), 3.00 (s, 3H), 3.49 (dd, J = 7.2, 15.6 Hz, 1H), 3.88 (t, J = 7.8 Hz, 1H), 4.14 (m, 1H), 4.69 (d, J = 8.1 Hz, 1H), 6.74 (d, J = 15.3 Hz, 1H), 6.83 (dd, J = 8.1, 15.9 Hz, 1H), 7.08 (dd, J = 8.1 Hz, 1H), 7.15~7.50 (m, 8H), 7.84 (dd, J = 2.7, 8.4 Hz, 1H), 8.78 (d, J = 2.4 Hz, 1H).
<Example 96> (±)-(1S,2S)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,3-dihydro-1H-indene-2-(N-methyl-N-methylsulfonyl)amine
Figure PCTKR2011004607-appb-I000071
The Example 95 compound (10 mg, 0.025 mmol) was reacted according to the same procedure as Example 49 to give the title compound (6 mg, 58%).
1H-NMR (300 MHz, CDCl3) δ 2.86 (s, 3H), 2.95 (s, 3H), 3.05~3.25 (m, 2H), 4.10 (t, J = 7.2 Hz, 1H), 4.73 (q, J = 8.7 Hz, 1H), 6.70~6.85 (m, 2H), 7.10 (dd, J = 8.4 Hz, 1H), 7.16~7.50 (m, 8H), 7.83 (dd, J = 2.4, 8.4 Hz, 1H), 8.77 (d, J = 2.4 Hz, 1H).
<Example 97> (±)-2-{(E)-2-[(1'S,3a'S,5'S,7a'R)-5'-fluorooctahydrospiro[(1,3)dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000072
(Step 1) (±)-(1'R,3a'R,7a'R)-1'-[(t-butyldimethylsilyloxy)methyl]octahydrospiro-[(1,3)dioxolane-2,2'-inden]-5'-ol
The compound of Step 2 of Preparation 4 was reacted according to the same procedures as Steps 1-3 of Preparation 5―3 step reaction―to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 0.02(s, 6H), 0.83(s, 9H), 1.48~2.19(m, 12H), 3.45~3.94(m, 6H).
(Step 2) (±)-t-Butyl-{[(1'R,3a'S,5'S,7a'R)-5'-fluorooctahydrospiro[(1,3)dioxolane-2,2'-inden]-1’-yl]methoxy}dimethylsilane
The Step 1 compound (0.28 g, 0.817 mmol) was dissolved in anhydrous CH2Cl2 (20 mL). While the temperature was maintained at -78 ℃, (diethylamino)sulfur trifluoride (0.857 mL, 6.54 mmol) was added and stirred for 1 h at room temperature. Aqueous NaHCO3 solution was added, and the mixture was extracted with CH2Cl2 and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 30:1) to give the title compound (0.110 g , 39%).
1H-NMR (300 MHz, CDCl3) δ 0.02 (s, 6H), 0.83 (s, 9H), 1.48~2.19 (m, 12H), 3.45~3.94 (m, 6H).
(Step 3) (±)-(1'R,3a'S,5'S,7a'R)-5'-fluorooctahydrospiro[(1,3)dioxolane-2,2'-indene]-1'-carbaldehyde
The Step 2 compound was reacted according to the same procedures as Steps 5 and 6 of Preparation 5―2 step reaction―to give the title compound.
H-NMR (300 MHz, CDCl3) δ 1.41~2.26 (m, 8H), 2.43~2.87 (m, 2H), 3.74~4.02 (m, 5H), 4.40~4.65 (m, 1H), 9.63 (s, 1H).
(Step 4) (±)-2-{(E)-2-[(1'S,3a'S,5'S,7a'R)-5'-fluorooctahydrospiro[(1,3)dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Step 3 compound (0.068 g, 0.210 mmol) was reacted according to the same procedure as Example 1 to give the title compound (32 mg, 38%).
1H-NMR (300 MHz, CDCl3) δ 0.82~2.27 (m, 8H), 2.82~2.90 (m, 1H), 3.76~3.98 (m, 6H), 4.39~4.55 (m, 1H), 6.53~6.75 (m, 2H), 7.05~7.14 (m, 1H), 7.29~7.55 (m, 4H), 7.79~7.91 (m, 1H), 8.76~8.87 (m, 1H).
<Example 98> (±)-2-{(E)-2-[(1'S,3a'S,5'R,7a'R)-5'-fluorooctahydrospiro[(1,3)dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000073
The isomer which is more nonpolar than the compound of Step 2 of Example 97 was reacted according to the same procedures as Steps 3 and 4 of Example 97 to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 1.46~2.23 (m, 10H), 3.08 (t, 1H, J = 9.9 Hz), 3.79~3.96 (m, 4H), 4.73~4.89 (m, 1H), 6.60~6.82 (m, 2H), 7.04~7.11 (m, 1H), 7.25~7.47 (m, 4H), 7.78~7.81 (m, 1H), 8.77 (s, 1H).
<Example 99> (±)-2-{(E)-2-[(1S,2S,3aR,5R,7aR)-2-methoxy-5-(methoxymethoxy)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000074
(Step 1) (±)-Methyl 2-[(1S,2S,3aR,7aR)-2-hydroxy-2,3,3a,4,7,7a-hexahydro-1H-inden-1-yl]acetate
Methyl 2-[(1S,3aR,7aR)-2-oxo-2,3,3a,4,7,7a-hexahydro-1H-inden-1-yl]acetate (5.0 g, 0.025 mol) was dissolved in anhydrous THF (150 mL). While maintaining at 0 ℃, LiAlH4 (1.95 g, 0.051 mol) was added in portions and stirred for 2 h at room temperature. After completion of the reaction, a small amount of water was added at 0 ℃ and the resulting solid was removed by filtration through celite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to give the title compound (2.0 g, 0.012 mmol).
1H-NMR (300 MHz, CDCl3) δ 0.00 (s, 6H), 0.86 (s, 9H), 1.44~2.10 (m, 9H), 3.24 (s, 3H), 3.51~3.64 (m, 3H), 5.61 (s, 2H).
(Step 2) (±)-[(1S,2S,3aR,7aR)-1-[(t-butyldimethylsilyloxy)methyl]-2,3,3a,4,7,7a-hexahydro-1H-inden-2-ol
In anhydrous DMF (50 mL) was dissolved the Step 1 compound (2.0 g, 0.012 mol). t-Butylchlorodimethylsilane (1.79 g, 0.012mol) and imidazole (0.97 g, 0.014 mol) were added and stirred for 2 h at room temperature. The mixture was extracted with CH2Cl2 and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to give the title compound (2.0 g, 55%) .
1H-NMR (300 MHz, CDCl3) δ 0.06 (s, 6H), 0.89 (s, 9H), 1.26~2.50 (m, 10H), 3.51~4.04 (m, 3H), 5.72~5.76 (m, 2H)
(Step 3) (±)-[(1S,2S,3aR,7aR)-1-[(t-butyldimethylsilyloxy)methyl]-2,3,3a,4,7,7a-hexahydro-2-methoxy-1H-indene
The Step 2 compound (0.85 g, 3.37 mmol) was dissolved in anhydrous ether (50 mL). NaH (1.35 g, 33.68 mmol) and methyl sulfate (3.2 mL, 33.68 mmol) were added and stirred under reflux for 24 h. The mixture was washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate = 5:1) to give the title compound (0.75 g, 2.53 mmol).
1H-NMR (300 MHz, CDCl3) δ 0.00 (s, 6H), 0.83 (s, 9H), 1.44~2.10 (m, 9H), 3.24 (s, 3H), 3.53~3.64 (m, 3H), 5.56~5.65 (m, 2H).
(Step 4) (±)-[(1R,2S,3aR,5R,7aR)-1-[(t-butyldimethylsilyloxy)methyl]-2-methoxyoctahydro-1H-inden-5-ol
The Step 3 compound was reacted according to the same procedures as Steps 2 and 3 of Preparation 5―2 step reaction―to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 0.04 (s, 6H), 0.89 (s, 9H), 1.25~2.29 (m, 12H), 3.28 (s, 3H), 3.47~3.60 (m, 3H), 3.89 (s, 1H).
(Step 5) (±)-[(1R,2S,3aR,5R,7aR)-1-[(t-butyldimethylsilyloxy)methyl]-2-methoxy-5-(methoxymethoxy)octahydro-1H-indene
In anhydrous CH2Cl2 (20 mL) was dissolved the Step 4 compound (0.180 g, 0.572 mmol). NEt3 (0.120 mL, 0.858 mmol) and methoxymethyl chloride (0.065 mL, 0.858 mmol) were added at 0 ℃ and stirred for 3 h at room temperature. The mixture was washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate = 5:1) to give the title compound (0.045 g, 22%).
1H-NMR (300 MHz, CDCl3) δ 0.03 (s, 6H), 0.89 (s, 9H), 1.23~2.21 (m, 14H) 3.28 (s, 3H), 3.36 (s, 3H), 3.46~3.78 (m, 4H), 4.66 (s, 2H).
(Step 6) (±)-[(1R,2S,3aR,5R,7aR)-2-methoxy-5-(methoxymethoxy)octahydro-1H-indene-1-carbaldehyde
The Step 5 compound was reacted according to the same procedures as Steps 5 and 6 of Preparation 5―2 step reaction―to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 1.25~2.20 (m, 10H), 2.62~2.66 (m, 1H), 3.29 (s, 3H), 3.36 (s, 3H), 3.75~3.81 (m, 1H), 4.08~4.13 (m, 1H), 4.66 (s, 2H), 9.74 (s, 1H).
(Step 7) (±)-2-{(E)-2-[(1S,2S,3aR,5R,7aR)-2-methoxy-5-(methoxymethoxy)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Step 6 compound (0.017 mg, 0.070 mmol) was reacted according to the same procedure as Example 1 to give the title compound (20 mg, 69%).
1H-NMR (300 MHz, CDCl3) δ 1.25~1.91 (m, 7H), 2.10~2.18 (m, 1H), 2.20~2.36 (m, 1H), 2.64~2.72 (m, 1H), 3.33 (s, 13H), 3.38 (s, 3H), 3.75~3.85 (m, 2H), 4.67 (s, 2H), 6.54~6.81 (m, 2H), 7.05~7.11 (m, 1H), 7.25~7.47 (m, 4H), 7.78 (dd, 1H, J = 2.4 Hz, 2.7 Hz), 8.76(s, 1H).
<Example 100> (±)-2-{(E)-2-[(1S,2S,3aR,5R,7aR)-2-methoxy-5-hydroxyoctahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000075
In methanol (2 mL) was dissolved the Example 99 compound (20 mg 0.048 mmol). Conc. hydrochloric acid (1 drop) was added and stirred under reflux for 1 h. The solvent was distilled under reduced pressure. The residue was extracted with CH2Cl2 and washed with aqueous NaHCO3 solution and saturated aqueous sodium chloride solution twice. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to give the title compound (10 mg, 56%).
1H-NMR (300 MHz, CDCl3) δ 0.83~1.92 (m, 11H), 2.10~2.21 (m, 1H), 2.33~2.37 (m, 1H), 2.62~2.70 (m, 1H), 3.33 (s, 3H), 3.75~4.13 (m, 2H), 7.05~7.11 (m, 1H), 7.25~7.47 (m, 4H), 7.80 (d, J = 8.1 Hz, 1H), 8.76 (s, 1H).
<Example 101> (±)-(1S,2S,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5-ylcarbamate
Figure PCTKR2011004607-appb-I000076
The Example 100 compound (9 mg, 0.024 mmol) was reacted according to the same procedure as Example 65 to give the title compound (10 mg, 0.024 mmol) .
1H-NMR (300 MHz, CDCl3) δ 0.82~2.04 (m, 7H), 2.12~2.29 (m, 2H), 2.65~2.73 (m, 1H), 3.34 (s, 3H), 3.76~3.82 (m, 1H), 4.57 (s, 2H), 4.93 (s, 1H), 6.54~6.81 (m, 2H), 7.06~7.11 (m, 1H), 7.29~7.47 (m, 4H), 7.76~7.82 (m, 1H), 8.76(s, 1H).
<Example 102> (±)-2-{(E)-2-[(1'S,2'S,3a'S,7a'R)-2'-methoxyoctahydrospiro[(1,3)dioxolane-2,5'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000077
(Step 1) (±)-[(1R,2S,3aR,7aR)-1-[(t-butyldimethylsilyloxy)methyl]-2-methoxyoctahydro-1H-inden-5(6H)-one
The compound of Step 4 of Example 99 (0.10 g, 0.318 mmol) was dissolved in anhydrous CH2Cl2 (30 mL). While maintaining at 0 ℃, pyridium chlorochromate (0.103 g, 0.479 mmol) was added and stirred for 3 h at room temperature. The mixture was diluted with CH2Cl2 and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 5:1) to give the title compound (0.085 g, 0.272 mmol).
1H-NMR (300 MHz, CDCl3) δ 0.03 (s, 6H), 0.88 (s, 9H), 1.40~2.45 (m, 11H), 3.31 (s, 3H), 3.59~3.65 (m, 3H).
(Step 2) (±)-{(1'R,2'S,3a'S,7a'R)-2'-methoxyoctahydrospiro[(1,3)dioxolane-2,5'-inden]-1’-yl}methanol
The Step 1 compound (130 mg, 0.416 mmol) was reacted according to the same procedure as Step 5 of Preparation 1 to give the title compound (62 mg, 62%).
1H-NMR (300 MHz, CDCl3) δ 1.49~2.17 (m, 12H), 3.30 (s, 3H), 3.54~3.77 (m, 3H), 3.88~3.96 (m, 4H).
(Step 3) (±)-(1'R,2'S,3a'S,7a'R)-2'-methoxyoctahydrospiro[(1,3)dioxolane-2,5'-indene]-1'-carbaldehyde
The Step 2 compound (100 mg, 0.413 mmol) was reacted according to the same procedure as Step 10 of Preparation 3 to give the title compound (60 mg, 63%).
1H-NMR (300 MHz, CDCl3) δ 1.25~1.91 (m, 6H), 2.00~2.25 (m, 4H), 2.74~2.78 (m, 1H), 3.28~3.33 (m, 3H), 3.89~3.97 (m, 4H), 4.07~4.13 (m, 1H), 9.77 (d, 1H, J = 2.1 Hz).
(Step 4) (±)-2-{(E)-2-[(1'S,2'S,3a'S,7a'R)-2'-methoxyoctahydrospiro[(1,3)dioxolane-2,5'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Step 3 compound (84 mg, 0.349 mmol) was reacted according to the same procedure as Example 1 to give the title compound (110 mg, 77%) as a more polar isomer.
1H-NMR (300 MHz, CDCl3) δ 1.52~1.85 (m, 8H), 2.13~2.29 (m, 2H), 2.71~2.79 (m, 1H), 3.31 (s, 3H), 3.73~3.81 (m, 2H), 3.92~3.95 (m, 3H), 6.56~6.80 (m, 1H), 7.06~7.11 (m, 1H), 7.29~7.45 (m, 4H), 7.79~7.82 (m, 1H), 8.76 (s, 1H)
<Example 103> (±)-2-{(E)-2-[(1'S,2'S,3a'R,7a'R)-2'-methoxyoctahydrospiro[(1,3)dioxolane-2,5'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000078
The same procedure as Example 102 was carried out to give the title compound (10 mg, 7%) as a more nonpolar isomer.
1H-NMR (300 MHz, CDCl3) δ 1.25~1.85 (m, 8H), 2.05~2.23 (m, 3H), 3.02~3.07 (m, 1H), 3.33 (s, 3H), 3.72~3.79 (m, 1H), 3.87~4.00 (m, 4H), 6.59~6.78 (m, 2H), 7.05~7.11 (m, 1H), 7.29~7.48 (m, 4H), 7.78~7.82 (m, 1H), 8.76 (s, 1H).
<Example 104> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5(6H)-one
Figure PCTKR2011004607-appb-I000079
The Example 102 compound (30 mg, 0.073 mmol) was reacted according to the same procedure as Example 3 to give the title compound (14 mg, 52%) as a more polar isomer.
1H-NMR (300 MHz, CDCl3) 1.41~2.49 (m, 10H), 2.61~2.69 (m, 1H), 3.36 (s, 3H), 3.72~3.80 (m, 1H), 6.60~6.87 (m, 2H), 7.07~7.12 (m, 1H), 7.27~7.48 (m, 4H), 7.80~7.84 (m, 1H), 8.78 (s, 1H).
<Example 105> (±)-(1S,2S,3aR,7aR,E)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5(6H)-one oxime
Figure PCTKR2011004607-appb-I000080
The Example 104 compound (14 mg, 0.038 mmol) was reacted according to the same procedure as Example 4 to give the title compound (1.6 mg, 11%) as a more nonpolar E-oxime isomer.
1H-NMR (300 MHz, CDCl3) δ 0.82~2.36 (m, 9H), 2.68~2.70 (m, 1H), 2.97 (d, 1H, J = 9.0 Hz), 3.33 (s, 3H), 3.72~3.79 (m, 1H), 6.58~6.83 (m, 2H), 7.09~7.12 (m, 1H), 7.29~7.45 (m, 4H), 7.79~7.83 (m, 1H), 8.77 (d, 1H, J = 1.8 Hz).
<Example 106> (±)-(1S,2S,3aR,7aR,Z)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5(6H)-one oxime
Figure PCTKR2011004607-appb-I000081
The Example 104 compound (14 mg, 0.038 mmol) was reacted according to the same procedure as Example 4 to give the title compound (5.2 mg, 37%) as a more polar Z-oxime isomer.
1H-NMR (300 MHz, CDCl3) δ 0.85~2.56 (m, 11H), 3.37 (s, 3H), 3.64~3.75 (m, 1H), 6.57~6.83 (m, 2H), 7.06~7.11 (m, 1H), 7.30~7.47 (m, 4H), 7.79~7.82 (m, 1H), 8.77(d, 1H, J = 2.1 Hz).
<Example 107> (±)-t-Butyl-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5-ylcarbamate
Figure PCTKR2011004607-appb-I000082
(Step 1) t-Butyl-(±)-(1S,2S,3aR,7aR)-1-formyl-2-methoxyoctahydro-1H-inden-5-ylcarbamate
The compound of Step 4 of Example 99 was reacted according to the same procedures as Steps 4-6 of Preparation 5 to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 1.13~1.39 (m, 2H), 1.43 (s, 9H), 1.58~2.81 (m, 8H), 3.27~3.78 (m, 4H), 4.05~4.52 (m, 2H), 9.75 (s, 1H).
(Step 2) (±)-t-Butyl-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5-ylcarbamate
The Step 1 compound (70 mg, 0.234 mmol) was reacted according to the same procedure as Example 1 to give the title compound (70 mg, 64%).
1H-NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.51~1.98 (m, 8H), 2.04~2.26 (m, 2H), 2.51~2.79 (m, 1H), 3.31 (m, 4H), 3.76~3.80 (m, 1H), 4.37~4.43 (m, 1H), 6.49~6.85 (m, 2H), 7.05~7.28 (m, 1H), 7.26~7.47 (m, 4H), 8.80 (d, 1H, J = 8.1 Hz), 8.75 (s, 1H).
<Example 108> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-indene-5-amine
Figure PCTKR2011004607-appb-I000083
The Example 107 compound (70 mg, 0.150 mmol) was reacted according to the same procedure as Example 85 to give the title compound (35 mg, 63%).
1H-NMR (300 MHz, CDCl3) δ 1.14~1.97 (m, 12H), 2.03~2.41 (m, 2H), 2.56~2.83 (m, 2H), 3.32 (s, 3H), 3.76~3.82 (m, 1H), 6.55~6.77 (m, 2H), 7.08 (dd, 1H, J = 8.4 Hz), 7.29~7.47 (m, 4H), 7.82~7.94 (m, 1H), 8.76 (s, 1H).
<Example 109> (±)-Ethyl (1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5-ylcarbamate
Figure PCTKR2011004607-appb-I000084
In CH2Cl2 (3 mL) was dissolved the Example 108 compound (11 mg, 0.030 mmol). NEt3 (0.005 mL, 0.036 mmol), ethyl chloroformate (0.003 mL, 0.036 mmol) and dimethylaminopyridine (0.4 mg, 0.003 mmol) were added and stirred for 2 h at room temperature. The mixture was diluted with CH2Cl2 and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (CH2Cl2:CH3OH = 20:1) to give the title compound (8 mg, 60%).
1H-NMR (300 MHz, CDCl3) δ 0.74~1.80 (m, 9H), 2.13~2.22 (m, 2H), 2.70~2.79 (m, 1H), 3.31~3.44 (m, 4H), 3.76~3.79 (m, 1H), 4.06~4.13 (m, 2H), 4.25~4.51 (m, 1H), 6.49~6.82 (m, 2H), 7.05~7.11 (m, 1H), 7.28~7.47 (m, 4H), 7.73~7.81 (m, 1H), 8.76 (s, 1H).
<Example 110> (±)-N-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5-yl}methanesulfonamide
Figure PCTKR2011004607-appb-I000085
The Example 109 compound (10 mg, 0.027 mmol) was reacted according to the same procedure as Example 47 to give the title compound (6 mg, 48%).
1H-NMR (300 MHz, CDCl3) δ 1.21~2.38(m, 9H), 2.69~2.77 (m, 1H), 2.99 (s, 3H), 3.27~3.34 (m, 4H), 3.80~3.82 (m, 1H), 4.10 (d, 1H, J = 7.8 Hz), 6.55~6.79 (m, 2H), 7.07~7.12 (m, 1H), 7.29~7.48 (m, 4H), 7.81 (d, 1H, J = 8.1 Hz), 8.77(s, 1H).
<Example 111> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-methoxy-5-(1H-pyrrol-1-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000086
To the Example 108 compound (0.020 g, 0.054 mmol) was added acetic acid (2 mL). 2,5-Dimethoxytetrahydrofuran (0.010 g, 0.082 mmol) was added and stirred for 2 h at 60 ℃. After completion of the reaction, aqueous NaHCO3 solution was added. The mixture was extracted with CH2Cl2 and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to give the title compound (0.004 g, 17%) .
1H-NMR (300 MHz, CDCl3) δ 1.51~2.28 (m, 10H), 2.81~2.90 (m, 1H), 3.33~3.40 (m, 3H), 3.77~3.83 (m, 2H), 6.15~6.16 (m, 2H), 6.55~6.80 (m, 4H), 7.29~7.48 (m, 4H), 7.79~7.83 (m, 1H), 8.77 (d, J = 2.4 Hz, 1H).
<Example 112> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-methoxy-5-(pyrrolidin-2-one-1-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000087
In anhydrous THF (3 mL) was dissolved the Example 108 compound (0.020 g, 0.054 mmol). NEt3 (0.015 mL, 0.109 mmol) and 4-chlorobutanoyl chloride (0.007 mL, 0.065 mmol) were added thereto at room temperature. After stirring for 1 h, 30% NaOMe (0.020 mL) was added and stirred for 1 h at room temperature. After completion of the reaction, the mixture was diluted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (CH2Cl2:CH3OH = 20:1) to give the title compound (0.012 g, 50%).
1H-NMR (300 MHz, CDCl3) δ 1.25~1.87 (m, 8H), 1.89~2.04 (m, 4H), 2.19~2.42 (m, 4H), 3.28~3.47 (m, 1H), 6.88~6.93 (m, 1H), 7.06~7.12 (m, 1H), 7.20~7.48 (m, 5H), 7.82 (dd, 1H, J = 2.1Hz, 2.4Hz), 8.80 (d, 1H, J = 2.1Hz).
<Example 113> (±)-t-Butyl-(1S,2S,3aR,6S,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-6-ylcarbamate
Figure PCTKR2011004607-appb-I000088
t-Butyl-(±)-(1S,2S,3aR,6S,7aR)-1-formyl-2-methoxyoctahydro-1H-inden-6-ylcarbamate (48 mg, 0.161 mmol) was reacted according to the same procedure as Example 1 to give the title compound (30 mg, 39%).
1H-NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 0.85~1.67 (m, 4H), 1.92~2.02 (m, 5H), 2.11~2.18 (m, 1H), 2.82~2.76 (m, 1H), 3.30 (s, 3H), 3.65~3.78 (m, 2H), 4.28~4.32 (m, 1H), 6.62~6.80 (m, 2H), 7.06~7.11 (m, 1H), 7.29~7.60 (m, 4H), 8.82 (dd, 1H, J = 2.4, 2.4 Hz), 8.76 (d, 1H, J = 2.1 Hz).
<Example 114> (±)-t-Butyl-(1S,2S,3aR,6R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-6-ylcarbamate
Figure PCTKR2011004607-appb-I000089
t-Butyl-(±)-(1S,2S,3aR,6R,7aR)-1-formyl-2-methoxyoctahydro-1H-inden-6-ylcarbamate (20 mg, 0.067 mmol) was reacted according to the same procedure as Example 1 to give the title compound (23 mg, 73%).
1H-NMR (300 MHz, CDCl3) δ 1.23~1.98 (m, 14H), 1.89~2.20 (m, 4H), 2.51~2.54 (m, 1H), 3.31~3.37(m, 4H), 3.75~3.81 (m, 1H), 4.11~4.43 (m, 2H), 6.49~6.85 (m, 2H), 7.06~7.11 (m, 1H), 7.26~7.54 (m, 4H), 8.80 (dd, 1H, J = 2.1 Hz, 2.4 Hz), 8.76 (d, 1H, J = 2.1 Hz).
<Example 115> (±)-t-Butyl (1S,2S,3aR,5S,6S,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dimethoxyoctahydro-1H-inden-6-ylcarbamate
Figure PCTKR2011004607-appb-I000090
(Step 1) (±)-(1R,2S,3aR,5S,6S,7aR)-6-azido-1-(benzyloxymethyl)-2-methoxyoctahydro-1H-inden-5-ol
(1aR,2aR,3R,4S,5aS,6aS)-3-(benzyloxymethyl)-4-methoxyoctahydro-1aH-indeno[5,6-b]oxirane (1.3 g, 4.50 mmol) was dissolved in anhydrous DMF (7 mL). NaN3 (2.9 g, 45 mmol) was added while stirring, and stirred at 100 ℃. After stirring for 20 h, H2O was added to stop the reaction. The organic layer was separated from the reaction mixture and the aqueous layer was extracted with ether. The organic layers were combined and dried over anhydrous MgSO4. The organic layer was filtered and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound (1.2 g, 85%).
1H-NMR (300 MHz, CDCl3) δ= 1.5 (m, 3H), 2.0 (m, 6H), 3.0 (m, 1H), 3.2 (s, 3H), 3.3 (m, 2H), 3.5 (m, 2H), 4.45 (s, 2H), 7.3 (m, 5H).
(Step 2) (±)-(1R,2S,3aR,5S,6S,7aR)-6-amino-1-(benzyloxymethyl)-2-methoxyoctahydro-1H-inden-5-ol
The Step 1 compound (800 mg, 0.241 mmol) in THF (5 mL) solution was cooled to 0 ℃, and LiAlH4 (109 mg, 2.89 mmol) was added thereto while stirring. After stirring for 10 min, H2O was added to the reaction vessel to stop the reaction. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give a crude compound (630 mg, 85%). This compound was used in the next reaction without further purification.
(Step 3) (±)-t-Butyl (1R,2S,3aR,5S,6S,7aR)-5-hydroxy-1-(benzyloxymethyl)-2-methoxyoctahydro-1H-inden-6-ylcarbamate
The solution of Step 2 compound (210 mg, 0.687 mmol) in CH2Cl2 (5 mL) was cooled to 0 ℃. NEt3 (114 μL, 0.82 mmol), di-t-butyldicarbonate (173 μL, 0.75 mmol) and dimethylaminopyridine (16 mg, 0.137 mmol) were added thereto while stirring. At room temperature, the mixture was stirred for 40 min. H2O was added to the reaction vessel to stop the reaction. The organic layer was separated from the reaction mixture and the aqueous layer was extracted with CH2Cl2. The organic layers were combined and dried over anhydrous MgSO4. The organic layer was filtered and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to give the title compound (240 mg, 86%).
1H-NMR (300 MHz, CDCl3) δ 0.9 (m, 1H), 1.4 (s, 9H), 1.5 (m, 2H), 1.9 (m, 3H), 2.1 (m, 4H), 3.26 (s, 3H), 3.35 (dd, 2H, J =7.1 Hz), 3.5 (m, 2H), 4.45 (s, 2H), 7.3 (m, 5H).
(Step 4) (±)-t-Butyl (1R,2S,3aR,5S,6S,7aR)-5-methoxy-1-(benzyloxymethyl)-2-methoxyoctahydro-1H-inden-6-ylcarbamate
The solution of Step 3 compound (360 mg, 0.887 mmol) in DMF (7 mL) was cooled to 0 ℃. NaH (42 mg, 1.064 mmol) and CH3I (61 μL, 0.975 mmol) were slowly added thereto while stirring. At room temperature, the mixture was stirred for 12 h. H2O was added to the reaction vessel to stop the reaction. The organic layer was separated from the reaction mixture and the aqueous layer was extracted with ether. The organic layers were combined and dried over anhydrous MgSO4. The organic layer was filtered and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to give the title compound (300 mg, 81%).
1H-NMR (300 MHz, CDCl3) δ 1.4 (s, 9H), 1.7 (m, 3H), 2.0 (m, 6H), 2.8 (d, 1H), 3.0 (m, 6H), 3.45 (s, 1H), 4.45 (s, 2H), 7.3 (m, 5H).
(Step 5) (±)-t-Butyl (1R,2S,3aR,5S,6S,7aR)-5-methoxy-1-(hydroxymethyl)-2-methoxyoctahydro-1H-inden-6-ylcarbamate
To the solution of Step 4 compound (300 mg, 0.715 mmol) in ethanol (7 mL) was added a small amount of 10% Pd/C under hydrogen gas, which was then stirred for 24 h. The solvent was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to give the title compound (200 mg, 85% ).
(Step 6) (±)-t-Butyl (1R,2S,3aR,5S,6S,7aR)-1-formyl-5-methoxy-2-methoxyoctahydro-1H-inden-6-ylcarbamate
The Step 5 compound was reacted according to the same procedure as Step 10 of Preparation 3 to give the title compound.
(Step 7) (±)-t-Butyl (1S,2S,3aR,5S,6S,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dimethoxyoctahydro-1H-inden-6-ylcarbamate
The Step 6 compound (100 mg, 0.303 mmol) was reacted according to the same procedure as Example 1 to give the title compound (110 mg, 72%).
1H-NMR (300 MHz, CDCl3) δ 1.5 (s, 9H), 2.4 (m, 2H), 2.8 (d, 4H, J =17.1 Hz), 3.3 (m, 10H), 3.5 (m, 1H), 8.8 (s, 1H), 3.8 (m, 1H), 6.6 (d, 1H), 6.8 (m, 1H), 7.1 (m, 1H), 7.3 (m, 5H),7.8 (d, 1H).
<Example 116> (±)-(1S,2S,3aR,5S,6S,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dimethoxyoctahydro-1H-indene-6-amine
Figure PCTKR2011004607-appb-I000091
The Example 115 compound (71 mg, 0.142 mmol) was reacted according to the same procedure as Example 85 to give the title compound (40 mg, 71%).
1H-NMR (300 MHz, CDCl3) δ 2.0 (m, 4H), 3.35 (m, 6H), 6.6 (d, 1H), 6.8 (dd, 1H, J =8.4, 8.4 Hz), 7.1 (m, 1H), 7.3 (m, 5H), 7.8 (d, 1H, J = 8.1 Hz), 8.8 (s, 1H).
<Example 117> (±)-(1S,2S,3aR,5S,6S,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dimethoxy-N,N-dimethyloctahydro-1H-indene-6-amine
Figure PCTKR2011004607-appb-I000092
The solution of Example 116 compound (40 mg, 0.100 mmol) in CH2Cl2 (4 mL) was stirred, during which formaldehyde (9 μL, 0.3 mmol), NaCNBH3 (19 mg, 0.3 mmol) and a small amount of acetic acid were added. After stirring for 24 h, saturated aqueous NaHCO3 solution was added to stop the reaction. The organic layer was separated from the reaction mixture and the aqueous layer was extracted with CH2Cl2. The organic layers were combined and dried over anhydrous MgSO4. The organic layer was filtered and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (CH2Cl2 : MeOH = 10:1) to give the title compound (31 mg, 73%).
1H-NMR (300 MHz, CDCl3) δ= 2.2 (m, 7H), 2.8 (s, 6H), 3.0 (t, 1H), 3.2 (q, 1H, J =14.4 Hz),3.3 (m, 6H), 3.9 (m, 1H), 6.6 (m, 2H), 7.3 (m, 7H), 7.8 (d, 1H, J = 8.1 Hz), 8.8 (s, 1H).
<Example 118> (±)-t-Butyl (1S,2S,3aR,5R,6S,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-fluoro-2-methoxyoctahydro-1H-inden-6-ylcarbamate
Figure PCTKR2011004607-appb-I000093
(Step 1) (±)-t-Butyl (1R,2S,3aR,5R,6S,7aR)-5-fluoro-1-(benzyloxymethyl)-2-methoxyoctahydro-1H-inden-6-ylcarbamate
The compound of Step 3 of Example 115 was reacted according to the same procedure as Step 2 of Example 97 to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 1.2 (s, 3H), 1.4 (s, 9H), 1.55 (d, 3H), 2.0 (m, 18H), 3.2 (s, 3H), 3.4 (m, 1H), 4.45 (s, 2H), 7.3 (m, 5H).
(Step 2) (±)-t-Butyl (1S,2S,3aR,5R,6S,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-fluoro-2-methoxyoctahydro-1H-inden-6-ylcarbamate
The Step 1 compound was reacted according to the same procedure as Steps 5-7 of Example 115―3 step reaction―to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 1.5 (s, 9H), 2.0 (m, 8H), 2.45 (m, 3H), 3.4 (s, 3H), 3.65 (m, 1H), 4.55 (m, 1H), 6.7 (m, 2H), 7.1 (dd, 1H, J = 8.4 Hz), 7.35 (m, 4H), 7.8 (d, 1H, J = 10.5 Hz), 8.8 (s, 1H).
<Example 119> (±)-2-{(E)-2-[(1'S,3a'R,7a'R)-1',3',3a',4',7',7a'-hexahydrospiro[(1,3)dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000094
The Preparation 3 compound was reacted according to the same procedure as Example 1 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.62-1.89 (m, 5H), 2.19-2.31 (m, 3H), 2.46 (dd, J = 9.9, 9.3 Hz, 1H), 3.81 (m, 2H), 3.98 (m, 2H), 5.71 (m, 2H), 6.58 (d, J = 15.9 Hz, 1H), 6.79 (dd, J = 15.9, 9.3 Hz, 1H), 7.08 (dd, J = 8.2, 1.5 Hz, 1H), 7.28 (m, 1H), 7.34-7.47 (m, 3H), 7.80 (dd, J = 8.1, 2.4 Hz, 1H), 8.78 (d, J = 2.4 Hz, 1H).
<Example 120> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(1H-1,2,4-triazol-1-yl)-2,3,3a,4,7,7a-hexahydro-1H-inden]-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000095
(Step 1) (±)-(1R,2R,3aS,7aR)-1-(hydroxymethyl)-2,3,3a,4,7,7a-hexahydro-1H-inden-2-ol
The compound of Step 7 of Preparation 3 (2.00 g, 10.3 mmol) was reacted according to the same procedure as Step 1 of Example 99 to give the title compound (805 mg, 46%) as a more nonpolar isomer in the form of a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.14 (dddd, J = 10.8, 10.8, 10.8, 5.1 Hz, 1H), 1.52-1.94 (m, 6H), 2.26 (m, 2H), 2.50 (brs, 1H), 2.68 (brs, 1H), 3.56 (dd, J = 10.2, 9.0 Hz, 1H), 3.87 (dd, J = 10.0, 4.8 Hz, 1H), 4.22 (m, 1H), 5.71 (s, 2H).
(Step 2) (±)-(1R,2R,3aS,7aR)-1-(benzyloxymethyl)-2,3,3a,4,7,7a-hexahydro-1H-inden-2-ol
At room temperature, the solution of Step 1 compound (805 mg, 4.78 mmol) in THF (20 mL) was stirred, to which was added NaH (287 mg, 7.18 mmol). The yellow suspension was stirred for 1 h. Benzyl bromide (686 μL, 5.73 mmol) was added to the reaction mixture and stirred for 12 h. Distilled water (10 mL) was added to the reaction mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 20 mL). The organic layers were combined and washed with saturated aqueous NH4Cl solution (20 mL) and saturated aqueous sodium chloride solution (20 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to give the title compound (612 mg, 50%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.14 (dddd, J = 10.8, 10.8, 10.8, 5.1 Hz, 1H), 1.57 (m, 1H), 1.73-1.92 (m, 5H), 2.13-2.27 (m, 3H), 3.40 (dd, J = 10.2, 9.0 Hz, 1H), 3.65 (dd, J = 10.0, 4.8 Hz, 1H), 4.17 (m, 1H), 4.50 (d, J = 12.1Hz, 1H), 4.56 (d, J = 12.1 Hz, 1H), 5.66 (m, 2H), 7.27-7.37 (m, 5H).
(Step 3) (±)-(1R,2R,3aS,7aR)-1-(benzyloxymethyl)-2,3,3a,4,7,7a-hexahydro-1H-inden-2-yl methanesulfonate
The Step 2 compound (306 mg, 1.18 mmol) was reacted according to the same procedure as Example 10 to give the title compound (353 mg, 89%) as a pale yellow liquid.
1H NMR (300 MHz, CDCl3) δ 1.28 (dddd, J = 10.8, 10.8, 10.8, 5.1 Hz, 1H), 1.61 (m, 1H), 1.72-1.93 (m, 3H), 2.05 (m, 1H), 2.17-2.30 (m, 3H), 2.89 (s, 3H), 3.44 (dd, J = 9.3, 6.9 Hz, 1H), 3.65 (dd, J = 9.3, 4.5 Hz, 1H), 4.49 (d, J = 11.7 Hz, 1H), 4.54 (d, J = 11.7 Hz, 1H), 5.03 (dt, J = 6.9, 3.9 Hz, 1H), 5.67 (m, 2H), 7.27-7.37 (m, 5H).
(Step 4) (±)-1-[(1S,2S,3aS,7aR)-1-(benzyloxymethyl)-2,3,3a,4,7,7a-hexahydro-1H-inden-2-yl]-1H-1,2,4-triazole
At room temperature, the solution of 1H-1,2,4-triazole (21.1 mg, 0.297 mmol) in DMF (1 mL) was stirred, to which were added NaH (12.2 mg, 0.297 mmol) and a catalytic amount of 18-crown-6. After the reaction mixture was heated to 50 ℃ for 1 h, the solution of Step 3 compound (50.2 mg, 0.149 mmol) in DMF (1 mL) was added thereto. The brown mixture was heated to 120 ℃ and stirred for 2 h. To the reaction mixture was added distilled water (1 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined and washed with saturated aqueous NaHCO3 solution (10 mL) and saturated aqueous sodium chloride solution (10 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound (37 mg, 82%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.15-1.88 (m, 3H), 2.02-2.36 (m, 5H), 2.56 (m, 1H), 2.72 (dd, J = 9.3, 6.9 Hz, 1H), 3.41 (dd, J = 9.3, 4.5 Hz, 1H), 4.07 (d, J = 11.7 Hz, 1H), 4.13 (d, J = 11.7 Hz, 1H), 5.01 (dt, J = 6.9, 3.9 Hz, 1H), 5.66 (m, 2H), 7.15-7.35 (m, 5H) 7.92 (s, 1H), 8.07 (s, 1H).
(Step 5) (±)-1-[(1S,2S,3aS,7aR)-1-(hydroxymethyl)-2,3,3a,4,7,7a-hexahydro-1H-inden-2-yl]-1H-1,2,4-triazole
The solution of lithium powder (9.49 mg, 1.33 mmol) in THF (1 mL) was stirred under argon atmosphere at 0 ℃, to which was added naphthalene (1.70 mg, 0.0133 mmol). The reaction mixture was stirred until it expressed a dark green color, and then cooled to -78 ℃. The solution of Step 4 compound (41 mg, 0.133 mmol) in THF (1 mL) was added thereto. The brown mixture was warmed to 0 ℃ using an ice-bath and stirred for 2 h. Distilled water (1 mL) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (5 × 10 mL). The organic layers were combined, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 1:2 → ethyl acetate) to give the title compound (22 mg, 76%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 1.64-2.38 (m, 8H), 2.56 (m, 2H), 3.11 (m, 1H), 3.51 (d, J = 11.4 Hz, 1H), 5.05 (dt, J = 8.4, 8.4 Hz, 1H), 5.72 (s, 2H), 7.96 (s, 1H), 8.13 (s, 1H).
(Step 6) (±)-[(1S,2S,3aS,7aR)-2-(1H-1,2,4-triazol-1-yl)-2,3,3a,4,7,7a-hexahydro-1H-inden-1-yl]-carbaldehyde
The Step 5 compound (20.2 mg, 0.092 mmol) was reacted according to the same procedure as Step 10 of Preparation 3 to give the yellow title compound (19 mg).
(Step 7) (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(1H-1,2,4-triazol-1-yl)-2,3,3a,4,7,7a-hexahydro-1H-inden]-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Step 6 compound was reacted according to the same procedure as Example 1 to give the title compound (24 mg, 58%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 1.26 (m, 1H), 1,74 (m, 2H), 2.04-2.43 (m, 4H), 2.67 (m, 2H), 5.01 (dt, J = 8.4, 8.4 Hz, 1H), 5.74 (s, 2H), 5.87 (dd, J = 15.9, 8.7 Hz, 1H), 6.53 (d, J = 15.9 Hz, 1H), 7.04-7.17 (m, 2H), 7.21- 7.48 (m, 3H), 7.71 (dd, J = 8.1, 1.8 Hz, 1H), 7.96 (s, 1H), 8.02 (s, 1H), 8.66 (d, J = 1.8 Hz, 1H).
<Example 121> (±)-2-{(E)-2-[(1S,2R,3aR,7aR)-2-(1H-1,2,4-triazol-1-yl)-2,3,3a,4,7,7a-hexahydro-1H-inden]-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000096
The more polar compound (783 mg, 45%) from the Step 1 reaction of Example 120 was reacted according to the same procedure as Example 120 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.65 (m, 1H), 1.84-2.10 (m, 4H), 2.12-2.65 (m, 3H), 2.78-3.22 (m, 1H), 4.69 (m, 1H), 5.71 (s, 2H), 6.44 (d, J = 15.3 Hz, 1H), 6.82 (dd, J = 15.3, 10.8 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 7.23-7.48 (m, 4H), 7.80 (m, 1H), 8.05 (s, 1H), 8.08 (s, 1H), 8.76 (d, J = 1.8 Hz, 1H).
<Example 122> (±)-2-{(E)-2-[(1'S,3a'R,5'R,7a'R)-5'-methoxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000097
(Step 1) (±)-t-Butyl {[(1'R,3a'R,5'R,7a'R)-5'-methoxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-1’-yl]methoxy}dimethylsilane
In anhydrous DMF (10 mL) was dissolved the compound of Step 1 of Example 97 (0.100 g, 0.292 mmol). NaH (0.014 g, 0.350 mmol) and CH3I (0.022 mL, 0.350 mmol) were added at 0 ℃, which was then stirred for 12 h at room temperature, diluted with CH2Cl2 and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to give the title compound (0.095 g, 91%).
1H-NMR (300 MHz, CDCl3) δ 0.04 (s, 6H), 0.88 (s, 9H), 1.09~1.52 (m, 9H), 2.00~2.07 (m, 1H), 2.19~2.24 (m. 1H), 3.31(s, 3H), 3.36~3.40( m, 1H), 3.46~3.52 (m, 1H), 3.67~3.73 (m, 1H), 3.80~3.92 (m, 4H).
(Step 2) (±)-2-{(E)-2-[(1'S,3a'R,5'R,7a'R)-5'-methoxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Step 1 compound was reacted according to the same procedures as Steps 3 and 4 of Example 97―2 step reaction―to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 1.39~1.84 (m, 8H), 2.07~2.19 (m, 2H), 2.32~2.35 (m, 1H), 2.78~2.85 (m, 1H), 3.31 (s, 3H), 3.49 (brs, 1H), 3.78~3.95 (m, 4H), 6.53~6.77 (m, 2H), 7.05~7.11 (m, 1H), 7.26~7.47 (m, 4H), 7.80 (dd, 1H, J = 2.4, 2.4 Hz), 8.76 (d, 1H, J = 2.1 Hz).
<Example 123> (±)-2-{(E)-2-[(1'S,3a'R,5'S,7a'R)-5'-methoxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000098
(Step 1) (±)-(1'R,3a'R,5'S,7a'R)-1'-(benzyloxymethyl)-5'-methoxyoctahydrospiro[(1,3)dioxolane-2,2'-indene]
The compound of Step 1 of Preparation 10 (250 mg, 0.785 mmol) was reacted according to the same procedure as Step 1 of Example 122 to give the title compound (95 mg, 34%).
1H-NMR (300 MHz, CDCl3) δ 1.35~1.87 (m, 8H), 1.94~2.02 (m, 2H), 2.26~2.34 (m, 1H), 3.06~3.13 (m, 1H), 3.32 (s, 3H), 3.36~3.41 (m, 1H), 3.54~3.60 (m, 1H), 3.77~3.85 (m, 3H), 3.91~3.96 (m, 1H), 4.49 (s, 2H), 7.24~7.32 (m, 5H).
(Step 2) (±)-(1'R,3a'R,5'S,7a'R)-5'-methoxyoctahydrospiro[(1,3)dioxolane-2,2'-indene]-1'-carbaldehyde
The Step 1 compound was reacted according to the same procedures as Steps 8 and 9 of Preparation 7―2 step reaction―to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 1.23~1.42 (m, 3H), 1.54~1.86 (m, 4H), 2.13~2.20 (m, 2H), 2.54~2.56 m, 1H), 2.84~2.88 (m, 1H), 3.08~3.12(m, 1H), 3.33 (s, 3H), 3.71~3.99 (m, 4H), 9.62 (s, 1H).
(Step 3) (±)-2-{(E)-2-[(1'S,3a'R,5'S,7a'R)-5'-methoxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Step 2 compound (60 mg, 0.249 mmol) was reacted according to the same procedure as Example 1 to give the title compound (54 mg, 53%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 1.26 (m, 1H), 1,74 (m, 2H), 2.04-2.43 (m, 4H), 2.67 (m, 2H), 5.01 (dt, J = 8.4, 8.4 Hz, 1H), 5.74 (s, 2H), 5.87 (dd, J = 15.9, 8.7 Hz, 1H), 6.53 (d, J = 15.9 Hz, 1H), 7.04-7.17 (m, 2H), 7.21- 7.48 (m, 3H), 7.71 (dd, J = 8.1, 1.8 Hz, 1H), 7.96 (s, 1H), 8.02 (s, 1H), 8.66 (d, J = 1.8 Hz, 1H).
<Example 124> (±)-2-{(E)-2-[(1'S,3a'R,5'R,7a'R)-5'-hydroxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000099
(Step 1) (±)-2-{(E)-2-[(1'S,3a'R,5'R,7a'R)-5'-(t-butyldimethylsilyloxy)octahydrospiro[(1,3)dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Preparation 9 compound (700 mg, 2.04 mmol) was reacted according to the same procedure as Example 1 to give the title compound (700 mg, 70%).
1H-NMR (300 MHz, CDCl3) δ 2.0 (m, 10H), 2.5 (brs, 1H), 2.8 (m, 1H), 3.9 (m, 4H), 4.1 (s, 1H), 6.6 (d, 1H, J = 15.8 Hz), 6.75 (dd, 1H, J =8.4, 8.4 Hz), 7.3 (m, 5H), 7.8 (d, 1H, J =8.1 Hz), 8.8 (s, 1H).
(Step 2) (±)-2-{(E)-2-[(1'S,3a'R,5'R,7a'R)-5'-hydroxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Step 1 compound (350 mg, 0.68 mmol) was reacted according to the same procedure as Step 5 of Preparation 5 to give the title compound (210 mg, 77%).
1H-NMR (300 MHz, CDCl3) δ 2.0 (m, 10H), 2.5 (brs, 1H), 2.8 (m, 1H), 3.9 (m, 4H), 4.1 (s, 1H), 6.6 (d, 1H, J = 15.8 Hz), 6.75 (dd, 1H, J =8.4, 8.4 Hz), 7.3 (m, 5H), 7.8 (d, 1H, J =8.1 Hz), 8.8 (s, 1H).
<Example 125> (±)-4-(1'S,3a'R,5'S,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-yl}morpholine
Figure PCTKR2011004607-appb-I000100
(Step 1) (±)-(1'S,3a'R,5'R,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-yl}methanesulfonate
The Example 124 compound (130 mg, 0.328 mmol) was reacted according to the same procedure as Example 10 to give the title compound (100 mg, 65%).
1H-NMR (300 MHz, CDCl3) δ 2.0 (m, 9H), 2.4 (m, 1H), 2.7 (t, 1H, J =20.7 Hz), 3.0 (s, 3H), 3.9 (m, 4H), 5.0 (s, 1H), 6.5 (d, 1H, J = 15.8 Hz), 6.75 (dd, 1H, J = 8.4, 8.4 Hz), 7.1 (dd, 1H, J = 15.6 Hz), 7.3 (m, 4H), 7.8 (d, 1H, J = 8.1 Hz), 8.8 (s, 1H).
(Step 2) (±)-4-(1'S,3a'R,5'S,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-yl}morpholine
The solution of Step 1 compound (20 mg, 0.042 mmol) in DMF (2 mL) was stirred, to which were added morpholine (18 μL, 0.21 mmol) and diisopropylethylamine (27 mg, 0.21 mmol) while stirring. The reaction mixture was stirred for 12 h at 100 ℃, and H2O was added thereto to stop the reaction. The organic layer was separated from the mixture, and the aqueous layer was extracted with Et2O. The organic layers were combined and dried over anhydrous MgSO4. The organic layer was filtered and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (ethyl acetate) to give the title compound (10 mg, 53%).
1H-NMR (300 MHz, CDCl3) δ 2.0 (m, 6H), 2.25 (m, 4H), 2.6 (s, 4H), 2.8 (t, 1H), 3.8 (m, 4H), 6.5 (d, 1H, J = 15.9 Hz), 6.75 (dd, 1H, J = 8.4, 8.4 Hz), 7.3 (m, 5H), 7.8 (d, 1H, J = 8.1 Hz), 8.8 (s, 1H).
<Example 126> (±)-2-{(E)-2-[(1'S,3a'R,5'S,7a'R)-5'-(1H-1,2,4-triazol-1-yl)octahydrospiro[(1,3)dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000101
The compound of Step 1 of Example 125 (20 mg, 0.042 mmol) was reacted according to the same procedure as Step 4 of Example 120 to give the title compound (10 mg, 56%).
1H-NMR (300 MHz, CDCl3) δ 2.0 (m, 8H), 3.0 (t, 1H), 3.9 (m, 4H), 4.2 (m, 1H), 6.5 (d, 1H, J = 15.7 Hz), 6.75 (dd, 1H, J = 8.4, 8.4 Hz), 7.3 (m, 8H), 7.8 (d, 1H, J = 8.1 Hz), 8.0 (s, 1H), 8.1 (s, 1H), 8.8 (s, 1H).
<Example 127> (±)-4-{2-{(1'S,3a'R,5'R,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-yloxy}ethyl}morpholine
Figure PCTKR2011004607-appb-I000102
In anhydrous toluene (10 mL) was dissolved the compound of Example 124 (0.020 g, 0.050 mmol). NaH (0.0024 g, 0.060 mmol) was added thereto, and the mixture was stirred for 1 h at 100 ℃. 4-(2-Chloroethyl)morpholine was added and stirred for 12 h at 100 ℃. The mixture was diluted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 5:1) to give the title compound (12.0 mg, 46%) .
1H-NMR (300 MHz, CDCl3) δ 1.24~1.88 (m, 10H), 2.00~2.25 (m, 6H). 2.32~2.53 (m, 4H), 2.76~2.83 (m, 1H), 3.59~3.92 (m, 6H), 4.07~4.13 (m, 1H), 6.52~6.78 (m, 2H), 7.06~7.11 (m, 1H), 7.06~7.11 (m, 4H), 7.80 (dd, J = 2.4, 2.4 Hz, 1H), 8.77 (d, J = 1.5 Hz, 1H)
<Example 128> (±)-2-{(E)-2-[(1'S,3a'R,5'S,7a'R)-5'-hydroxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000103
(Step 1) (±)-2-{(E)-2-[(1'S,3a'R,5'S,7a'R)-5'-(t-butyldimethylsilyloxy)octahydrospiro[(1,3)dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Preparation 10 compound (860 mg, 2.52 mmol) was reacted according to the same procedure as Example 1 to give the title compound (1g, 83%).
1H-NMR (300 MHz, CDCl3) δ 0.0 (s, 6H), 0.8 (s, 9H), 1.5 (m, 10H), 2.8 (t, 1H, J = 12.3 Hz), 3.5 (m, 4H), 3.8 (m, 4H), 6.5 (d, 1H, J = 15.9 Hz), 6.7 (dd, 1H, J = 8.4, 8.4 Hz), 7.2 (m, 5H), 7.8 (d, 1H, J = 8.4 Hz), 8.8 (s, 1H).
(Step 2) (±)-2-{(E)-2-[(1'S,3a'R,5'S,7a'R)-5'-hydroxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Step 1 compound (1 g, 1.96 mmol) was reacted according to the same procedure as Step 5 of Preparation 5 to give the title compound (700 mg, 90%).
<Example 129> (±)-(1'S,3a'R,5'S,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-indene]-5'-carbonitrile
Figure PCTKR2011004607-appb-I000104
(Step 1) (±)-(1'S,3a'R,5'S,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-yl}methanesulfonate
The Example 128 compound (800 mg, 2.02 mmol) was reacted according to the same procedure as Example 10 to give the title compound (850 mg, 89%).
(Step 2) (±)-(1'S,3a'R,5'S,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-indene]-5'-carbonitrile
The solution of KCN (27 mg, 0.42 mmol) and a catalytic amount of 18-crown-6 in DMSO (3 mL) was stirred for 30 min at 30 ℃. The solution of Step 1 compound (100 mg, 0.21 mmol) in DMSO (2 mL) was added and stirred for 12 h at 60 ℃. To the reaction mixture was added H2O to stop the reaction. The organic layer was separated from the reaction mixture and the aqueous layer was extracted with CH2Cl2. The organic layers were combined and dried over anhydrous MgSO4. The organic layer was filtered and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to give the title compound (70 mg, 82%).
1H-NMR (300 MHz, CDCl3) δ 2.0 (m, 11H), 2.8 (t, 1H, J = 12.3 Hz), 3.9 (m, 4H), 6.55 (d, 1H, J = 15.7 Hz), 6.75 (dd, 1H, J = 8.4 Hz, J = 8.4 Hz), 7.3 (m, 5H), 7.8 (d, 1H, J = 8.1 Hz), 8.8 (s, 1H).
<Example 130> (±)-(1'S,3a'R,5'R,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-indene]-5'-amine
Figure PCTKR2011004607-appb-I000105
(Step 1) (±)-2-{(E)-2-[(1'S,3a'R,5'R,7a'R)-5'-azidooctahydrospiro[(1,3)dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
The compound of Step 1 of Example 129 (100 mg, 0.21 mmol) was reacted according to the same procedure as Step 1 of Example 115 to give the title compound (84 mg, 95%).
1H-NMR (300 MHz, CDCl3) δ 1.5 (m, 11H), 2.8 (t, 1H, J = 12.3 Hz), 3.5 (m, 4H), 6.5 (d, 1H, J = 8.4 Hz), 6.7 (dd, 1H, J = 8.4 Hz, J = 8.4 Hz), 7.3 (m, 5H), 7.8 (d, 1H, J = 8.1 Hz), 8.8 (s, 1H).
(Step 2) (±)-(1'S,3a'R,5'R,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-indene]-5'-amine
The solution of Step 1 compound (90 mg, 0.21 mmol) in THF (3 mL) was stirred, during which PPh3 (61 mg, 0.25 mmol) was added and stirred for 2 h at room temperature. A small amount of H2O was added to the reaction vessel, of which temperature was raised to 80 ℃ and stirred for 14 h. The mixture was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (CH2Cl2:MeOH = 10:1) to give the title compound (71 mg, 84%).
1H-NMR (300 MHz, CDCl3) δ 1.7 (m, 8H), 2.5 (m, 1H), 2.7 (t, 1H), 2.9 (d, 1H, J = 7.2 Hz), 3.3 (s, 1H), 3.9 (m, 4H), 6.5 (d, 1H, J = 8.4 Hz), 6.7 (dd, 1H, J = 8.4, 8.4 Hz), 7.3 (m, 5H), 7.8 (d, 1H, J = 8.1 Hz), 8.8 (s, 1H).
<Example 131> (±)-2-{(E)-2-[(1'S,3a'R,5'R,7a'R)-5'-(1H-pyrrol-1-yl)octahydrospiro[(1,3)dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000106
The Example 130 compound (20 mg, 0.05 mmol) was reacted according to the same procedure as Example 111 to give the title compound (18 mg, 81%).
1H-NMR (300 MHz, CDCl3) δ 1.8 (m, 9H), 2.7 (m, 2H), 3.9 (m, 4H), 4.1 (s, 1H), 6.1 (s, 2H), 6.5 (m, 1H), 6.8 (m, 2H), 7.3 (m, 6H), 7.8 (d, 1H, J = 8.1 Hz), 8.8 (s, 1H).
<Example 132> (±)-Ethyl (1'S,3a'R,5'R,7a'R)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate
Figure PCTKR2011004607-appb-I000107
The Example 130 compound (23 mg, 0.058 mmol) was reacted according to the same procedure as Example 109 to give the title compound (19 mg, 70%).
1H-NMR (300 MHz, CDCl3) δ 1.2 (m, 3H), 1.7 (m, 9H), 2.7 (t, 1H), 3.8 (m, 4H), 4.1 (m, 2H), 4.7 (s, 1H), 6.5 (d, 1H, J = 8.4 Hz), 6.75 (dd, 1H, J = 8.4, 8.4 Hz), 7.1 (m, 1H), 7.3 (m, 5H), 7.8 (d, 1H, J = 8.1 Hz), 8.8 (s, 1H).
<Example 133> (±)-(1S,2S,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-ol
Figure PCTKR2011004607-appb-I000108
(Step 1) 2-{(E)-2-[(1S,2R,3aR,5R,7aR)-2-(t-butyldimethylsilyloxy)-5-(methoxymethoxy)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Preparation 12 compound (10 mg, 0.029 mmol) was reacted according to the same procedure as Example 1 to give the title compound (9 mg, 62%).
1H-NMR (300 MHz, CDCl3) δ 0.86 (s, 9H), 1.40~1.55 (m, 3H), 1.72~1.86 (m, 5H), 2.13~2.17 (m, 1H), 2.51~2.67 (m, 1H), 3.37 (s, 3H), 3.85~3.87 (m, 1H), 4.09~4.12 (m, 1H), 4.67 (s, 2H), 6.05~6.64 (m, 2H), 7.07~7.08 (m, 1H), 7.25~7.44 (m, 4H), 7.79 (dd, 1H, J = 2.4, 2.4 Hz), 8.75 (d, 1H, J = 2.1 Hz).
(Step 2) (±)-(1S,2S,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-ol
The Step 1 compound (130 mg, 0.263 mmol) was reacted according to the same procedure as Step 5 of Preparation 5 to give the title compound (102 mg, 97%).
1H-NMR (300 MHz, CDCl3) δ 1.25~2.03 (m, 10H), 2.17~2.38 (m, 1H), 2.56~2.64 (m, 1H), 3.38 (s, 3H), 3.88~4.20 (m, 2H), 4.67 (s, 2H), 6.57~6.75 (m, 2H), 7.06~7.11 (m, 1H), 7.26~7.47 (m, 4H), 7.82 (dd, 1H, J = 2.1, 2.4 Hz), 8.76 (d, 1H, J = 2.1 Hz).
<Example 134> (±)-(1S,2S,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-yl methanesulfonate
Figure PCTKR2011004607-appb-I000109
The Example 133 compound (100 mg, 0.263 mmol) was reacted according to the same procedure as Example 10 to give the title compound (110 mg, 88%).
1H-NMR (300 MHz, CDCl3) δ 1.50~1.95 (m, 8H), 2.39~2.45 (m, 2H), 2.93~2.97 (m, 4H), 3.38 (s, 3H), 3.88~3.90 (m, 1H), 3.89 (s, 2H), 4.96~5.00 (m, 1H), 6.59~6.76 (m, 2H), 7.06~7.13 (m, 1H), 7.25~7.46 (m, 4H), 7.83 (dd, 1H, J = 2.4, 2.4 Hz), 8.76 (d, 1H, J = 1.2 Hz).
<Example 135> (±)-(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-indene-2-amine
Figure PCTKR2011004607-appb-I000110
(Step 1) (±)-2-{(E)-2-[(1S,2R,3aS,5R,7aR)-2-azido-5-(methoxymethoxy)octahydro-1H-inden]-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Example 134 compound (65 mg, 0.136 mmol) was reacted according to the same procedure as Step 1 of Example 115 to give the title compound (54 mg, 94%).
1H-NMR (300 MHz, CDCl3) δ 1.26~1.66 (m, 4H), 1.77~1.94 (m, 3H), 2.00~2.14 (m, 2H), 2.51~2.53 (m, 1H), 2.75~2.84 (m, 1H), 3.38 (s, 3H), 3.83~3.85 (m, 1H), 4.17~4.22 (m, 1H), 4.67 (s, 2H), 6.57~6.80 (m, 2H), 7.06~7.11 (m, 1H), 7.26~7.48 (m, 4H), 7.82 (dd, 1H, J = 2.4, 2.4 Hz), 8.78(d, 1H, J = 1.5 Hz).
(Step 2) (±)-(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-indene-2-amine
The Step 1 compound (50 mg, 0.118 mmol) was reacted according to the same procedure as Step 2 of Example 130 to give the title compound (40 mg, 85%).
1H-NMR (300 MHz, CDCl3) δ 1.25~1.96 (m, 12H), 2.10~2.19 (m, 1H), 2.48~2.50 (m, 1H), 2.67~2.75 (m, 1H), 3.38 (s, 3H), 3.63~3.70 (m, 1H), 3.83~3.85 (m, 1H), 4.68 (s, 2H), 6.54~6.84 (m, 2H), 7.05~7.11 (m, 1H), 7.26~7.47 (m, 4H), 7.80 (dd, 1H, J = 2.4, 2.4 Hz), 8.76 (d, 1H, J = 2.4 Hz).
<Example 136> (±)-N-{(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-yl}methanesulfonamide
Figure PCTKR2011004607-appb-I000111
The Example 135 compound (40 mg, 0.100 mmol) was reacted according to the same procedure as Example 47 to give the title compound (32 mg, 67%).
1H-NMR (300 MHz, CDCl3) δ 1.35~1.56(m, 3H), 1.66~1.87 (m, 4H), 2.02~2.14 (m, 2H), 2.56~2.58 (m, 1H), 2.83~2.89 (m, 1H), 3.91 (s, 3H), 3.37 (s, 3H), 3.78~3.82 (m, 1H), 4.10~4.26 (m, 1H), 4.52~4.54 (m, 1H), 4.66 (s, 2H) 6.55~6.79 (m, 2H), 7.07~7.12 (m, 1H), 7.26~7.45 (m, 4H), 7.81 (dd, 1H, J = 2.4, 2.4 Hz), 8.75 (d, 1H, J = 2.4 Hz).
<Example 137> (±)-N-{(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-hydroxyoctahydro-1H-inden-2-yl}methanesulfonamide
Figure PCTKR2011004607-appb-I000112
The Example 136 compound (10 mg, 0.021 mmol) was reacted according to the same procedure as Example 100 to give the title compound (8 mg, 86%).
1H-NMR (300 MHz, CDCl3) δ 1.25~1.42 (m, 2H), 1.51~2.15 (m, 8H), 2.60~2.67 (m, 1H), 2.82~2.78 (m, 1H), 2.91 (s, 3H), 3.57~3.72 (m, 1H), 3.94~3.95 (m, 1H), 4.22~4.27 (m, 1H), 4.84~4.78 (m, 1H), 6.55~6.79 (m, 2H), 7.07~7.13 (m, 1H), 7.25~7.48 (m, 4H), 7.82 (dd, 1H, J = 2.1, 2.4 Hz), 8.74 (d, 1H, J = 1.2 Hz).
<Example 138> (±)-2-{(E)-2-[(1S,2R,3aS,5R,7aR)-5-(methoxymethoxy)-2-(1H-pyrrol-1-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000113
The Example 135 compound (25 mg, 0.063 mmol) was reacted according to the same procedure as Example 111 to give the title compound (18 mg, 63%).
1H-NMR (300 MHz, CDCl3) δ 1.35~1.47 (m, 1H), 1.58~1.97 (m, 6H), 2.08~2.25 (m, 2H), 2.40~2.49 (m, 2H), 2.62~2.64 (m, 1H), 2.92~3.02 (m, 1H), 3.41 (s, 3H), 3.92 (brs, 1H), 4.70 (s, 2H), 4.72~4.82 (m, 1H), 5.53~5.58 (m, 1H), 6.16 (d, 2H, J = 2.1 Hz), 6.48~6.55 (m, 1H), 6.72 (d, 2H), 7.04~7.13 (m, 2H), 7.23~7.46 (m, 3H), 7.72 (dd, 1H, J = 2.1, 2.4 Hz), 8.69(d, 1H, J = 2.1 Hz).
<Example 139> (±)-1-{(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-yl}pyrrolidin-2-one
Figure PCTKR2011004607-appb-I000114
The Example 135 compound (25 mg, 0.063 mmol) was reacted according to the same procedure as Example 112 to give the title compound (18 mg, 62%).
1H-NMR (300 MHz, CDCl3) δ 1.25~2.10 (m, 10H), 2.17~2.31 (m, 2H), 2.53~2.57 (m, 1H), 2.89~2.98 (m, 1H), 3.38 (s, 3H), 3.40~3.83 (m, 2H), 3.82~3.84 (m, 1H), 4.67 (s, 3H), 5.61~5.58 (m, 1H), 6.49~6.74 (m, 2H), 7.06~7.12 (m, 1H), 7.25~7.49 (m, 4H), 7.80 (dd, 1H, J = 2.4, 2.4 Hz), 8.74(d, 1H, J = 2.4 Hz).
<Example 140> (±)-{(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-yl}pivalamide
Figure PCTKR2011004607-appb-I000115
The Example 135 compound (0.010g, 0.025 mmol) was dissolved in anhydrous CH2Cl2 (5 mL). NEt3 (0.004 mL, 0.030 mmol) and pivaloyl chloride (0.004 mL, 0.030 mmol) were slowly added thereto. The mixture was stirred for 1 h at room temperature, diluted with CH2Cl2 and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate =1:1) to give the title compound (0.007 g, 56%).
1H-NMR (300 MHz, CDCl3) δ 1.05 (s, 9H), 1.41~1.86 (m, 7H), 2.01~2.09 (m, 2H), 2.53~2.55 (m, 1H), 2.93~2.96 (m, 1H), 3.37 (s, 3H), 3.81~3.53 (m, 1H), 4.67 (s, 3H), 5.63~5.66 (m, 1H), 6.63~6.72 (m, 2H), 7.07~7.10 (m, 1H), 7.22~7.44 (m, 4H), 7.78 (dd, 1H, J = 2.4, 2.1 Hz), 8.73 (d, 1H, J = 2.1 Hz).
<Example 141> (±)-1-{(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-yl}sultam
Figure PCTKR2011004607-appb-I000116
The Example 135 compound (0.025g, 0.063 mmol) was dissolved in anhydrous CH2Cl2 (5 mL). NEt3 (0.010 mL, 0.075 mmol) and 3-chloropropanesulfonyl chloride (0.009 mL, 0.075 mmol) were added thereto and stirred for 2 h at room temperature. The solvent was distilled under reduced pressure and the residue was dissolved in anhydrous THF (3 mL). NaH (0.003g, 0.075 mmol) was added and stirred under reflux for 4 h. The reaction mixture was diluted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to give the title compound (0.010 g, 0.020 mmol).
1H-NMR (300 MHz, CDCl3) δ 1.25~1.54 (m, 3H), 1.70~1.98 (m, 5H), 2.07~2.27 (m, 4H), 2.56~2.60 (m, 1H), 2.98~3.01 (m, 1H), 2.92~3.02 (m, 1H), 3.07~3.12 (m, 2H), 3.19~3.24 (m, 1H), 3.36 (s, 2H), 3.81~3.82 (m, 1H), 4.28~4.33 (m, 1H), 4.65 (brs, 2H), 6.57~6.89 (m, 2H), 7.06~7.09 (m, 1H), 7.26~7.56 (m, 4H), 7.83 (dd, 1H, J = 2.1, 2.4 Hz), 8.75(d, 1H, J = 2.1 Hz).
<Example 142> (±)-(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-ol
Figure PCTKR2011004607-appb-I000117
(Step 1) 2-{(E)-2-[(1S,2R,3aR,5R,7aR)-2-(t-butyldimethylsilyloxy)-5-(methoxymethoxy)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Preparation 13 compound (29 mg, 0.084 mmol) was reacted according to the same procedure as Example 1 to give the title compound (24 mg, 57%).
1H-NMR (300 MHz, CDCl3) δ 0.0 (s, 6H), 0.8 (s, 9H), 1.8 (m, 10H), 2.5 (m, 1H), 3.8 (m, 1H), 4.4 (m, 1H), 4.7(s, 2H), 6.5 (d, 1H, J = 8.4 Hz), 6.8 (dd, 1H, J = 8.4, 8.4 Hz), 7.2 (m, 5H), 7.8 (d, 1H, J = 8.1 Hz), 8.8 (s, 1H).
(Step 2) (±)-(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-ol
The Step 1 compound (24 mg, 0.046 mmol) was reacted according to the same procedure as Step 5 of Preparation 5 to give the title compound (9 mg, 41%).
<Example 143> (±)-(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-yl methanesulfonate
Figure PCTKR2011004607-appb-I000118
The Example 142 compound (9 mg, 0.018 mmol) was reacted according to the same procedure as Example 10 to give the title compound (7 mg, 82%).
1H-NMR (300 MHz, CDCl3) δ 1.5 (m, 10H), 2.6 (m, 1H), 2.9 (m, 4H), 3.4 (s, 3H), 3.8 (m, 1H), 4.6(s, 2H), 6.6 (d, 1H, J = 8.4 Hz), 6.7 (dd, 1H, J =8.4, 8.4 Hz), 7.2 (m, 5H), 7.8 (d, 1H, J = 8.1 Hz), 8.8 (s, 1H).
<Example 144> (±)-(1S,2S,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-indene-2-amine
Figure PCTKR2011004607-appb-I000119
(Step 1) (±)-2-{(E)-2-[(1S,2S,3aS,5R,7aR)-2-azido-5-(methoxymethoxy)octahydro-1H-inden]-1-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Example 143 compound (7 mg, 0.014 mmol) was reacted according to the same procedure as Step 1 of Example 115 to give the title compound (6 mg, 96%).
(Step 2) (±)-(1S,2S,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-indene-2-amine
The Step 1 compound (6 mg, 0.014 mmol) was reacted according to the same procedure as Step 2 of Example 130 to give the title compound (5 mg, 90%).
<Example 145> (±)-N-{(1S,2S,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-yl}methanesulfonamide
Figure PCTKR2011004607-appb-I000120
The Example 144 compound (5 mg, 0.012 mmol) was reacted according to the same procedure as Example 47 to give the title compound (265 mg, 53%).
<Example 146> (±)-t-Butyl (1'S,3a'S,7a'R){1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro[(1,3)dioxolane-2,2'-inden]-6'-ylcarbamate
Figure PCTKR2011004607-appb-I000121
The Preparation 6 compound (200 mg, 0.615 mmol) was reacted according to the same procedure as Example 1 to give the title compound (3 mg, 87%).
1H NMR (300 MHz, CDCl3) δ 0.85-1.40 (m, 4H), 1.41 (s, 9H), 1.62 (dd, 10.3, 10.3 Hz, 1H), 1.89 (d, J = 8.1 Hz, 2H), 2.07 (m, 3H), 2.43 (dd, J = 7.6, 7.6 Hz, 1H), 3.50 (m, 1H), 3.78 (m, 2H), 3.94 (m, 2H), 4.42 (br s, 1H), 6.52-6.73 (m, 2H), 7.10 (dd, J = 8.1 Hz, 1H), 7.27-7.45 (m, 4H), 7.81 (m, 2.4 Hz, 1H), 8.76 (d, J = 1.8 Hz, 1H).
<Example 147> (±)-t-Butyl (1'S,3a'S,7a'R){1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate
Figure PCTKR2011004607-appb-I000122
The Preparation 5 compound was reacted according to the same procedure as Example 1 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 0.85-1.34 (m, 4H), 1.44 (s, 9H), 1.40-1.67 (m, 3H), 1.83 (m, 1H), 2.10 (dd, J = 12.6, 6.0 Hz, 1H), 2.19 (d, J = 11.7 Hz, 1H), 2.42 (dd, J = 11.4, 9.6 Hz, 1H), 3.52 (m, 1H), 3.77 (m, 2H), 3.94 (m, 2H), 4.20 (d, J = 7.2 Hz, 1H), 6.56 (d, J = 15.6 Hz, 1H), 6.74 (dd, J = 15.6, 9.6 Hz, 1H), 7.10 (dd, J = 8.2, 1.3 Hz, 1H), 7.25-7.47 (m, 4H), 7.81 (dd, J = 8.1, 2.4 Hz, 1H), 8.71 (d, J = 2.4 Hz, 1H).
<Example 148> (±)-t-Butyl (1S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-oxooctahydro-1H-inden]-6-ylcarbamate
Figure PCTKR2011004607-appb-I000123
The solution of Example 146 compound (235 mg, 0.475 mmol) in acetone : water (10:1, 5 mL) was stirred at room temperature, during which p-toluenesulfonic acid (27.1 mg, 0.143 mmol) was added. After stirring for 12 h, saturated NaHCO3 (5 mL) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 10 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to give the title compound (107 mg, 50%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.00-1.77 (m, 4H), 1.43 (s, 9H), 1.95 (dd, J = 18.0, 11.8 Hz, 1H), 1.96-2.18 (m, 3H), 2.38 (d, J = 11.1 Hz, 1H), 2.50 (dd, J = 18.0, 6.1 Hz, 1H), 2.74 (dd, J = 11.5, 6.0 Hz, 1H), 3.62 (m, 1H), 4.44 (br s, 1H), 6.61 (m, 2H), 7.08 (dd, J = 8.4, 2.4 Hz, 1H), 7.22-7.47 (m, 4H), 7.81 (dd, J = 8.2, 2.4 Hz, 1H), 8.78 (d, J = 2.4 Hz, 1H).
<Example 149> (±)-t-Butyl (1S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-oxooctahydro-1H-inden]-5-ylcarbamate
Figure PCTKR2011004607-appb-I000124
The Example 147 compound was reacted according to the same procedure as Example 148 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.04-1.84 (m, 5H), 1.44 (s, 9H), 1.97 (dd, J = 18.0, 12.3 Hz, 1H), 2.17 (m, 2H), 2.37 (d, J = 11.7 Hz, 1H), 2.50 (dd, J = 18.0, 6.3 Hz, 1H), 2.71 (d, J = 12.0 Hz, 1H), 3.62 (m, 1H), 4.46 (br s, 1H), 6.64 (m, 2H), 7.08 (dd, J = 8.4 Hz, 1H), 7.26-7.47 (m, 4H), 7.80 (dd, J = 8.1, 1.8 Hz, 1H), 8.75 (d, J = 1.8 Hz, 1H).
<Example 150> (±)-t-Butyl (1S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxy-2-methyloctahydro-1H-inden]-6-ylcarbamate
Figure PCTKR2011004607-appb-I000125
The solution of Example 148 compound (110 mg, 0.244 mmol) in Et2O (5 mL) was stirred under -78 ℃ nitrogen. Methyllithium (305 μL, 1.6 M Et2O solution, 0.488 mmol) was added thereto. This orange reaction mixture was warmed to 0 ℃ and stirred for 1 h. To the reaction mixture was added saturated aqueous NH4Cl solution (1 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound (82 mg, 72%) as a pale yellow liquid.
1H NMR (300 MHz, CDCl3) δ 0.94-1.70 (m, 4H), 1.36 (s, 3H), 1.41 (s, 9H), 1.86-2.15 (m, 7H), 3.52 (m, 1H), 4.36 (br s, 1H), 6.55 (d, J = 15.7 Hz, 1H), 6.72 (dd, J = 15.7, 8.7 Hz, 1H), 7.09 (dd, J = 8.3 Hz, 1H), 7.26-7.47 (m, 4H), 7.82 (dd, J = 8.1, 2.4 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H).
<Example 151> (±)-t-Butyl (1S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxy-2-methyloctahydro-1H-inden]-5-ylcarbamate
Figure PCTKR2011004607-appb-I000126
The Example 149 compound was reacted according to the same procedure as Example 150 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 0.94-1.65 (m, 4H), 1.33 (s, 3H), 1.44 (s, 9H), 1.85 (d, J = 9.3 Hz, 1H), 1.97-2.09 (m, 5H), 2.18 (d, J = 12.6 Hz, 1H), 3.47 (m, 1H), 4.41 (br s, 1H), 6.57 (d, J = 15.6 Hz, 1H), 6.77 (dd, J = 15.6, 8.8 Hz, 1H), 7.10 (dd, J = 8.2 Hz, 1H), 7.25-7.47 (m, 4H), 7.81 (dd, J = 8.2, 2.4 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H).
<Example 152> (±)-t-Butyl (1'S,3a'R,7a'R){1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate
Figure PCTKR2011004607-appb-I000127
The Preparation 11 compound (97 mg, 0.29 mmol) was reacted according to the same procedure as Example 1 to give the title compound (90 mg, 65%).
1H NMR (300 MHz, CDCl3) δ 1.2 (m, 2H), 1.4 (s, 9H), 1.7 (m, 5H), 2.2 (m, 4H), 2.85 (m, 1H), 3.8 (m, 4H), 6.5 (d, 1H, J =15.8 Hz), 6.7 (m, 1H), 7.3 (m, 5H), 7.8 (d, 1H, J = 8.1 Hz), 8.8 (s, 1H).
<Example 153> (±)-t-Butyl (1S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-oxooctahydro-1H-inden]-5-ylcarbamate
Figure PCTKR2011004607-appb-I000128
The Example 152 compound (114 mg, 0.23 mmol) was reacted according to the same procedure as Example 148 to give the title compound (50 mg, 49%).
1H NMR (300 MHz, CDCl3) δ 1.2 (t, 1H, J = 10.5 Hz), 1.4 (d, 9H, J = 8.7 Hz), 1.6 (s, 2H), 2.3 (m, 5H), 3.0 (dd, 1H, J = 6.6, 6.6 Hz), 3.5 (m, 1H), 4.5 (m, 1H), 6.6 (m, 1H), 7.1 (dd, 1H, J =2.5 Hz), 7.4 (m, 5H), 7.8 (d, 1H, J =8 .1 Hz), 8.8 (s, 1H).
<Example 154> (±)-t-Butyl (1S,2S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxyoctahydro-1H-inden]-5-ylcarbamate
Figure PCTKR2011004607-appb-I000129
(Step 1) (±)-t-Butyl (1S,2S,3aS,7aR)-2-(t-butyldimethylsilyloxy)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-5-ylcarbamate
The Preparation 7 compound (90 mg, 0.23 mmol) was reacted according to the same procedure as Example 1 to give the title compound (92 mg, 71%).
1H NMR (300 MHz, CDCl3) δ 0.00 (s, 3H), 0.02 (s, 3H), 0.88 (s, 9H), 0.96-1.43 (m, 5H), 1.46 (s, 9H), 1.76-1.88 (m, 2H), 2.04-2.35 (m, 4H), 3.49 (m, 1H), 4.40 (m, 2H), 6.51 (d, J = 16.0 Hz, 1H), 6.80 (dd, J = 16.0, 9.3 Hz, 1H), 7.09 (t, J = 8.2 Hz, 1H), 7.32-7.48 (m, 4H), 7.81 (d, J = 8.4 Hz, 1H), 8.76 (s, 1H).
(Step 2) (±)-t-Butyl (1S,2S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxyoctahydro-1H-inden]-5-ylcarbamate
The Step 1 compound (92.1 mg, 0.162 mmol) was reacted according to the same procedure as Step 5 of Preparation 5 to give the title compound (52.1 mg, 71%).
1H NMR (300 MHz, CDCl3) δ 0.96-1.41 (m, 5H), 1.44 (s, 9H), 1.85 (m, 2H), 1.98-2.29 (m, 3H), 2.39 (m, 1H), 3.49 (m, 1H), 4.25 (t, J = 6.6 Hz, 1H), 4.42 (m, 2H), 6.57 (d, J = 15.9 Hz, 1H), 6.82 (dd, J = 15.9, 8.7 Hz, 1H), 7.08 (dd, J = 8.1 Hz, 1H), 7.22-7.46 (m, 4H), 7.77 (d, J = 8.1 Hz, 1H), 8.72 (s, 1H).
<Example 155> (±)-t-Butyl (1S,2R,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxyoctahydro-1H-inden]-5-ylcarbamate
Figure PCTKR2011004607-appb-I000130
(Step 1) (±)-t-Butyl (1S,2R,3aS,7aR)-2-(t-butyldimethylsilyloxy)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-5-ylcarbamate
The Preparation 8 compound was reacted according to the same procedure as Example 1 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 0.01 (s, 6H), 0.86 (s, 9H), 0.93-1.34 (m, 4H), 1.43 (s, 9H), 1.51-2.30 (m, 7H), 3.49 (m, 1H), 4.14 (m, 1H), 4.41 (d, J = 5.7 Hz, 1H), 6.52 (d, J = 15.6 Hz, 1H), 6.67 (dd, J = 15.6, 8.7 Hz, 1H), 7.07 (dd, J = 8.4, 2.1 Hz, 1H), 7.25-7.46 (m, 4H), 7.78 (dd, J = 8.2, 1.5 Hz, 1H), 8.76 (d, J = 1.5 Hz, 1H).
(Step 2) (±)-t-Butyl (1S,2R,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxyoctahydro-1H-inden]-5-ylcarbamate
The Step 1 compound was reacted according to the same procedure as Step 5 of Preparation 5 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.02-1.41 (m, 4H), 1.44 (s, 9H), 1.52-1.86 (m, 4H), 2.01-2.40 (m, 3H), 2.68 (d, J = 7.5 Hz, 1H), 3.50 (m, 1H), 4.26 (m, 1H), 4.41 (d, J = 7.5 Hz, 1H), 6.58 (d, J = 15.6 Hz, 1H), 6.74 (dd, J = 15.6, 8.7 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 7.25-7.47 (m, 4H), 7.79 (d, J = 8.4 Hz, 1H), 8.75 (s, 1H).
<Example 156> (±)-(1S,2S,3aS,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-2-yl methanesulfonate
Figure PCTKR2011004607-appb-I000131
The Example 154 compound was reacted according to the same procedure as Example 10 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 0.98-1.19 (m, 2H), 1.31-1.56 (m, 2H), 1.44 (s, 9H), 1.66 (m, 2H), 1.90-2.09 (m, 2H), 2.24 (m, 1H), 2.43 (m, 1H), 2.56 (ddd, J = 7.2, 14.1, 7.2 Hz, 1H), 2.98 (s, 3H), 3.38 (m, 1H), 4.43 (d, J = 7.5 Hz, 1H), 5.20 (dt, J = 6.9, 6.9 Hz, 1H), 6.59 (d, J = 15.9 Hz, 1H), 6.75 (dd, J = 15.9, 8.7 Hz, 1H), 7.09 (dd, J = 8.1 Hz, 1H), 7.26-7.47 (m, 4H), 7.80 (dd, J = 8.1, 2.1 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H).
<Example 157> (±)-(1S,2R,3aS,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-2-yl methanesulfonate
Figure PCTKR2011004607-appb-I000132
The Example 155 compound (52.1 mg, 0.115 mmol) was reacted according to the same procedure as Example 10 to give the title compound (47.2 mg, 87%).
1H NMR (300 MHz, CDCl3) δ 1.05-1.41 (m, 4H), 1.44 (s, 9H), 1.67-1.95 (m, 4H), 12.05-2.25 (m, 2H), 2.56 (m, 1H), 2.98 (s, 3H), 3.52 (m, 1H), 4.41 (d, J = 7.5 Hz, 1H), 5.01 (dt, J = 5.7, 5.7 Hz, 1H), 6.62 (d, J = 15.6 Hz, 1H), 6.75 (dd, J = 15.6, 8.4 Hz, 1H), 7.109 (dd, J = 8.4 Hz, 1H), 7.26-7.48 (m, 4H), 7.81 (d, J = 8.1 Hz, 1H), 8.75 (s, 1H).
<Example 158> (±)-t-Butyl (1S,2R,3aR,7aR)-2-amino-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-5-ylcarbamate
Figure PCTKR2011004607-appb-I000133
(Step 1) (±)-t-Butyl (1S,2R,3aS,7aR)-2-azido-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-5-ylcarbamate
The Example 156 compound (40 mg, 0.0857 mmol) was reacted according to the same procedure as Step 1 of Example 115 to give the title compound (37 mg, 90%).
1H NMR (300 MHz, CDCl3) δ 0.85-1.32 (m, 5H), 1.44 (s, 9H), 1.61-1.79 (m, 2H), 1.84-2.23 (m, 3H), 2.32 (m, 1H), 3.50 (m, 1H), 3.85 (m, 1H), 4.41 (d, J = 6.3 Hz, 1H), 6.61 (d, J = 15.3 Hz, 1H), 6.74 (dd, J = 15.3, 8.7 Hz, 1H), 7.08 (dd, J = 8.4, 1.2 Hz, 1H), 7.25-7.47 (m, 4H), 7.81 (dd, J = 8.1, 2.1 Hz, 1H), 8.78 (d, J = 2.1 Hz, 1H).
(Step 2) (±)-t-Butyl (1S,2R,3aR,7aR)-2-amino-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-5-ylcarbamate
The Step 1 compound was reacted according to the same procedure as Step 2 of Example 130 to give the title compound.
<Example 159> (±)-t-Butyl (1S,2R,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(methanesulfonamido)octahydro-1H-inden-5-ylcarbamate
Figure PCTKR2011004607-appb-I000134
The Example 158 compound was reacted according to the same procedure as Example 47 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 0.85-1.30 (m, 4H), 1.44 (s, 9H), 1.79-2.25 (m, 5H), 2.50 (m, 2H), 2.89 (s, 3H), 4.12 (m, 1H), 4.42 (m, 2H), 6.55 (d, J = 15.3 Hz, 1H), 6.75 (dd, J = 15.3, 8.7 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 7.29-7.48 (m, 4H), 7.82 (d, J = 7.8 Hz, 1H), 8.78 (s, 1H).
<Example 160> (±)-t-Butyl (1S,2R,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(1H-1,2,3-triazol-1-yl)octahydro-1H-inden-5-ylcarbamate
Figure PCTKR2011004607-appb-I000135
The solution of Step 1 azide compound of Example 158 (17.0 mg, 0.0356 mmol) in toluene (2 mL) was stirred at room temperature, during which (triphenylphosphoranylidene)acetaldehyde (32.0 mg, 0.107 mmol) was added thereto. The brown reaction mixture was stirred under reflux for 16 h. The reaction vessel was cooled, and the mixture was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1 - 1:2) to give the title compound as a pale yellow solid.
1H NMR (300 MHz, CDCl3) δ 0.68-1.35 (m, 4H), 1.45 (s, 9H), 1.74-2.17 (m, 3H), 2.33 (m, 2H), 2,554-2.83 (m, 2H), 3.56 (m, 1H), 4.45 (br s, 1H), 5.17 (m, 1H), 5.69 (dd, J = 15.9, 9.1 Hz, 1H), 6.50 (d, J = 15.9 Hz, 1H), 7.07 (m, 3H), 7.26-7.70 (m, 6H), 8.74 (d, J = 2.1 Hz, 1H).
Figure PCTKR2011004607-appb-I000136
<Example 161> (±)-t-Butyl (1S,2R,3aR,7aR)-2-(N-cyclopropylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-5-ylcarbamate
The solution of Example 156 compound (20.0 mg, 0.0429 mmol) in CH3CN (2 mL) was stirred at room temperature, during which cyclopropylamine (9.00 μL, 0.129 mmol) and K2CO3 (18.2 mg, 0.129 mmol) were added thereto. After the mixture was stirred for 16 h, ice water (1 mL) was added to stop the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 10 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound (7 mg, 33%) as a pale yellow liquid.
1H NMR (300 MHz, CDCl3) δ 0.30-0.54 (m, 2H), 0.65-0.88 (m, 2H), 0.97-1.41 (m, 5H), 1.44 (s, 9H), 1.60-1.91 (m, 3H), 2.04-2.46 (m, 4H), 3.50 (m, 1H), 4.41 (m, 2H), 6.59 (d, J = 15.9 Hz, 1H), 6.84 (dd, J = 15.9, 8.7 Hz, 1H), 7.08 (dd, J = 8.7, 1.2 Hz, 1H), 7.26-7.47 (m, 4H), 7.80 (dd, J = 8.1, 2.4 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H).
<Example 162> (±)-t-Butyl (1S,2R,3aS,7aR)-2-(N-cyclopropyl-N-methylsulfonamido)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-5-ylcarbamate
The solution of Example 161 compound (7.00 mg, 0.0142 mmol) in CH2Cl2 (1 mL) was stirred at room temperature, during which methanesulfonyl chloride (2.00 μL, 0.0284 mmol) and NEt3 (4.00 μL, 0.0284 mmol) were added. After stirring for 10 h, saturated NaHCO3 (1 mL) was added to the mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound (5.6 mg, 70%) as a pale yellow liquid.
1H NMR (300 MHz, CDCl3) δ 0.68-1.41 (m, 10H), 1.44 (s, 9H), 1.90-2.60 (m, 6H), 2.93 (s, 3H), 4.41 (m, 1H), 6.59 (d, J = 15.9 Hz, 1H), 6.75 (d, J = 15.9, 8.7 Hz, 1H), 7.07 (dd, J = 8.1, 2.1 Hz, 1H), 7.26-7.45 (m, 4H), 7.81 (dd, J = 8.1, 2.4 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H).
<Example 163> (±)-1-{(1S,2R,3aS,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-sultam
Figure PCTKR2011004607-appb-I000137
The solution of Example 158 compound (40 mg) in CH2Cl2 (2 mL) was stirred at room temperature, and 3-chloropropanesulfonyl chloride (10.0 μL, 0.0797 mmol) and NEt3 (11.2 μL, 0.0797 mmol) were added thereto. After stirring for 9 h, saturated NaHCO3 (1 mL) was added to the mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give pale yellow sulfonamide (18 mg) which was used in the next reaction without further purification.
The solution of sulfonamide compound (18 mg) in DMF (2 mL) was stirred at room temperature, to which was added 1,8-diazabicyclo[5.4.0]undec-7-ene (20.0 μL, 0.0535 mmol). After stirring for 16 h at room temperature, the reaction mixture was diluted with EtOAc (3 mL) and washed with 1 N HCl (2 × 5 mL) and brine (5 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to give the title compound (10 mg) as a pale yellow liquid.
1H NMR (300 MHz, CDCl3) δ 0.82-1.41 (m, 6H), 1.44 (s, 9H), 1.85-2.22 (m, 6H), 2.57 (m, 1H), 3.06 (m, 2H), 3.19-3.41 (m, 2H), 3.50 (m, 1H), 4.34 (m, 2H), 6.57 (d, J = 16.0 Hz, 1H), 6.86 (dd, J = 16.0, 7.2 Hz, 1H), 7.10 (dd, J = 8.4, 1.2 Hz, 1H), 7.29-7.55 (m, 4H), 7.82 (dd, J = 8.1, 1.8 Hz, 1H), 8.74 (d, J = 1.8 Hz, 1H).
<Example 164> (±)-t-Butyl (1S,2S,3aR,7aR)-2-amino-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-5-ylcarbamate
Figure PCTKR2011004607-appb-I000138
The Example 157 compound was reacted according to the same procedure as Example 158 to give the the title compound.
1H NMR (300 MHz, CDCl3) δ 0.85-1.32 (m, 5H), 1.44 (s, 9H), 1.61-1.79 (m, 2H), 1.84-2.23 (m, 3H), 2.32 (m, 1H), 3.50 (m, 1H), 3.85 (m, 1H), 4.41 (d, J = 6.3 Hz, 1H), 6.61 (d, J = 15.3 Hz, 1H), 6.74 (dd, J = 15.3, 8.7 Hz, 1H), 7.08 (dd, J = 8.4, 1.2 Hz, 1H), 7.25-7.47 (m, 4H), 7.81 (dd, J = 8.1, 2.1 Hz, 1H), 8.78 (d, J = 2.1 Hz, 1H).
<Example 165> (±)-t-Butyl 1-{(1S,2S,3aS,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-sultam
Figure PCTKR2011004607-appb-I000139
The Example 164 compound was reacted according to the same procedure as Example 163 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 0.85-1.34 (m, 4H), 1.44 (s, 9H), 1.64-2.20 (m, 6H), 2.35 (m, 3H), 3.12 (m, 2H), 3.30 (t, J = 6.6 Hz, 2H), 3.33 (m, 1H), 3.99 (m, 1H), 4.40 (br s, 1H), 6.63 (d, J = 15.6 Hz, 1H), 6.68 (dd, J = 15.6, 7.2 Hz, 1H), 7.08 (dd, J = 8.1 Hz, 1H), 7.28-7.70 (m, 4H), 7.79 (d, J = 8.1 Hz, 1H), 8.74 (s, 1H).
<Example 166> (±)-t-Butyl (1S,2S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(2-oxooxazolidin-3-yl)-octahydro-1H-inden-5-ylcarbamate
Figure PCTKR2011004607-appb-I000140
The solution of Example 158 compound (30 mg, 0.066 mmol) in CH2Cl2 (2 mL) was stirred at room temperature, to which were added 2-chloroethyl chloroformate (20.6 μL, 0.199 mmol) and NEt3 (27.7 μL, 0.199 mmol). After stirring for 6 h, saturated NaHCO3 (1 mL) was added to the mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give pale yellow amide which was used in the next reaction without further purification.
The solution of the amide in ethanol (1 mL) was stirred at room temperature, to which was added 2 N aqueous NaOH solution (1 mL). After stirring for 12 h at room temperature, the reaction mixture was diluted with ethyl acetate (3 mL) and washed with 1 N HCl (2 × 5 mL) and saturated aqueous sodium chloride solution (5 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to give the title compound (19 mg, 55%) as a pale yellow liquid.
1H NMR (300 MHz, CDCl3) δ 0.83-1.33 (m, 4H), 1.44 (s, 9H), 1.58-2.01 (m, 5H), 2.19-2.50 (m, 2H), 3.56 (m, 3H), 4.33 (t, J = 7.8 Hz, 2H), 4.35 (m, 1H), 4.43 (d, J = 7.2 Hz, 1H), 6.56 (d, J = 15.9 Hz, 1H), 6.66 (dd, J = 15.9, 7.5 Hz, 1H), 7.08 (dd, J = 8.4 Hz, 1H), 7.28-7.49 (m, 4H), 7.80 (d, J = 8.1 Hz, 1H), 8.74 (s, 1H).
<Example 167> (±)-(1S,2S,3aS,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl dimethylsulfamate
Figure PCTKR2011004607-appb-I000141
The solution of Example 154 compound (25.0 mg, 0.0552 mmol) in THF (1 mL) was stirred at room temperature, to which was added NaH (6.64 mg, 0.166 mmol). The yellow suspension was stirred for 1 h. Dimethylsulfamoyl chloride (178 μL, 0.166 mmol) was added and stirred for 48 h. Distilled water (1 mL) was added to the reaction mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1-2:1) to give the title compound (19 mg, 62%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 0.85-1.25 (m, 2H), 1.44 (s, 9H), 1.61-1.80 (m, 4H), 1.72-2.24 (m, 4H), 2.52 (m, 1H), 2.83 (s, 6H),3 .52 (m, 1H), 4.39 (br s, 1H), 4.90 (m, 1H), 6.61 (d, J = 15.9 Hz, 1H), 6.75 (dd, J = 15.9, 8.1 Hz, 1H), 7.09 (dd, J = 8.1 Hz, 1H), 7.26-7.47 (m, 4H), 7.81 (dd, J = 8.1, 1.8 Hz, 1H), 8.74 (d, J = 1.8 Hz, 1H).
<Example 168> (±)-(1S,2S,3aS,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-ylsulfamate
Figure PCTKR2011004607-appb-I000142
Formic acid (3.34 μL, 0.0884 mmol) and chlorosulfonyl isocyanate (7.69 μL, 0.0884 mmol) were introduced to a reaction vessel at 0 ℃ and vigorously stirred. After stirring until the viscous suspension turned into a white solid, CH2Cl2 (1 mL) was added to the reaction mixture and stirred for 1 h. The reaction vessel was warmed to room temperature and stirred. After stirring for 11 h, the reaction vessel was cooled to 0 ℃. The Example 154 compound (20.0 mg, 0.0442 mmol) and pyridine (7.15 μL, 0.0884 mmol) were dissolved in CH2Cl2 (1 mL), and this solution was added to the reaction vessel. After stirring for 1 h, distilled water (1 mL) was added to the reaction mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The organic layers were combined and washed with saturated aqueous sodium chloride solution (5 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound (9 mg, 38%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 0.83-1.25 (m, 2H), 1.44 (s, 9H), 1.52-1.80 (m, 4H), 1.91-2.24 (m, 4H), 2.55 (m, 1H), 3.52 (m, 1H), 4.39 (br s, 2H), 4.84 (br s, 1H), 4.96 (m, 1H), 6.61 (d, J = 15.6 Hz, 1H), 6.75 (dd, J = 15.6, 8.4 Hz, 1H), 7.09 (dd, J = 8.4 Hz, 1H), 7.26-7.48 (m, 4H), 7.82 (dd, J = 8.1, 2.1 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H).
Figure PCTKR2011004607-appb-I000143
<Example 169> (±)-t-Butyl (1S,2S,3aS,7aR)-2-cyano-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxyoctahydro-1H-inden-5-ylcarbamate
The solution of Example 149 compound (94.0 mg, 0.209 mmol) in CH2Cl2 (2 mL) was stirred at room temperature, to which were added NaCN (30.7 mg, 0.627 mmol) and a catalytic amount of 18-crown-6. After stirring for 30 min, trimethylsilyl cyanide (52.3 μL, 0.418 mmol) was added to the reaction mixture. After stirring for 12 h, the reaction mixture was concentrated under reduced pressure. The concentrate was diluted with THF (1 mL) at 0 ℃, 1 N HCl (1 mL) was added and stirred for 20 min. Saturated NaHCO3 (2 mL) was added to the mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined and washed with saturated NaHCO3 (3 mL) and brine (3 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound (27 mg, 27%) as a more nonpolar isomer than the Example 170 compound.
1H NMR (300 MHz, CDCl3) δ 0.82-1.21 (m, 4H), 1.44 (s, 9H), 1.61-1.90 (m, 4H), 2.10 (m, 2H), 2.24 (m, 1H), 2.58 (dd, J = 11.0, 7.8 Hz, 1H), 2.75 (dd, J = 13.0, 6.6 Hz, 1H), 4.42 (br s, 1H), 6.67 (dd, J = 15.9, 7.8 Hz, 1H), 6.75 (d, J = 15.9 Hz, 1H), 7.09 (m, 1H), 7.22-7.47 (m, 4H), 7.78 (dd, J = 8.1, 2.1 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H).
<Example 170> (±)-t-Butyl (1S,2R,3aS,7aR)-2-cyano-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxyoctahydro-1H-inden-5-ylcarbamate
The same procedure as Example 169 was carried out to give the title compound (56 mg, 56%) as a more polar isomer than the Example 169 compound.
1H NMR (300 MHz, CDCl3) δ 0.83-1.35 (m, 4H), 1.44 (s, 9H), 1.60-1.88 (m, 3H), 2.09 (m, 2H), 2.30 (m, 2H), 2.53 (m, 1H), 3.51 (m, 1H), 4.42 (br s, 1H), 6.69 (d, J = 4.2 Hz, 2H), 7.09 (t, J = 8.4 Hz, 1H), 7.26-7.47 (m, 4H), 7.78 (d, J = 8.1 Hz, 1H), 8.68 (s, 1H).
<Example 171> (±)-5-{(E)-(4aR,5S,7aR)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-methyloctahydrocyclopenta[c]pyran-6-ol
Figure PCTKR2011004607-appb-I000144
(Step 1) 3-(Prop-2-ynyloxy)propan-1-ol
Propargyl bromide (20 g, 168.12 mmol) and 1,3-propandiol (25.5 g, 336.24 mmol) were introduced at 0 ℃ and stirred, to which was added the pulverized NaOH (8 g, 201.74 mmol). After reacting for 24 h at room temperature, the mixture was extracted with CHCl3 and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the title compound (14 g, 73%)
1H-NMR (300 MHz, CDCl3) δ 1.82 (m, 2H), 2.47 (s, 1H), 3.69 (t, 2H, J = 5.7 Hz), 3.74 (t, 2H, J = 5.4 Hz), 4.16 (s, 2H).
(Step 2) 3-(Prop-2-ynyloxy)propanal
In anhydrous CH2Cl2 (400 mL) was dissolved the Step 1 compound (14 g, 122.65 mmol). Molecular sieve, sodium acetate (50.3 g, 613.25 mmol) and pyridinium chlorochromate (65.8 g, 306.66 mmol) were added at 0 ℃. The mixture was filtered through a celite pad and extracted with ether. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the title compound (6 g, 44%)
1H-NMR (300 MHz, CDCl3) δ 2.46 (s, 1H), 2.68 (t, 2H, J = 6.06 Hz), 3.88 (t, 2H, J = 6.06 Hz), 4.16 (s, 2H), 9.79 (s, 1H).
(Step 3) (E)-Methyl 5-(prop-2-ynyloxy)pent-2-enoate
In anhydrous CH2Cl2 was dissolved the Step 2 compound (9 0 mg, 0.80 mmol). Methyl (triphenylphosphoranylidene)acetate (576 mg, 1.72 mmol) was added and stirred under reflux. The reaction solution was concentrated under reduced pressure. The residue was filtered through a silica gel pad and extracted with hexane and a solvent mixture of hexane:ethyl acetate (7:1). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 5:1) to give the title compound (80 mg, 0.47 mmol).
1H-NMR (300 MHz, CDCl3) δ 2.48 (s, 1H), 2.51(q, 2H, J = 6.39 Hz, J = 13.0 Hz), 3.65 (t, 2H, J = 6.39 Hz), 3.73 (s, 3H), 4.15 (s, 2H), 5.94~5.88 (m, 1H), 6.99~6.94 (m, 1H).
(Step 4) (E)-5-(prop-2-ynyloxy)pent-2-en-1-ol
In anhydrous toluene (3 mL) was added the Step 3 compound (150 mg, 0.89 mmol). Diisobutylaluminum hydride (2.67 mL, 1.0 M toluene solution) was added at -78 ℃. After 7 h, the mixture was diluted with methanol and filtered through a silica gel pad. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to give the title compound (100 mg, 80%).
1H-NMR (300 MHz, CDCl3) δ 2.37 (q, 2H, J = 6.54, 12.7 Hz), 2.44 (t, 2H, J = 4.03 Hz), 3.58 (t, 2H, J = 6.63 Hz), 4.14 (s, 2H), 5.74~5.70 (m, 2H).
(Step 5) (E)-t-butyldimethyl[5-(prop-2-ynyloxy)pent-2-enyloxy]silane
The Step 4 compound (50mg, 0.356 mmol) was reacted according to the same procedure as Step 1 of Preparation 5 to give the title compound (42 mg, 45%).
1H-NMR (300 MHz, CDCl3) δ 0.03 (s, 6H), 0.84 (s, 9H), 2.29~2.34 (m, 2H), 2.35 (s, 1H), 3.49 (t, 2H, J = 6.87 Hz), 4.06~4.06 (m, 4H), 5.56~5.58 (m, 2H).
(Step 6) (±)-(4aR,5S)-5-(t-butyldimethylsilyloxymethyl)-3,4,4a,5-tetrahydrocyclopenta[c]pyran-6(1H)-one
In anhydrous CH2Cl2 (19.6 mL) was dissolved the Step 5 compound (500 mg, 1.96 mmol), and Co2(CO)8 (671 mg, 1.96 mmol) was added thereto. When the compound and Co form a complex (after 2~3 h), N-methylmorpholine-N-oxide (1.37 g, 11.766 mmol) was added at 0 ℃. After 1 h, the mixture was filtered through a silica gel pad and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to give the title compound (250 mg, 45%) .
1H-NMR (300 MHz, CDCl3) δ 0.04 (s, 6H), 0.08 (s, 9H), 1.58~1.64 (m, 1H), 2.09~2.18 (m, 2H), 2.83~2.88 (m, 1H), 3.56~3.64 (m, 1H), 3.80~3.89 (m, 2H), 4.02~4.13 (m, 1H), 4.15 (d, 1H, J = 13.4 Hz), 4.65 (d, 1H, J = 13.4 Hz), 5.88 (s, 1H).
(Step 7) (±)-(4aR,5S,7aR)-5-(t-butyldimethylsilyloxymethyl)hexahydrocyclopenta[c]pyran-6(1H)-one
In anhydrous ethanol (3 mL) was added the Step 6 compound (250 mg, 0.88 mmol), and Pd/C was added thereto under hydrogen atmosphere. After stirring for 24 h, the mixture was filtered through a silica gel pad. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4.5:1) to give the title compound (110 mg, 44%).
1H-NMR (300 MHz, CDCl3) δ 0.02 (s, 6H), 0.85 (s, 9H), 1.57~1.63 (m, 1H), 1.82~1.90 (m, 1H), 2.14~2.25 (m, 3H), 2.45~2.61 (m, 2H), 3.30~3.36 (m, 1H), 3.60~3.88 (m, 4H), 3.90~3.95 (m, 1H).
(Step 8) (±)-(4aR,5S,7aR)-5-(t-butyldimethylsilyloxymethyl)-6-methyloctahydrocyclopenta[c]pyran-6-ol
The Step 7 compound (50 mg, 0.17 mmol) was reacted according to the same procedure as Step 2 of Example 62 to give the title compound (10 mg, 18%).
1H-NMR (300 MHz, CDCl3) δ 0.004(s, 6H), 0.85 (s, 9H), 1.19 (s, 3H), 1.31~1.43 (m, 2H), 1.68~1.77(m, 3H), 2.08~2.09 (m, 1H), 2.21~2.23 (m, 1H), 2.62 (s, 1H), 3.34 (t, 1H, J = 10.7 Hz), 3.51~3.75 (m, 5H).
(Step 9) (±)-(4aR,5S,7aR)-5-(hydroxymethyl)-6-methyloctahydrocyclopenta[c]pyran-6-ol
The Step 8 compound (15 mg, 0.045 mmol) was reacted according to the same procedure as Step 5 of Preparation 5 to give the title compound (7 mg, 82%).
1H-NMR (300 MHz, CDCl3) δ 1.33 (s, 3H), 1.33~1.57 (m, 2H), 1.77~1.94 (m, 4H), 2.15~2.39 (m, 3H), 3.44 (t, 1H, J = 10.8 Hz), 3.61~3.75 (m, 4H), 3.76~3.81 (m, 1H).
(Step 10) (±)-(4aR,5S,7aR)-6-hydroxy-6-methyloctahydrocyclopenta[c]pyran-5-carbaldehyde
The Step 9 compound (12 mg, 0.064 mmol) was reacted according to the same procedure as Step 10 of Preparation 3 to give the title compound (7 mg, 59%).
1H-NMR (300 MHz, CDCl3) δ 1.33 (s, 3H), 1.72~1.89 (m, 4H), 1.92~2.25 (m, 1H), 2.54~2.61 (m, 1H), 2.95~2.99 (m, 1H), 3.49~3.76 (m, 5H), 9.84 (s, 1H).
(Step 11) (±)-5-{(E)-(4aR,5S,7aR)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-methyloctahydrocyclopenta[c]pyran-6-ol
The Step 10 compound (7 mg, 0.037 mmol) was reacted according to the same procedure as Example 1 to give the title compound (1 mg, 6%).
1H-NMR (300 MHz, CDCl3) 1.50 (s, 3H), 1.89~2.21 (m, 3H), 2.45~2.50 (m, 3H), 3.14 (t, 1H, J = 15 Hz), 3.48~3.80 (m, 4H), 6.65~6.81 (m, 2H), 7.08~7.84 (m, 6H), 8.77 (s, 1H).
<Example 172> (±)-2-{(E)-2-[(4aS,5S,7aR)-6-(methoxymethoxy)octahydrocyclopenta[c]pyran-7-yl]vinyl}-5-(3-fluorophenyl)pyridine
Figure PCTKR2011004607-appb-I000145
(Step 1) (E)-but-2-en-1,4-diol
To anhydrous THF (500 mL) was slowly added LiAlH4 (17 g, 453.0 mmol) at 0 ℃. But-2-yne-1,4-diol (30 g, 348.4 mmol) dissolved in anhydrous THF (200 mL) was slowly added thereto. The mixture was stirred under reflux for 4 h. H2O and 2 N NaOH were added and filtered through a silica gel pad. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to give the title compound (30 g, 75%).
1H-NMR (300 MHz, CDCl3) δ 4.16~4.20 (m, 4H), 5.89~5.91 (m, 2H).
(Step 2) (E)-4-(t-butyldimethylsilyloxy)but-2-en-1-ol
NaH (19.2 g, 408.5 mmol) was added to anhydrous THF (580 mL), and the Step 1 compound (30 g, 340 mmol) dissolved in anhydrous THF (100 mL) was added thereto. The mixture was stirred for 1 h at room temperature. t-Butyldimethylsilyl chloride (51.3g, 340 mmol) was added and stirred for 24 h. Saturated aqueous NH4Cl solution was added, which was then extracted with ether and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to give the title compound (40 g, 58%).
1H-NMR (300 MHz, CDCl3) δ 0.01 (s, 6H), 0.84 (s, 9H), 2.21~2.25 (m, 2H), 3.59~3.60 (m, 2H), 4.07~4.08 (m, 2H), 5.56~5.60 (m, 2H).
(Step 3) (E)-(4-bromobut-2-enyloxy)(t-butyl)dimethylsilane
In anhydrous CH2Cl2 (5 mL) was dissolved the Step 2 compound (100 mg, 0.49 mmol). CBr4 (327 mg, 0.98 mmol) and PPh3 (194 mg, 0.74 mmol) were added thereto at 0 ℃. After stirring for 3 h at room temperature, the mixture was diluted with hexane and filtered through a silica gel pad. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to give the title compound (60 mg, 45%).
1H-NMR (300 MHz, CDCl3) δ 0.01 (s, 6H), 0.84 (s, 9H), 3.86~3.91 (m, 2H), 4.11~4.12 (m, 2H), 5.73~5.90 (m, 2H).
(Step 4) (E)-[4-(but-3-ynyloxy)but-2-enyloxy](t-butyl)dimethylsilane
NaH (18mg, 0.45 mmol) and tetrabutylammonium iodide (a catalytic amount) were added to anhydrous THF (1 mL). The Step 3 compound (60mg, 0.22 mmol) and 3-butynol (0.03mL, 0.45 mmol) dissolved in anhydrous THF were added thereto. After stirring for 2 h at room temperature, saturated aqueous NH4Cl solution was added. The mixture was extracted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 8:1) to give the title compound (45 mg, 38%) .
1H-NMR (300 MHz, CDCl3) δ 0.01 (s, 6H), 0.84 (s, 9H), 1.91 (t, 1H, J = 13.9 Hz), 3.94~3.96 (m, 2H), 4.10~4.11 (m, 2H), 5.70~5.74 (m, 2H).
(Step 5) (±)-(7R,7aS)-7-[(t-butyldimethylsilyloxy)methyl]-3,5,7,7a-tetrahydrocyclopenta[c]pyran-6(1H)-one
The Step 4 compound (800 mg, 3.01 mmol) was reacted according to the same procedure as Step 6 of Example 171 to give the title compound (100 mg, 12%).
1H-NMR (300 MHz, CDCl3) δ 0.01 (s, 6H), 0.84 (s, 9H), 2.02 (m, 1H), 2.66~2.72 (m, 2H), 2.96 (m, 1H), 3.11 (t, 1H, J = 11.0 Hz), 3.35~3.58 (m, 2H), 3.74~3.90 (m, 2H), 4.20~4.34 (m, 2H), 5.92 (s, 1H).
(Step 6) (±)-(4aR,7R,7aS)-7-[(t-butyldimethylsilyloxy)methyl]hexahydrocyclopenta[c]pyran-6(1H)-one
The Step 5 compound (90 mg, 0.31 mmol) was reacted according to the same procedure as Step 7 of Example 171 to give the title compound (80 mg, 90%).
1H-NMR (300 MHz, CDCl3) δ 0.03 (s, 6H), 0.82 (s, 9H), 1.25~1.44 (m, 2H), 1.60 (s, 1H), 2.09~2.40 (m, 5H), 3.36~3.44 (m, 1H), 3.66~3.70 (m, 2H), 3.88~3.99 (m, 3H).
(Step 7) (±)-(4aR,7R,7aS)-7-[(t-butyldimethylsilyloxy)methyl]hexahydrocyclopenta[c]pyran-6-ol
The Step 6 compound (0.28 mmol) was dissolved in anhydrous methanol, and NaBH4 was added thereto at 0 ℃. After stirring for 30 min at 0 ℃, the mixture was diluted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 5:1) to give the title compound (69 mg, 86%) .
1H-NMR (300 MHz, CDCl3) δ 0.009 (s, 6H), 0.83 (s, 9H), 1.42~1.58 (m, 4H), 1.97~2.11 (m, 3H), 3.33~3.78 (m, 6H), 4.05~4.07 (m, 1H).
(Step 8) (±)-t-Butyl {[(4aR,7R,7aS)-6-(methoxymethoxy)octahydrocyclopenta[c]pyran-7-yl]methoxy}dimethylsilane
The Step 7 compound (10 mg, 0.034 mmol) was dissolved in anhydrous CH2Cl2 (0.5 mL), and methoxymethyl chloride (0.008 mL, 0.10 mmol) and diisopropylethylamine (0.036 mL, 0.20 mmol) were added thereto. After stirring for 24 h at room temperature, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 5:1) to give the title compound (10 mg, 0.03 mmol) .
1H-NMR (300 MHz, CDCl3) δ 0.009 (s, 6H), 0.84 (s, 9H), 1.58~1.80 (m, 4H), 1.90~2.25 (m, 3H), 3.31 (s, 3H), 3.34~3.45 (m, 1H), 3.55~3.77 (m, 6H), 3.95~4.00 (m, 1H), 4.56~4.62 (m, 2H).
(Step 9) (±)-[(4aR,7R,7aR)-6-(methoxymethoxy)octahydrocyclopenta[c]pyran-7-yl]methanol
The Step 8 compound (20 mg, 0.06 mmol) was reacted according to the same procedure as Step 5 of Preparation 5 to give the title compound (7 mg, 62%).
1H-NMR (300 MHz, CDCl3) δ 1.58~1.77 (m, 5H), 2.01~2.25 (m, 3H), 3.39 (s, 3H), 3.43~3.86 (m, 5H), 4.02~4.07 (m, 1H), 4.68~4.73 (m, 2H).
(Step 10) (±)-(4aR,7S,7aR)-6-(methoxymethoxy)octahydrocyclopenta[c]pyran-7-carbaldehyde
The Step 9 compound (7 mg, 0.037 mmol) was reacted according to the same procedure as Step 10 of Preparation 3 to give the title compound (2 mg, 24%).
1H-NMR (300 MHz, CDCl3) δ 1.54~1.76 (m, 3H), 2.07~2.20 (m, 3H), 3.03~3.10 (m, 1H), 3.36 (s, 3H), 3.38~3.40 (m, 1H), 3.64~3.87 (m, 3H), 4.42~4.46 (m, 1H), 4.63~4.69 (m, 2H).
(Step 11) (±)-2-{(E)-2-[(4aS,5S,7aR)-6-(methoxymethoxy)octahydrocyclopenta[c]pyran-7-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Step 10 compound (7 mg, 0.037 mmol) was reacted according to the same procedure as Example 1 to give the title compound (1 mg, 6%).
1H-NMR (300 MHz, CDCl3) δ 1.67~1.85 (m, 3H), 2.16~2.27 (m, 3H), 3.03~3.05 (m, 1H), 3.33 (s, 3H), 3.56~4.11 (m, 3H), 4.60~4.68 (m, 4H), 6.61~6.83 (m, 2H), 7.28~7.49 (m, 4H), 7.64~7.81 (m, 2H), 8.76 (s, 1H).
<Example 173> (±)-t-Butyl (1S,2R,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxyoctahydro-1H-inden-5-ylcarbamate
Figure PCTKR2011004607-appb-I000146
(Step 1) (±)-t-Butyl-(1S,2R,3aR,7aR)-2-(t-butyldimethylsilyloxy)-1-(hydroxymethyl)octahydro-1H-inden-5-ylcarbamate
(±)-{(1'S,3a'R,7a'R)-2,3,3a,4,7,7a-hexahydrospiro-[(1,3)dioxolane-2,2'-inden]-1’-yl}-methanol was reacted according to the same procedures as Steps 1-8 of Preparation 7 to give the title compound.
1H-NMR (300 MHz, CDCl3) δ 0.04 (s, 6H), 0.87 (s, 9H), 1.25 (m, 2H), 1.43 (s, 9H), 1.67~2.07 (m, 9H), 2.10 (m, 1H), 2.33 (m, 1H), 2.83 (m, 1H), 3.33 (brs, 1H), 3.73 (m, 2H), 4.34 (brs, 1H), 4.55 (m, 1H).
(Step 2) (±)-t-Butyl-(1S,2R,3aR,7aR)-2-(t-butyldimethylsilyloxy)-1-formyloctahydro-1H-inden-5-ylcarbamate
The Step 1 compound (600 mg, 1.44 mmol) was reacted according to the same procedure as Step 10 of Preparation 3 to give the title compound, which was then used in the next reaction without further purification.
(Step 3) (±)-t-Butyl-(1S,2R,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(t-butyldimethylsilyloxy)octahydro-1H-inden-5-ylcarbamate
The Step 2 compound (540 mg, 1.30 mmol) was reacted according to the same procedure as Example 1 to give the title compound (700 mg, 95%).
1H-NMR (300 MHz, CDCl3) δ 0.04 (s, 6H), 0.09 (s, 9H), 1.47 (s, 9H), 1.80 (m, 7H), 2.22 (m, 2H), 2.58 (m, 1H), 2.62 (m, 1H), 3.77 (brs, 1/2H), 4.40 (m, 2H), 4.68 (brs, 1/2H), 6.60 (m, 2H), 7.09 (m, 1H), 7.40 (m. 4H), 7.82 (d, 1H, J= 8.1 Hz), 8.77 (s, 1H).
(Step 4) (±)-t-Butyl-(1S,2R,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxyoctahydro-1H-inden-5-ylcarbamate
The Step 3 compound (700 mg, 1.23 mmol) was reacted according to the same procedure as Step 5 of Preparation 5 to give the title compound (500 mg, 89%).
1H-NMR (300 MHz, CDCl3) δ 1.15 (m, 1H), 1.44 (s, 9H), 1.44~2.10 (m, 8H), 2.24 (m, 1H), 2.50 (m, 1H), 2.64 (m, 1H), 3.46 (brs, 1H), 4.43 (m, 2H), 6.74 (m, 2H), 7.08 (m, 1H), 7.33 (m. 4H), 7.79 (d, 1H, J = 7.8 Hz), 8.74 (s, 1H).
<Example 174> (±)-(1S,2R,3aR,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-2-yl methanesulfonate
Figure PCTKR2011004607-appb-I000147
The Example 173 compound (230 mg, 0.508 mmol) was reacted according to the same procedure as Example 10 to give the title compound (220 mg, Yield 81%).
1H NMR (300 MHz, CDCl3) δ 0.82~1.39 (m, 1H), 1.44 (s, 9H), 1.54~1.81 (m, 4H), 1.99~2.37 (m, 3H), 2.48~2.53 (m, 1H), 2.82~2.94 (m, 1H), 2.98 (s, 3H), 3.38~3.75 (m, 1H), 4.39~4.56 (m, 1H), 5.24~5.30 (m, 1H), 6.55~6.84 (m, 2H), 7.09 (m, 1H), 7.29~7.48 (m. 4H), 7.77 (d, 1H, J = 8.1 Hz), 8.75 (s, 1H).
<Example 175> (±)-(1S,2R,3aR,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-2-yl carbamate
Figure PCTKR2011004607-appb-I000148
The Example 173 compound (15 mg, 0.033 mmol) was reacted according to the same procedure as Example 65 to give the title compound (5.2 mg, Yield 34%).
1H NMR (300 MHz, CDCl3) δ 01.42~2.42 (m, 18H) 2.71~2.91 (m, 1H) 4.57 (m, 3H), 5.09 (brs, 1H), 5.29 (m, 1H), 6.50~6.83 (m, 2H), 7.08 (m, 1H), 7.28~7.47 (m. 4H), 7.80 (d, 1H, J = 8.1 Hz), 8.39 (brs, 1H), 8.75 (s, 1H).
<Example 176> (±)-t-Butyl (1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(methanesulfonamido)octahydro-1H-inden-5-ylcarbamate
Figure PCTKR2011004607-appb-I000149
(Step 1) (±)-t-Butyl (1S,2S,3aR,7aR)-2-azido-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-5-ylcarbamate
The Example 174 compound (200 mg, 0.377 mmol) was reacted according to the same procedure as Step 1 of Example 115 to give the title compound (130 mg, Yield 72%).
1H NMR (300 MHz, CDCl3) δ 0.96~1.38 (m, 1H), 1.45 (s, 9H), 1.54~1.81 (m, 4H), 1.99~2.37 (m, 3H), 2.48~2.53 (m, 1H), 2.82~2.94 (m, 1H), 2.98 (s, 3H), 3.38~3.75 (m, 1H), 4.39~4.56 (m, 1H), 5.24~5.30 (m, 1H), 6.52~6.82 (m, 2H), 7.09 (m, 1H), 7.29~7.47 (m. 4H), 7.80 (dd, 1H, J = 2.1, 2.7 Hz), 8.75 (d, 1H, J = 2.1 Hz).
(Step 2) (±)-t-Butyl (1S,2S,3aR,7aR)-2-amino-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-5-ylcarbamate
The Step 1 compound (120 mg, 0.251 mmol) was reacted according to the same procedure as Example 130 to give the title compound (90 mg, Yield 79%).
(Step 3) (±)-t-Butyl (1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(methanesulfonamido)octahydro-1H-inden-5-ylcarbamate
The Step 2 compound (50 mg, 0.110 mmol) was reacted according to the same procedure as Example 47 to give the title compound (22 mg, Yield 38%).
1H NMR (300 MHz, CDCl3) δ 0.85~1.38 (m, 1H), 1.42 (s, 9H), 1.49~2.04 (m, 7H) 2.10~2.61 (m, 3H), 2.92 (s, 3H), 3.38 (brs, 1H), 3.73 (m, 1H), 4.53 (m, 1H), 4.47 (m, 1H), 6.53~6.79 (m, 2H), 7.12 (m, 1H), 7.26~7.47 (m. 4H), 7.81 (d, 1H, J = 8.1 Hz), 8.74 (s, 1H).
<Example 177> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(methanesulfonamido)octahydro-1H-inden-5-yl}formamide
Figure PCTKR2011004607-appb-I000150
(Step 1) (±)-N-{(1S,2S,3aR,7aR)-5-amino-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methanesulfonamide
The Example 176 compound (60 mg, 0.111 mmol) was dissolved in anhydrous CH2Cl2 (10 mL). Trifluoroacetic acid (1 drop) was added at 0 ℃ and stirred for 3 h at room temperature. NaHCO3 solution was carefully added to neutralize the mixture, which was then extracted with CH2Cl2 and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated to give the title compound (35 mg, Yield 86%).
(Step 2) (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(methanesulfonamido)octahydro-1H-inden-5-yl}formamide
Acetic anhydride (0.005 mL, 0.046 mmol) and formic acid (0.002 mL, 0.046 mmol) were stirred for 2 h at 55 ℃ to give acetic formic anhydride. The Step 1 compound (10 mg, 0.023 mmol) was dissolved in anhydrous diethylether (2 mL) and acetic formic anhydride was added thereto. The mixture was stirred for 4 h at room temperature, extracted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate = 1:2) to give the title compound(7 mg, Yield 65%).
1H NMR (300 MHz, CDCl3) δ 1.29~2.04 (m, 8H) 2.47~2.24 (m, 3H), 2.93 (s, 3H), 3.75 (m, 1H), 4.16 (m, 1H), 4.64 (d, 1H, J = 7.8 Hz), 5.48 (d, 1H, J =8.1 Hz), 6.56~6.77 (m, 2H), 7.10 (m, 1H), 7.24~7.48 (m. 4H), 7.81 (d, 1H, J = 8.1 Hz), 8.15 (s, 1H), 8.76 (s, 1H).
<Example 178> (±)-t-Butyl (1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(formamido)octahydro-1H-inden-5-ylcarbamate
Figure PCTKR2011004607-appb-I000151
The compound of Step 2 of Example 176 (0.015g, 0.033 mmol) was reacted according to the same procedure as Example 177 to give the title compound (12 mg, Yield 76%).
1H NMR (300 MHz, CDCl3) δ 0.83~1.86 (m, 8H), 1.44 (s, 9H), 1.58~2.09 (m, 5H) 2.19~2.64 (m, 1H), 3.41 (brs, 1H), 3.73 (m, 1H), 4.26 (m, 1H), 4.48 (brs, 1H), 5.85 (m, 1H), 6.51~6.76 (m, 2H), 7.08 (m, 1H), 7.26~7.47 (m. 4H), 7.80 (d, 1H, J = 8.1 Hz), 8.13 (s, 1H), 8.75 (s, 1H).
<Example 179> (±)-t-Butyl (1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(2-oxazolidin-3-yl)octahydro-1H-inden-5-ylcarbamate
Figure PCTKR2011004607-appb-I000152
The compound of Step 2 of Example 176 (40 mg, 0.088 mmol) was reacted according to the same procedure as Example 166 to give the title compound (23 mg, Yield 50%).
1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.49~2.44 (m, 8H) 2.53~2.96 (m, 1H), 3.39 (brs, 1H), 3.60 (m, 2H), 3.76 (brs, 1H), 4.08~4.58 (m, 4H), 6.46~6.76 (m, 2H), 7.08 (m, 1H), 7.26~7.47 (m. 4H), 7.80 (d, 1H, J= 8.1 Hz), 8.74 (s, 1H).
<Example 180> (±)-1-{(1S,2S,3aR,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-sultam
Figure PCTKR2011004607-appb-I000153
The compound of Step 2 of Example 176 (40 mg, 0.088 mmol) was reacted according to the same procedure as Example 163 to give the title compound (30 mg, Yield 61%).
1H NMR (300 MHz, CDCl3) δ 0.83~1.86 (m, 8H), 1.44 (s, 9H), 2.01~2.36 (m, 5H) 2.66~2.88 (m, 1H), 3.11 (m, 2H), 3.24~3.41 (m, 2H), 3.81~3.89 (m, 1H), 4.51 (m, 1H), 6.47~6.73 (m, 2H), 7.08 (m, 1H), 7.26~7.47 (m. 4H), 7.81 (d, 1H, J = 8.1 Hz), 8.75 (s, 1H).
<Example 181> (±)-(1S,2R,3aS,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-ylsulfamate
Figure PCTKR2011004607-appb-I000154
The Example 155 compound was reacted according to the same procedure as Example 168 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.01-1.44 (m, 5H), 1.44 (s, 9H), 1.88-2.25 (m, 4H), 2.41 (m, 1H), 2.55 (m, 1H), 3.52 (m, 1H), 4.41 (br s, 1H), 5.18 (m, 1H), 5.42 (s, 2H), 6.61 (d, J = 15.6 Hz, 1H), 6.77 (dd, J = 15.6, 8.7 Hz, 1H), 7.10 (t, J = 8.7 Hz, 1H), 7.26-7.48 (m, 4H), 7.82 (dd, J = 8.1, 2.4 Hz, 1H), 8.74 (d, J = 1.5 Hz, 1H).
<Example 182> (±)-t-Butyl (1S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(hydroxyimino)octahydro-1H-inden]-5-ylcarbamate
Figure PCTKR2011004607-appb-I000155
The Example 153 compound (12 mg, 0.027 mmol) was reacted according to the same procedure as Example 4 to give the title compound (6 mg, Yield 48%).
1H NMR (300 MHz, CDCl3) δ 0.82~1.41 (m, 3H) 1.44 (s, 9H), 1.58~2.34 (m, 6H), 2.80~3.00 (m, 2H), 3.56~4.21 (m, 1H), 4.42~4.73 (m, 1H), 6.58~6.71 (m, 2H), 7.10 (m, 1H), 7.28~7.60 (m. 4H), 7.80(d, 1H, J = 7.8 Hz), 8.75 (s, 1H).
Figure PCTKR2011004607-appb-I000156
<Example 183> (±)-2-{(E)-2-[(1'S,3a'R,5'R,7a'R)-5'-hydroxyoctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
(Step 1) (±)-{(1'R,3a'S,5'R,7a'R)-1'-(benzyloxymethyl)octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-yloxy}-t-butyl-dimethylsilane
The compound of Step 3 of Preparation 7 (700 mg, 2.19 mmol) was reacted according to the same procedure as Step 7 of Preparation 7 to give the title compound (890 mg, Yield 93%).
(Step 2) (±)-{(1'R,3a'S,5'R,7a'R)-5'-(t-butyldimethylsilyloxy)octahydrospiro-[(1,3)dioxolane-2,2'-inden]-1’-yl}methanol
The Step 1 compound (890 mg, 2.05 mmol) was reacted according to the same procedure as Step 8 of Preparation 7 to give the title compound (600 mg, Yield 85%).
(Step 3) (±)-2-{(E)-2-[(1'S,3a'R,5'R,7a'R)-5'-(t-butyldimethylsilyloxy)octahydrospiro[(1,3)-dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Step 2 compound (870 mg, 2.53 mmol) was reacted according to the same procedures as Step 10 of Preparation 3 and Example 1 to give the title compound (1.0 g, Yield 83%).
1H NMR (300 MHz, CDCl3) δ 0.0 (s, 6H), 0.9 (s, 9H), 1.5~2.1 (m, 10H), 2.4 (t, 1H, J = 10.8 Hz), 3.7~3.95 (m, 4H), 6.55 (d, 1H, J = 15.8 Hz), 6.75 (dd, 1H, J = 9.6, 15.7 Hz), 7.05 (t, 1H, J = 8.5 Hz), 7.2~7.45 (m, 4H), 7.75 (d, 1H, J = 8.1 Hz), 8.75 (s, 1H).
(Step 4) (±)-2-{(E)-2-[(1'S,3a'R,5'R,7a'R)-5'-hydroxyoctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Step 3 compound (1.0 g, 1.96 mmol) was reacted according to the same procedure as Step 5 of Preparation 5 to give the title compound (700 mg, Yield 90%).
1H NMR (300 MHz, CDCl3) δ 1.2~2.2 (m, 10H), 2.45 (t, 1H, J = 10.8 Hz), 3.7~4.2 (m, 4H), 3.7~4.2 (m, 4H), 6.55 (d, 1H, J = 15.6 Hz), 6.75 (dd, 1H, J = 9.3, 15.9 Hz), 7.1 (t, 1H, J = 8.4 Hz), 7.25~7.5 (m, 4H), 7.8 (d, 1H, J = 8.1 Hz), 8.75 (s, 1H).
<Example 184> (±)-2-{(E)-2-[(1'S,3a'S,7a'R)-5'-oxooctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Example 183 compound (45 mg, 0.11 mmol) was dissolved in CH2Cl2 (3 mL) and cooled to 0 ℃ while stirring, to which was added Dess-Martin periodinane (71 mg, 0.16 mmol). After stirring for 1 h, saturated aqueous NaHCO3 solution was added to the reaction mixture to stop the reaction. The organic layer was separated from the mixture and the aqueous layer was extracted with CH2Cl2. The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound (36 mg, 81%).
1H-NMR (300MHz, CDCl3) δ1.2~2.6 (m, 11H), 3.75~4.0 (m, 4H), 6.6 (d, 1H, J = 15.9 Hz), 6.8 (dd, 1H, J = 9.6, 15.9 Hz), 7.1 (t, 1H, J = 8.4 Hz), 7.25~7.5 (m, 4H), 7.8 (d, 1H, J = 8.1 Hz), 8.75 (s, 1H).
<Example 185> (±)-Methyl (1'S,3a'S,7a'R){1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate
(Step 1) (±)-2-{(E)-2-[(1'S,3a'S,7a'R)-5'-aminooctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
The solution of Example 184 compound (32 mg, 0.08 mmol) in methanol (2 mL) was stirred at room temperature. NH4OAc (62 mg, 0.81 mmol) and NaCNBH3 (6 mg, 0.097 mmol) were added thereto. After stirring for 1 h at room temperature, the reaction mixture was concentrated under reduced pressure and used in the next reaction without further purification.
(Step 2) (±)-Methyl (1'S,3a'S,7a'R){1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate
The Step 1 compound (3 mg, 0.007 mmol) was dissolved in CH2Cl2 (2 mL). Diisopropylethylamine (2 μL, 0.014 mmol), methyl chloroformate (1 μL, 0.014 mmol) and a catalytic amount of 4-dimethylaminopyridine were added while stirring. After stirring for 2 h, water was added to the reaction mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound (2.1 mg, Yield 70%).
1H-NMR (300MHz, CDCl3) δ1.15~2.7 (m, 11H), 3.75 (S, 3H), 3.8~4.0 (m, 4H), 6.6 (d, 1H, J = 15.6 Hz), 6.75 (dd, 1H, J = 9.6, 15.6 Hz), 7.1 (t, 1H, J = 10.2 Hz), 7.25~7.5 (m, 4H), 7.8 (d, 1H, J = 8.4 Hz), 8.75 (s, 1H).
<Example 186> (±)-Ethyl (1'S,3a'S,7a'R){1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate
The compound of Step 1 of Example 185 (3 mg, 0.007 mmol) was reacted according to the same procedure as Step 2 of Example 185 except for using ethyl chloroformate instead of methyl chloroformate to give the title compound (2.4 mg, Yield 80%).
1H NMR (300 MHz, CDCl3) δ 1.1~2.8 (m, 14H), 3.75~4.0 (m, 4H), 4.15 (m, 2H), 6.6 (d, 1H, J = 15.6 Hz), 6.75 (dd, 1H, J = 9.6, 15.6 Hz), 7.1 (t, 1H, J = 10.2 Hz), 7.25~7.5 (m, 4H), 7.8 (d, 1H, J = 8.4 Hz), 8.75 (s, 1H).
<Example 187> (±)-2-{(E)-2-[(1'S,3a'R,7a'R)-5',5'-difluorooctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Example 184 compound (700 mg, 1.779 mmol) was dissolved in CH2Cl2 (4 mL), and diethylaminosulfur trifluoride (466 μL, 3.55 mmol) was added thereto while stirring. The mixture was heated to 60 ℃ and stirred for 2 h. Saturated aqueous NaHCO3 solution was added to the reaction mixture to stop the reaction. The organic layer was separated from the mixture and the aqueous layer was extracted with CH2Cl2. The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to give the title compound (600 mg, Yield 81%).
1H NMR (300 MHz, CDCl3) δ 1.2~2.4 (m, 10H), 2.45 (t, 1H, J = 9.6 Hz), 3.75~4.0 (m, 4H), 6.6 (d, 1H, J = 15.9 Hz), 6.75 (dd, 1H, J = 9.3, 15.6 Hz), 7.1 (t, 1H, J = 8.7 Hz), 7.25~7.45 (m, 4H), 7.8 (d, 1H, J = 7.8 Hz), 8.8 (s, 1H).
<Example 188> (±)-2-{(E)-2-[(1'S,3a'R,5'S,7a'R)-5'-hydroxyoctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Example 183 compound (70 mg, 0.177 mmol) was dissolved in benzene (3 mL), and 4-nitrobenzoic acid (133 mg, 0.8 mmol), triphenylphosphine (232 mg, 0.88 mmol) and diisopropylazodicarboxylate (139 mg, 0.88 mmol) were added thereto while stirring. After stirring for 3 h, saturated aqueous NaHCO3 solution was added to the reaction mixture to stop the reaction. The organic layer was separated from the mixture and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to give the benzoic acid.
To this benzoic acid were added THF (1 mL) and water (1 mL), and NaOH (21 mg, 0.53 mmol) was added. After stirring for 6 h, the organic layer was separated from the reaction mixture. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 2:1) to give the title compound (55 mg, Yield 78%).
1H-NMR (300MHz, CDCl3) δ 1.1~2.2 (m, 10H), 2.45 (t, 1H, J = 11.4 Hz), 3.65~4.0 (m, 4H), 6.55 (d, 1H, J = 15.6 Hz), 6.75 (dd, 1H, J = 9.3, 15.9 Hz), 7.1 (t, 1H, J = 8.4 Hz), 7.25~7.5 (m, 4H), 7.8 (d, 1H, J = 8.1 Hz), 8.75 (s, 1H).
Figure PCTKR2011004607-appb-I000157
<Example 189> (±)-2-{(E)-2-[(1'S,3a'R,5'S,7a'R)-5'-fluorooctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Example 183 compound (6 mg, 0.015 mmol) was dissolved in CH2Cl2 (1 mL) and cooled to -78 ℃. To the reaction solution was added diethylaminosulfur trifluoride (15 mg, 0.12 mmol) while stirring. After stirring for 15 min, saturated aqueous NaHCO3 solution was added to the reaction mixture to stop the reaction. The organic layer was separated from the mixture and the aqueous layer was extracted with CH2Cl2. The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 5:1) to give the title compound (3.7 mg, 74%).
<Example 190> (±)-2-{(E)-2-[(1'S,3a'R,5'R,7a'R)-5'-fluorooctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
The Example 188 compound (6 mg, 0.015 mmol) was reacted according to the same procedure as Example 189 to give the title compound (3.7 mg, Yield 74%).
1H NMR (300 MHz, CDCl3) δ 1.0~2.4 (m, 10H), 2.5 (t, 1H, J = 10.5 Hz), 3.75~4.0 (m, 4H), 6.6 (d, 1H, J = 15.9 Hz), 6.75 (dd, 1H, J = 9.0, 15.6 Hz), 7.1 (t, 1H, J = 9.3 Hz), 7.3~7.5 (m, 4H), 7.8 (d, 1H, J = 8.4 Hz), 8.75 (s, 1H).
Figure PCTKR2011004607-appb-I000158
<Example 191> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}hexahydro-1H-inden-2(3H)-one
The Example 187 compound (600 mg, 1.44 mmol) was dissolved in THF (3 mL), and conc. HCl (300 μL) was added thereto while stirring. After stirring for 3 h, saturated aqueous NaHCO3 solution was added to the reaction vessel to stop the reaction. The organic layer was separated from the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous MgSO4. The organic layer was filtered and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane : ethyl acetate = 4:1) to give the title compound (480 mg, Yield 89%).
<Example 192> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-ol
The Example 191 compound (100 mg, 0.269 mmol) was reacted according to the same procedure as Step 2 of Example 62 to give the title compound (90 mg, Yield 86%).
1H NMR (300 MHz, CDCl3) δ 1.2~2.4 (m, 12H), 6.6 (d, 1H, J = 15.9 Hz), 6.8 (dd, 1H, J = 9.0, 15.9 Hz), 7.1 (t, 1H, J = 8.7 Hz), 7.3~7.5 (m, 4H), 7.8 (d, 1H, J = 8.1 Hz), 8.75 (s, 1H).
<Example 193> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-yl carbamate
The Example 192 compound (10 mg, 0.025 mmol) was reacted according to the same procedure as Example 65 to give the title compound (9 mg, Yield 86%).
1H NMR (300 MHz, CDCl3) δ 1.5~2.4 (m, 14H), 4.7 (brs, 1H), 6.5 (d, 1H, J = 15.6 Hz), 6.85 (dd, 1H, J = 9.0, 15.6 Hz), 7.1 (t, 1H, J = 7.8 Hz), 7.25~7.5 (m, 4H), 7.85 (d, 1H, J = 8.1 Hz), 8.75 (s, 1H).
<Example 194> (±)-(1S,2S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-ol
The Example 191 compound (600 mg, 1.61 mmol) was reacted according to the same procedure as Example 6 to give the title compound (530 mg, Yield 87%).
1H NMR (300 MHz, CDCl3) δ .2~2.4 (m, 12H), 4.3 (brs, 1H), 6.6 (d, 1H, J =15.6 Hz), 6.75 (dd, 1H, J =8.7, 15.6 Hz), 7.1 (t, 1H, J =8.4 Hz), 7.25~7.5 (m, 4H), 7.8 (d, 1H, J =8.1 Hz), 8.75 (s, 1H).
<Example 195> (±)-(1S,2S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl methanesulfonate
The Example 194 compound (330 mg, 0.883 mmol) was reacted according to the same procedure as Example 10 to give the title compound (280 mg, Yield 85%).
1H NMR (300 MHz, CDCl3) δ 1.2~2.6 (m, 11H), 2.95 (s, 3H), 5.15~5.3 (m, 1H), 6.6 (d, 1H, J = 15.6 Hz), 6.75 (dd, 1H, J = 8.6, 15.6 Hz), 7.1 (t, 1H, J =8.7 Hz), 7.25~7.5 (m, 4H), 7.85 (d, 1H, J = 8.1 Hz), 8.75 (s, 1H).
Figure PCTKR2011004607-appb-I000159
<Example 196> (±)-(1S,5R,3aR,7aR)-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-hydroxyoctahydro-1H-inden-2-one
The Example 183 compound (200 mg, 0.392 mmol) was reacted according to the same procedure as Example 191 to give the title compound (70 mg, Yield 51%).
<Example 197> (±)-(1S,2S,5R,3aR,7aR)-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dihydroxyoctahydro-1H-indene-2-carbonitrile
The Example 196 compound (65 mg, 0.185 mmol) was reacted according to the same procedure as Example 169 to give the title compound (43 mg, Yield 61%).
1H NMR (300 MHz, CDCl3) δ 1.25~1.68 (m, 7H), 1.86 (m, 1H), 2.01~2.34 (m, 4H), 2.61 (m, 1H), 4.21 (s, 1H), 6.76~6.72 (m, 2H), 7.09 (m, 1H), 7.26~7.60 (m. 4H), 7.81 (dd, 1H, J = 1.8, 2.1 Hz), 8.76 (d, 1H, J = 1.8 Hz).
<Example 198> (±)-(1S,2R,5R,3aR,7aR)-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dihydroxyoctahydro-1H-indene-2-carbonitrile
The Example 196 compound (65 mg, 0.185 mmol) was reacted according to the same procedure as Example 169 to give the title compound (6 mg, Yield 8%).
1H NMR (300 MHz, CDCl3) δ 0.86~1.72 (m, 6H), 1.82~2.23 (m, 6H), 2.75~2.79 (m, 1H), 4.23~4.34 (m, 1H), 6.65 (m, 2H), 7.08 (m, 1H), 7.26~7.47 (m. 4H), 7.81 (dd, 1H, J = 1.8, 2.1 Hz), 8.78 (d, 1H, J = 1.8 Hz).
<Example 199> (±)-(1S,2S,5R,3aR,7aR)-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dihydroxyoctahydro-1H-indene-2-carboxamide
The Example 197 compound (35 mg, 0.092 mmol) was dissolved in c-H2SO4:H2O (9:1) (3 mL) at 0 ℃, and the mixture was stirred for 1 h. The solution was neutralized with 2N NaOH solution, extracted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to give the title compound (8 mg, Yield 22%).
1H NMR (300 MHz, CDCl3) δ 1.14~1.97 (m, 12H), 2.03~2.41 (m, 2H), 2.56~2.83 (m, 2H), 3.32 (s, 3H), 3.76~3.82 (m, 1H), 6.55~6.77 (m, 2H), 7.08 (m, 1H), 7.29~7.47 (m, 4H), 7.82~7.94 (m, 1H), 8.76 (s, 1H).
<Example 200> (±)-(4aR,5S,7aS)-t-butyl-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-(methoxymethoxy)hexahydro-1H-cyclopenta[c]pyridine-2(3H)-carboxylate
Figure PCTKR2011004607-appb-I000160
(Step 1) t-Butyl 3,3-diethoxypropylcarbamate
2,2-diethoxypropane-1-amine (302 mg, 1.49 mmol) was dissolved in anhydrous dioxane (3 mL), to which were added NEt3 (0.2 mL, 1.49 mmol) and di-t-butyl dicarbonate at 0℃. After stirring for 2 h at room temperature, the mixture was concentrated. To the residue were added water and 1N HCl. The mixture was extracted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 5:1) to give the title compound (320 mg, Yield 87%).
1H NMR (300 MHz, CDCl3) δ 1.55 (t, 6H, J = 7.05 Hz), 1.43 (s, 9H), 1.78~1.84 (q, 2H, J = 9.66 Hz), 3.20~3.22 (m, 2H), 3.44~3.55 (m, 2H), 3.60~3.68 (m, 2H), 4.54 (t, 1H, J = 10.8 Hz), 4.85 (s, 1H).
(Step 2) t-Butyl 3-oxopropylcarbamate
To the Step 1 compound (320 mg, 1.29 mmol) were added acetic acid (2.25 mL) and H2O (0.75 mL), which was then stirred for 24 h at room temperature. Aqueous Na2CO3 solution was added to the mixture, which was then extracted with ether and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to give the title compound (200 mg, Yield 82%).
1H NMR (300 MHz, CDCl3) δ 1.4 (s, 9H), 2.6~2.75 (m, 2H), 3.4 (m, 2H), 9.8 (s, 1H).
(Step 3) (E)-methyl 5-(t-butoxycarbonylamino)pent-2-enoate
The Step 2 compound (150 mg, 0.61 mmol) was dissolved in anhydrous CH2Cl2 (3 mL). Methyl(triphenylphosphoranylidene)acetate (446 mg, 1.85 mmol) was added and heated under reflux. After the solvent was removed, the residue was filtered through a silica gel pad using hexane/ethyl acetate (3:1) solution. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 5:1) to give the title compound (60 mg, Yield 48%).
1H NMR (300 MHz, CDCl3) δ 1.43 (s, 9H), 2.37~2.44 (m, 2H), 3.00~3.23 (m, 2H), 3.37 (s, 3H), 4.36 (s, 1H), 5.87~5.91 (d, 1H, J = 18.3 Hz), 6.85~6.95 (m, 1H).
(Step 4) (E)-t-butyl 5-hydroxypent-3-enylcarbamate
The Step 3 compound (150 mg, 0.61 mmol) was dissolved in anhydrous THF (3 mL). At -78℃, diisobutylaluminum hydride (0.3 mL, 1 M/toluene) was added and stirred for 7 h. Methanol was added to stop the reaction and the mixture was filtered through a silica gel pad. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to give the title compound (90 mg, Yield 72%).
1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.58 (s, 1H), 2.21~2.27 (m, 2H), 3.15~3.22 (m, 2H), 4.09~4.13 (m, 2H), 5.64~5.75 (m, 2H).
(Step 5) (E)-t-butyl 5-(t-butyldimethylsilyloxy)pent-3-enylcarbamate
To anhydrous THF (2 mL) was added NaH (26 mg, 0.71 mmol). The Step 4 compound (90 mg, 0.44 mmol) dissolved in anhydrous THF was added, and t-butyldimethylsilyl chloride (107 mg, 0.71 mmol) was added. After stirring for 24 h at room temperature, aqueous NH4Cl solution was added to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated aqueous sodium chloride solution, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 8:1) to give the title compound (106 mg, Yield 76%).
1H NMR (300 MHz, CDCl3) δ 0.008 (s, 6H), 0.85 (s, 9H), 2.12~2.18 (m, 2H), 3.07~3.13 (m, 2H), 4.5~4.07 (m, 2H), 4.46 (s, 1H), 5.47~5.60 (m, 2H).
(Step 6) (E)-t-butyl 5-(t-butyldimethylsilyloxy)pent-3-enyl(prop-2-ynyl)carbamate
To anhydrous THF (15 mL) were added NaH (285 mg, 7.13 mmol) and tetrabutylammonium iodide (173 mg, 0.47 mmol). The Step 5 compound (1.5 g, 4.75 mmol) dissolved in anhydrous THF was added, and propargyl bromide (0.7 mL, 0.51 mmol) was added thereto. After stirring under reflux for 5 h, aqueous NH4Cl solution was added to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated aqueous sodium chloride solution, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 8:1) to give the title compound (600 mg, Yield 35%).
1H NMR (300 MHz, CDCl3) δ 0.009 (s, 6H), 0.84 (s, 9H), 1.37 (s, 9H), 2.18~2.23 (m, 2H), 3.07~3.13 (m, 1H), 3.26~3.31 (s, 1H), 4.04~4.07 (m, 2H), 5.51~5.55 (m, 2H).
(Step 7) (±)-(4aS,5R)-t-butyl 5-[(t-butyldimethylsilyloxy)methyl]-6-oxo-4,4a,5,6-tetrahydro-1H-cyclopenta[c]pyridine-2(3H)-carboxylate
The Step 6 compound (600 mg, 1.67 mmol) was reacted according to the same procedure as Step 6 of Example 171 to give the title compound (320 mg, Yield 51%).
1H NMR (300 MHz, CDCl3) δ 0.028 (s, 6H), 0.83 (s, 9H), 1.02 (s, 1H), 1.41 (s, 9H), 2.09~2.11 (m, 2H), 2.75~2.80 (m, 1H), 2.86~2.94 (m, 1H), 3.57 (m, 1H), 3.79~3.87 (m, 2H), 4.19~4.38 (m, 1H), 4.93~5.00 (m, 1H), 5.90 (s, 1H).
(Step 8) (±)-(4aS,5R,7aR)-t-butyl 5-[(t-butyldimethylsilyloxy)methyl]-6-oxohexahydro-1H-cyclopenta[c]pyridine-2(3H)-carboxylate
The Step 7 compound (320 mg, 0.86 mmol) was reacted according to the same procedure as Step 7 of Example 171 to give the title compound (240 mg, Yield 72%).
1H NMR (300 MHz, CDCl3) δ 0.001 (s, 6H), 0.85 (s, 9H), 1.22 (s, 1H), 1.42 (s, 9H), 1.62~1.77 (m, 3H), 1.97~2.09 (m, 2H), 2.48 (s, 1H), 3.00~3.07 (m, 1H), 3.23~3.45 (m, 2H), 3.44~3.56 (m, 2H), 3.72~3.77 (m, 1H), 3.93~3.98 (m, 1H).
(Step 9) (±)-(4aS,5R,7aR)-t-butyl 5-[(t-butyldimethylsilyloxy)methyl]-6-hydroxyhexahydro-1H-cyclopenta[c]pyridine-2(3H)-carboxylate
The Step 8 compound (240 mg, 0.62 mmol) was reacted according to the same procedure as Step 7 of Example 172 to give the title compound (200 mg, Yield 87%).
1H NMR (300 MHz, CDCl3) δ 0.07 (s, 6H), 0.91 (s, 9H), 1.34~1.40 (m, 1H), 1.46 (s, 9H), 1.52~1.58 (m, 1H), 1.74~1.88 (m, 3H), 2.04~2.13 (m, 2H), 2.60 (s, 1H), 3.08~3.15 (m, 1H), 3.33~3.39 (m, 2H), 3.52~3.58 (m, 2H), 3.80~3.85 (m, 1H), 4.01~4.06 (m, 1H).
(Step 10) (±)-(4aS,5R,7aR)-t-butyl 5-[(t-butyldimethylsilyloxy)methyl]-6-(methoxymethoxy)hexahydro-1H-cyclopenta[c]pyridine-2(3H)-carboxylate
The Step 9 compound (20 mg, 0.05 mmol) was reacted according to the same procedure as Step 8 of Example 172 to give the title compound (24 mg, Yield 100%).
1H NMR (300 MHz, CDCl3) δ 0.04 (s, 6H), 0.87 (s, 9H), 1.44 (s, 9H), 1.62~1.68 (m, 2H), 1.87~1.90 (m, 2H), 3.5~3.30 (m, 2H), 3.34 (s, 3H), 3.39~3.47 (m, 2H), 3.60~3.62 (m, 2H) 3.90~3.93 (m, 2H), 4.62 (s, 2H).
(Step 11) (±)-(4aR,5S,7aS)-t-butyl-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-(methoxymethoxy)hexahydro-1H-cyclopenta[c]pyridine-2(3H)-carboxylate
The Step 10 compound (16.5 mg, 0.052 mmol) was reacted according to the same procedures as Step 9 of Example 172, Step 10 of Preparation 3 and Example 1―3 step reaction―to give the title compound (20 mg, Yield 79%).
1H NMR (300 MHz, CDCl3) δ 1.25~1.26 (m, 1H), 1.46 (s, 9H), 1.60~1.70 (m, 1H), 1.73~1.90 (m, 1H), 1.98~2.10 (m, 1H), 2.17~2.30 (m, 2H), 2.65~2.80 (m, 2H), 3.03~3.11 (m, 1H), 3.32 (s, 3H) 3.40~2.60 (m, 2H), 3.61~3.82(m, 2H), 3.95~4.15 (m, 1H), 4.02~4.15 (m, 1H), 4.65 (s, 2H), 6.59 (d, 1H, J = 15.6 Hz), 6.69~6.77 (dd, 1H, J = 5.6 Hz, J = 8.5 Hz), 7.05~7.10 (m, 1H), 7.32~7.47 (m, 3H), 7.78~7.81 (dd, 1H, J = 8.1 Hz, J = 2.3 Hz), 8.75~8.7 (d, 1H, J = 2.2 Hz).
<Example 201> (±)-(1S,3aS,7aR)-5-(t-butyloxycarbonylamino)-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-yl methanesulfonate
Figure PCTKR2011004607-appb-I000161
The Example 151 compound (19 mg, 0.040 mmol) was reacted according to the same procedure as Example 10 to give the title compound (17 mg, Yield 80%).
Figure PCTKR2011004607-appb-I000162
<Example 202> (±)-2-{(E)-2-[(1'S,3a'S,7a'R)-5',5'-difluorooctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
1H NMR (300 MHz, CDCl3) δ 1.64~1.94 (m, 6H), 2.03~2.27 (m, 3H), 2.37 (m, 1H), 2.77 (m, 1H), 3.75~3.98 (m, 4H), 6.54~6.76 (m, 2H), 7.09 (m, 1H), 7.20~7.47 (m, 4H), 7.81~7.94 (dd, 1H, J = 2.1, 2.4 Hz), 8.77 (d, 1H, J = 1.8 Hz).
<Example 203> (±)-2-{(E)-2-[(1'S,3a'S,7a'R)-6',6'-difluorooctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine
1H NMR (300 MHz, CDCl3) δ 1.76~1.91 (m, 4H), 2.04~2.26 (m, 6H), 2.93 (m, 1H), 3.80~3.96 (m, 4H), 6.59~6.79 (m, 2H), 7.08 (m, 1H), 7.29~7.45 (m, 4H), 7.80 (d, 1H, J = 7.8 Hz), 8.77(s, 1H).
Figure PCTKR2011004607-appb-I000163
<Example 204> (±)-t-Butyl(1S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2'-oxooctahydrospiro[indene-2,5'-oxazolidin]-5-ylcarbamate
(Step 1) (±)-t-Butyl (1R,3aS,7aR)-1-(benzyloxymethyl)-2-cyano-2-hydroxyoctahydro-1H-inden-5-yl carbamate
The compound of Step 5 of Preparation 7 (200 mg, 0.535 mmol) was reacted according to the same procedure as Example 169 to give the title compound (178 mg, Yield 83%).
1H NMR (300 MHz, CDCl3) δ 0.82-1.33 (m, 5H), 1.43 (s, 9H), 1.61-2.09 (m, 5H), 2.22 (m, 1H), 3.33 (br s, 1H), 3.47 (m, 1H), 3.66 (dd, 1H, J = 11.1, 9.0 Hz), 3.80 (dd, 1H, J = 9.0, 4.8 Hz), 4.37 (br s, 1H), 4.50 (d, 1H, J = 11.4 Hz), 4.67 (d, 1H, J = 11.4 Hz), 7.26 (m, 5H).
(Step 2) (±)-t-Butyl (1R,3aS,7aR)-1-(benzyloxymethyl)-2'-oxooctahydrospiro[indene-2,5'-oxazolidin]-5-ylcarbamate
The solution of Step 1 compound (121 mg, 0.302 mmol) in methanol (5 mL) was stirred at room temperature, cobalt(II) chloride 6 hydrate (1.44 g, 6.04 mmol) was added thereto, and the mixture was stirred for 5 min. To the deep blue mixture was added NaBH4 (114 mg, 3.02 mmol) in three portions. After stirring for 5 h, the mixture was diluted with H2O (10 mL). The reaction mixture was extracted with ethyl acetate (5 × 20 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give an aminoalcohol (140 mg) having light green color, which was then used in the next reaction without further purification.
The solution of the aminoalcohol (140 mg) in THF (2 mL) was stirred at room temperature, during which carbonyl diimidazole (245 mg, 1.51 mmol) was added thereto. After stirring for 12 h, the reaction mixture was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound (73 mg, 2 Step Yield 56%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 0.82-1.34 (m, 5H), 1.44 (s, 9H), 1.61-1.87 (m, 4H), 2.02-2.21 (m, 2H), 3.27-3.51 (m, 2H), 3.58-3.81 (m, 3H), 4.46 (m, 2H), 5.44 (br s, 1H), 5.59 (brs, 1H), 7.31 (m, 5H).
(Step 3) (±)-t-Butyl (1R,3aS,7aR)-1-(hydroxymethyl)-2'-oxooctahydrospiro[indene-2,5'-oxazolidin]-5-ylcarbamate
The solution of Step 2 compound (72.7 mg, 0.169 mmol) in methanol (3 mL) was stirred at room temperature, during which 20 wt% Pd(OH)2/C (15 mg) was added thereto. For the black suspension, the air in the reaction vessel was removed under reduced pressure condition, and the reaction mixture was heated to 50 ℃ under 1 atm of hydrogen gas. After stirring for 12 h, the mixture was filtered through a celite 545 pad using methanol (40 mL). The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to give the title compound (42 mg, 73%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 0.82-1.38 (m, 5H), 1.44 (s, 9H), 1.54-1.94 (m, 3H), 2.00-2.21 (m, 3H), 3.46 (d, J = 8.4 Hz, 1H), 3.50 (m, 1H), 3.67 (d, J = 8.4 Hz, 1H), 3.85 (m, 2H), 4.43 (t, J = 8.1 Hz, 1H), 5.35 (d, J = 5.7 Hz, 1H), 7.11 (s, 1H).
(Step 4) (±)-t-Butyl (1S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2'-oxooctahydrospiro[indene-2,5'-oxazolidin]-5-ylcarbamate
The solution of Step 3 compound (30.0 mg, 0.0881 mmol) in DMSO (2 mL) was stirred at room temperature, during which o-iodoxybenzoic acid (73.9 mg, 0.264 mmol) was added. The reaction mixture was stirred for 2 h at room temperature, and ice water (1 mL) was added thereto to stop the reaction. The mixture was extracted with CH2Cl2 (3 × 10 mL). The organic layers were combined and washed with saturated aqueous sodium chloride solution (2 × 5 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a colorless aldehyde (43 mg), which was reacted without further purification according to the same procedure as Example 1 to give the title compound (15 mg, 2 Step Yield 34%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 0.82-1.36 (m, 5H), 1.44 (s, 9H), 1.72-1.92 (m, 2H), 1.99-2.29 (m, 3H), 2.44 (m, 1H), 3.34 (d, J = 8.7 Hz, 1H), 3.56 (m, 1H), 3.76 (d, J = 8.7 Hz, 1H), 4.40 (d, J = 6.9 Hz, 1H), 4.89 (br s, 1H), 6.60 (d, J = 15.9 Hz, 1H), 6.72 (dd, J = 15.9, 8.7 Hz, 1H), 7.09 (t, J = 8.4 Hz, 1H), 7.26-7.48 (m, 4H), 7.82 (dd, J = 8.1, 2.4 Hz, 1H), 8.75 (d, J = 2.1 Hz, 1H).
<Example 205> (±)-t-Butyl (1'S,3a'S,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dioxooctahydrospiro[imidazolidine-4,2'-inden]-5'-ylcarbamate
(Step 1) (±)-t-Butyl (1'S,3a'S,7a'R)-1'-(benzyloxymethyl)-2,5-dioxooctahydrospiro[imidazolidine-4,2'-inden]-5'-ylcarbamate
The solution of Step 5 compound of Preparation 7 (220 mg, 0.589 mmol) in EtOH/H2O (1:1, v/v, 5 mL) was stirred at room temperature, during which KCN (76.7 mg, 1.18 mmol) and (NH4)2CO3 (283 mg, 2.95 mmol) were added. The reaction vessel was heated to 60 ℃ and the mixture was stirred for 48 h. The reaction mixture was diluted with ethyl acetate (3 mL) and extracted with ethyl acetate (3 × 10 mL). The organic layers were combined and washed with saturated aqueous sodium chloride solution (5 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to give the title compound (130 mg, 50%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 0.85-1.34 (m, 5H), 1.44 (s, 9H), 1.58-1.79 (m, 2H), 1.88 (m, 2H), 2.00-2.36 (m, 2H), 3.41-3.62 (m, 3H), 4.31- 4.46 (m, 2H), 4.51 (d, J = 8.1 Hz, 1H), 7.25 (m, 5H).
(Step 2) (±)-t-Butyl (1'S,3a'S,7a'R)-1'-(hydroxymethyl)-2,5-dioxooctahydrospiro[imidazolidine-4,2'-inden]-5'-ylcarbamate
The Step 1 compound (120 mg, 0.270 mmol) was reacted according to the same procedure as Step 3 of Example 204 to give the title compound (71mg, Yield 75%) as a white solid.
(Step 3) (±)-t-Butyl (1'S,3a'S,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dioxooctahydrospiro[imidazolidine-4,2'-inden]-5'-ylcarbamate
The Step 2 compound (47 mg, 0.132 mmol) was reacted according to the same procedure as Step 4 of Example 204 to give the title compound (37mg, Yield 55%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 0.89-1.36 (m, 5H), 1.44 (s, 9H), 1.55-2.18 (m, 5H), 2.49 (m, 1H), 3.50 (m, 1H), 4.50 (br s, 1H), 6.52 (d, J = 15.0 Hz, 1H), 6.64 (dd, J = 15.0, 10.1 Hz, 1H), 7.07 (t, J = 8.4 Hz, 1H), 7.26-7.46 (m, 4H), 7.79 (dd, J = 8.1, 2.1 Hz, 1H), 8.80 (d, J = 2.1 Hz, 1H).
<Example 206> (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one
Figure PCTKR2011004607-appb-I000164
(±)-(1R,3aR,7aR)-1-(benzyloxymethyl)-5,5-difluorohexahydro-1H-inden-2(3H)-one (47 mg, 0.132 mmol) was reacted according to the same procedure as Example 204 to give the title compound as a white solid.
1H NMR (300 MHz, CDCl3) δ 1.29 (m, 1H), 1.57-1.80 (m, 4H), 1.89 (m, 1H), 2.03 (dd, J = 14.0, 10.0 Hz, 1H), 2.11-2.23 (m, 2H), 2.33 (m, 2H), 3.58 (s, 2H), 4.99 (br s, 1H), 6.65 (m, 2H), 7.09 (t, J = 8.7 Hz, 1H), 7.25-7.49 (m, 4H), 7.81 (dd, J = 8.1, 2.4 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H).
<Example 207> (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-3'-methyloctahydrospiro[indene-2,5'-oxazolidin]-2'-one
Figure PCTKR2011004607-appb-I000165
The solution of Example 206 compound (10.0 mg, 0.0233 mmol) in THF (1 mL) was stirred at room temperature, during which NaH (1.87 mg, 0.0466 mmol) was added. After stirring for 30 min, iodomethane (2.90 μL, 0.0466 mmol) was added and stirred for 3 h. H2O (1 mL) was added to the reaction mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound (7 mg, 69%) as a pale yellow solid.
1H NMR (300 MHz, CDCl3) δ 1.33-1.75 (m, 5H), 1.78-2.17 (m, 2H), 2.12-2.24 (m, 2H), 2.28-2.38 (m, 2H), 2.81 (s, 3H), 3.50 (s, 2H), 6.62 (m, 2H), 7.09 (m, 1H), 7.26-7.50 (m, 4H), 7.81 (dd, J = 8.1, 2.4 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H).
Figure PCTKR2011004607-appb-I000166
<Example 208> (±)-(1'S,3'aS,7a'R)-5',5'-difluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[imidazolidine-4,2'-inden]-2,5-dione
(Step 1) (±)-(1'S,3a'R,7a'R)-1'-(benzyloxymethyl)-5',5'-difluorooctahydrospiro[imidazolidine-4,2'-inden]-2,5-dione
(±)-(1R,3aR,7aR)-1-(benzyloxymethyl)-5,5-difluorohexahydro-1H-inden-2(3H)-one (200 mg, 0.682 mmol) was reacted according to the same procedure as Step 1 of Example 205 to give the title compound (136 mg, 55%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 1.23-1.67 (m, 4H), 1.74-2.04 (m, 3H), 2.12-2.39 (m, 4H), 3.49 (d, J = 3.9 Hz, 2H), 4.40 (d, J = 11.7 Hz, 1H), 4.51 (d, J = 11.7 Hz, 1H), 6.51 (s, 1H), 7.26-7.36 (m, 5H), 8.62 (s, 1H).
(Step 2) (±)-(1'S,3a'R,7a'R)-1'-(hydroxymethyl)-5',5'-difluorooctahydrospiro[imidazolidine-4,2'-inden]-2,5-dione
The Step 1 compound (86 mg, 0.236 mmol) was reacted according to the same procedure as Step 3 of Example 204 to give the title compound (53 mg, Yield 82%) as a white solid.
1H NMR (300 MHz, CD3OD) δ 1.11-1.70 (m, 4H), 1.75-1.98 (m, 4H), 2.06-2.26 (m, 2H), 2.32 (dd, J = 13.4, 7.1 Hz, 1H), 3.63 (m, 2H).
(Step 3) (±)-(1'S,3a'S,7a'R)-5',5'-difluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[imidazolidine-4,2'-inden]-2,5-dione
The Step 2 compound (46 mg, 0.168 mmol) was reacted according to the same procedure as Step 4 of Example 204 to give the title compound (34 mg, Yield 47%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 1.20-1.63 (m, 4H), 1.75-2.04 (m, 3H), 2.12-2.40 (m, 2H), 2.55 (dd, J = 13.8, 6.9 Hz, 1H), 2.83 (dd, J = 10.8, 9.9 Hz, 1H), 6.25 (s, 1H), 6.50-6.72 (m, 2H), 7.09 (t, J = 8.4 Hz, 1H), 7.26-7.47 (m, 4H), 7.80 (d, J = 8.1 Hz, 1H), 8.26 (s, 1H), 8.81 (s, 1H).
<Example 209> (±)-(1'S,3'aS,7a'R)-5',5'-difluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[imidazolidine-4,2'-inden]-2-one
(Step 1) (±)-(1'S,3a'R,7a'R)-1'-(benzyloxymethyl)-5',5'-difluorooctahydrospiro[imidazolidine-4,2'-inden]-2-one
The solution of Step 1 compound of Example 208 (103 mg, 0.283 mmol) in THF (3 mL) was stirred at 0 ℃, during which LiAlH4 (53.6 mg, 1.41 mmol) was added. The mixture was stirred under reflux for 4 h. Distilled water (1 mL) was added at 0 ℃ to stop the reaction, 2 N aqueous NaOH solution (10 mL) was added thereto and stirred for 30 min. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 1:2 → ethyl acetate) to give the title compound (80 mg, 81%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.23-1.51 (m, 5H), 1.55-1.84 (m, 3H), 2.11-2.34 (m, 3H), 3.32 (d, J = 8.4 Hz, 1H), 3.36 (d, J = 8.4 Hz, 1H), 3.62 (m, 2H), 4.45 (m, 2H), 5.22 (s, 1H), 5.38 (s, 1H), 7.26-7.37 (m, 5H).
(Step 2) (±)-(1'S,3a'R,7a'R)-1'-(hydroxymethyl)-5',5'-difluorooctahydrospiro[imidazolidine-4,2'-inden]-2-one
The Step 1 compound (80 mg, 0.228 mmol) was reacted according to the same procedure as Step 3 of Example 204 to give the title compound (49 mg, Yield 83%) as a white solid.
1H NMR (300 MHz, CD3OD) δ 1.12-1.50 (m, 5H), 1.56-1.86 (m, 2H), 1.92 (m, 1H), 2.13-2.26 (m, 3H), 3.36 (s, 2H), 3.79 (m, 2H), 5.02 (s, 1H), 5.72 (s, 1H).
(Step 3) (±)-(1'S,3a'S,7a'R)-5',5'-difluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[imidazolidine-4,2'-inden]-2-one
The Step 2 compound (47 mg, 0.181 mmol) was reacted according to the same procedure as Step 4 of Example 204 to give the title compound (26mg, Yield 34%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 1.23-1.44 (m, 3H), 1.49-1.77 (m, 3H), 2.12-2.43 (m, 4H), 3.45 (d, J = 8.7 Hz, 1H), 3.51 (d, J = 8.7 Hz, 1H), 4.43 (s, 1H), 4.91 (s, 1H), 6.55 (d, J = 15.6 Hz, 1H), 6.68 (dd, J = 15.6, 8.7 Hz, 1H), 7.09 (td, J = 8.4, 2.4 Hz, 1H), 7.26-7.47 (m, 4H), 7.80 (dd, J = 8.1, 2.4 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H).
<Example 210> (±)-(1'S,3a'S,7a'R)-5',5'-difluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-1,3-dimethyloctahydrospiro[imidazolidine-4,2'-inden]-2-one
The solution of Example 209 compound (11.0 mg, 0.0257 mmol) in THF (1 mL) was stirred at room temperature, and NaH (3.08 mg, 0.0771 mmol) was added thereto. After stirring for 30 min, CH3I (4.80 μL, 0.0771 mmol) was added and stirred for 3 h. H2O (1 mL) was added to the reaction mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to give the title compound (9 mg, 74%) as a pale yellow solid.
1H NMR (300 MHz, CDCl3) δ 1.20-1.47 (m, 2H), 1.51-1.85 (m, 5H), 1.92-2.02 (m, 2H), 2.20 (dd, J = 11.4, 7.8 Hz, 1H), 2.33 (dd, J = 14.1, 8.1 Hz, 1H), 2.76 (s, 3H), 2.81 (s, 3H), 3.21 (d, J = 8.7 Hz, 1H), 3.29 (d, J = 8.7 Hz, 1H), 6.55 (d, J = 15.9 Hz, 1H), 6.68 (dd, J = 15.9, 7.8 Hz, 1H), 7.09 (td, J = 8.4, 2.4 Hz, 1H), 7.26-7.48 (m, 4H), 7.81 (dd, J = 8.1, 2.4 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H).
Figure PCTKR2011004607-appb-I000167
<Example 211> (±)-(1S,3aR,7aR)-6,6-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden]-2-ol
(±)-(1R,3aR,7aR)-1-(benzyloxymethyl)-6,6-difluorohexahydro-1H-inden-2(3H)-one was reacted according to the same procedures as Step 2 of Example 62, Step 8 of Preparation 7 and Step 4 of Example 204 in the order to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.20~1.32 (m, 2H), 1.32 (s, 3H), 1.45~2.11 (m, 10H), 2.12~2.28 (m, 2H), 2.47~2.61 (m, 2H), 6.62~6.79 (m, 2H), 7.08 (m, 1H), 7.24~7.47 (m. 4H), 7.81 (dd, 1H, J = 2.4, 2.1 Hz), 8.76 (d, 1H, J = 1.8 Hz).
<Example 212> (±)-(1S,2R,3aR,7aR)-6,6-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden]-2-yl carbamate
The Example 211 compound (13 mg, 0.033 mmol) was reacted according to the same procedure as Example 65 to give the title compound (3.4 mg, Yield 24%).
1H NMR (300 MHz, CDCl3) δ 1.53 (s, 3H), 2.40~0.82 (m, 10H), 3.08 (t, 1H, J = 9.3, 9.6 Hz), 4.51 (brs, 2H), 6.64 (m, 2H), 7.08 (m, 1H), 7.29~7.45 (m. 4H), 7.82 (dd, 1H, J = 2.7, 2.4 Hz), 8.77 (d, 1H, J = 2.4 Hz).
<Example 213> (±)-(1S,2S,3aR,7aR)-6,6-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden]-2-yl carbamate
The Example 211 compound (13 mg, 0.033 mmol) was reacted according to the same procedure as Example 65 to give the title compound (6.2 mg, Yield 42%).
1H NMR (300 MHz, CDCl3) δ 0.82~2.29 (m, 9H), 1.63 (s, 3H), 2.5 1(m, 1H), 2.90 (m, 1H), 4.58 (brs, 2H), 6.70 (m, 2H), 7.09 (m, 1H), 7.29~7.48 (m. 4H), 7.83 (dd, 1H, J = 2.7, 2.1 Hz), 8.77 (d, 1H, J = 2.1 Hz).
<Example 214> (±)-N-{(1S,3aR,7aR)-6,6-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden]-2-yl}acetamide
In anhydrous CH3CN (1 mL) was dissolved the Example 211 compound (30 mg, 0.077 mmol), to which was slowly added conc. sulfuric acid (0.015 mL, 0.154 mmol) at -78 ℃. After stirring for 1 h at room temperature, the reaction mixture was neutralized by 2 N NaOH, extracted with CH2Cl2 and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to give the title compound (0.4 mg, Yield 12%).
1H-NMR (300MHz, CDCl3) δ 1.50 (s, 3H), 1.51~1.82 (m, 4H), 1.92 (s, 3H), 1.93~2.23 (m, 4H), 2.63 (m, 2H), 2.94 (m, 1H), 5.45 (brs, 1H), 6.62~6.77 (m, 2H), 7.10 (m, 1H), 7.26~7.49 (m, 4H), 7.85 (dd, 1H, J = 2.4, 2.4 Hz), 8.78 (d, 1H, J = 2.4 Hz)
<Example 215> (±)-(1S,2R,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydrospiro-1H-inden]-2-ylcarbamate
Figure PCTKR2011004607-appb-I000168
(Step 1) (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydrospiro-1H-inden]-2-ol
(±)-(1R,3aS,7aR)-1-(benzyloxymethyl)-5,5-difluorohexahydro-1H-inden-2(3H)-one was reacted according to the same procedures as Step 2 of Example 62, Step 8 of Preparation 7 and Step 4 of Example 204 in the order to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.20~1.30 (m, 1H), 1.38 (s, 3H), 1.57~1.90 (m, 9H), 2.04~2.22 (m, 3H), 2.38~2.40 (m, 3H), 6.58~6.79 (m, 2H), 7.05~7.12 (m, 1H), 7.23~7.47 (m. 4H), 7.8 (dd, 1H, J = 2.4, 2.4 Hz), 8.76 (d, 1H, J = 4.8 Hz).
(Step 2) (±)-(1S,2R,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydrospiro-1H-inden]-2-ylcarbamate
The Step 1 compound was reacted according to the same procedure as Example 65 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.25~1.89 (m, 6H), 1.53 (s, 3H), 2.09 (m, 1H), 2.34~2.41 (m, 3H), 2.87~2.95 (m, 1H), 4.57 (brs, 2H), 6.54~6.83 (m, 2H), 7.06~7.13 (m, 1H), 7.26~7.48 (m. 4H), 7.83 (dd, 1H, J = 2.4, 2.4 Hz), 8.88 (d, 1H, J = 1.8 Hz).
<Example 216> (±)-(1S,2S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydrospiro-1H-inden]-2-ylcarbamate
Figure PCTKR2011004607-appb-I000169
The same procedure as Example 215 was carried out to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.53 (s, 3H), 1.77~2.35 (m, 9H), 3.02~3.06 (m, 3H), 3.33~3.35 (m, 1H), 4.51 (brs, 2H), 6.56~6.75 (m, 2H), 7.11 (m, 1H), 7.26~7.45 (m. 4H), 7.82 (dd, 1H, J = 2.4, 2.4 Hz), 8.87 (d, 1H, J = 1.9 Hz).
<Example 217> (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one
Figure PCTKR2011004607-appb-I000170
(±)-(1R,3aS,7aR)-1-(benzyloxymethyl)-5,5-difluorohexahydro-1H-inden-2(3H)-one was reacted according to the same procedure as Example 204 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 0.88~1.96 (m, 7H), 2.02~2.25 (m, 3H), 2.37~2.41 (m, 1H), 3.37 (d, 1H, J = 8.7 Hz), 3.80 (dd, 1H, J = 0.75 Hz, 0.72 Hz) 4.77 (brs, 1H), 6.62~6.71 (m, 2H), 7.09~7.10 (m, 1H), 7.28~7.46 (m. 4H), 7.83 (dd, 1H, J = 2.4, 2.4 Hz), 8.76 (d, 1H, J = 1.8 Hz).
<Example 218> (±)-(1S,3aR,7aR)-6,6-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one
Figure PCTKR2011004607-appb-I000171
(±)-(1R,3aR,7aR)-1-(benzyloxymethyl)-6,6-difluorohexahydro-1H-inden-2(3H)-one was reacted according to the same procedure as Example 204 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.02~2.35 (m, 7H), 2.35 (m, 1H), 2.63 (m, 3H), 3.54 (m, 2H), 4.85 (brs, 1H), 6.55~6.77 (m, 2H), 7.05~7.12 (m, 1H), 7.28~7.47 (m. 4H), 7.81 (dd, 1H, J = 2.4, 2.4 Hz), 8.76 (d, 1H, J = 1.8 Hz).
<Example 219> (±)-N-{(1S,2R,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden]-2-yl}acetamide
Figure PCTKR2011004607-appb-I000172
The Example 192 compound was reacted according to the same procedure as Example 214 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.2~2.5 (m, 16H), 2.85(t, 1H, J =9.6 Hz), 6.5 (d, 1H, J =15.6 Hz), 6.75 (dd, 1H, J = 9.3, 15.6 Hz), 7.1 (t, 1H, J = 8.1 Hz), 7.3~7.45 (m, 4H), 7.8 (d, 1H, J = 8.1 Hz), 8.75 (s, 1H).
<Example 220> (±)-N-{(1S,2S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden]-2-yl}acetamide
Figure PCTKR2011004607-appb-I000173
The same procedure as Example 219 was carried out to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.2~2.4 (m, 17H), 6.6 (d, 1H, J =15.9 Hz), 6.75 (dd, 1H, J = 8.1, 15.9 Hz), 7.1 (t, 1H, J = 8.4 Hz), 7.3~7.5 (m, 4H), 7.85 (d, 1H, J = 8.1 Hz), 8.75 (s, 1H).
Figure PCTKR2011004607-appb-I000174
<Example 221> (±)-3-{(1S,2R,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-2-yl}oxazolidin-2-one
The Example 195 compound was reacted according to the same procedures as Step 1 of Example 115, Example 130 and Example 166 in the order to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.5~2.5 (m, 10H), 3.2 (dd, 1H, J = 9.6, 18.6 Hz), 3.6 (m, 2H), 4.2 (m, 2H), 4.6 (dd, 1H, J = 8.7, 17.1 Hz), 6.7 (m, 2H), 7.1 (t, 1H, J = 8.1 Hz), 7.25~7.5 (m, 4H), 7.85 (d, 1H, J = 8.1 Hz), 8.75 (s, 1H).
<Example 222> (±)-N-{(1S,2R,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-2-yl}methanesulfonamide
The Example 195 compound was reacted according to the same procedure as Example 176 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.2~2.4 (m, 11H), 2.9 (s, 3H), 4.65 (d, 1H, J = 8.7 Hz), 6.6 (d, 1H, J = 15.6 Hz), 6.75 (dd, 1H, J = 9.3, 15.3 Hz), 7.1 (t, 1H, J = 8.1 Hz), 7.3~7.5 (m, 4H), 7.85 (d, 1H, J = 8.1 Hz), 8.75 (s, 1H).
<Example 223> (±)-N-{(1S,2R,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-2-yl}-N-methylmethanesulfonamide
The Example 222 compound (18 mg, 0.039 mmol) was reacted according to the same procedure as Example 49 to give the title compound (15 mg, Yield 83%).
1H NMR (300 MHz, CDCl3) δ 1.2~2.4 (m, 10H), 2.75 (s 3H), 2.9 (s 3H), 3.15 (m, 1H), 4.8 (m, 1H), 6.6 (d, 1H, J = 15.6 Hz), 6.75 (dd, 1H, J = 8.7, 15.3 Hz), 7.1 (t, 1H, J = 8.1 Hz), 7.25~7.5 (m, 4H), 7.85 (d, 1H, J = 8.1 Hz), 8.75 (s, 1H).
Figure PCTKR2011004607-appb-I000175
<Example 224> (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiroindene-2,5'-oxathiazolidin-2',2'-dione
(Step 1) (±)-(1S,3aS,7aR)-5,5-difluoro-1-(benzyloxymethyl)octahydrospiroindene-2,5'-oxathiazolidin-2',2'-dione
The aminoalcohol compound (200 mg, 0.615 mmol) was dissolved in anhydrous CH2Cl2 (5 mL). Triethylamine (0.128 mL, 0.922 mmol) and SO2Cl2 (0.074 mL, 0.922 mmol) were added thereto at 0 ℃. After stirring for 2 h at room temperature, the mixture was extracted with CH2Cl2. The organic layer was washed twice with saturated aqueous sodium chloride solution, dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to give the title compound (80 mg, Yield 33%).
1H NMR (300 MHz, CDCl3) δ 1.26~1.32 (m, 1H), 1.64~2.18 (m, 8H), 2.48~2.67 (m, 2H), 3.07 (m, 1H), 3.68~3.87 (m, 2H), 4.22 (m, 1H), 4.60 (m, 3H), 7.25~7.39 (m, 5H).
(Step 2) (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiroindene-2,5'-oxathiazolidin-2',2'-dione
The Step 1 compound was reacted according to the same procedures as Steps 3 and 4 of Example 204 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.23~1.42 (m, 2H), 1.57~2.28 (m. 8H), 2.33~2.63 (m, 2H), 3.01 (brs, 1H), 3.27 (s, 1H), 3.46 (m, 1H), 3.70~4.07 (m, 1H), 4.12 (d, 1H, J = 7.2 Hz).
<Example 225> (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,2'-morpholine]-5'-one
(Step 1) (±)-(1S,3aS,7aR)-5,5-difluoro-1-(benzyloxymethyl)octahydrospiro[indene-2,2'-morpholine]-5'-one
The aminoalcohol compound (200 mg, 0.615 mmol) was dissolved in anhydrous CH2Cl2 (5 mL). NEt3 (0.128 mL, 0.922 mmol) and chloroacetyl chloride (0.073 mL, 0.922 mmol) were added at 0 ℃.
After stirring for 4 h at room temperature, the mixture was extracted with CH2Cl2 and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and used in the next reaction without further purification.
The residue was dissolved in anhydrous DMF (3 mL), NaH (37 mg, 92 mmol) was added at 0 ℃, and the mixture was stirred for 12 h at room temperature. The mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated aqueous sodium chloride solution, dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (CH2Cl2:MeOH = 20:1) to give the title compound (200 mg, Yield 89%).
1H-NMR (300MHz, CDCl3) δ 1.64~2.04 (m, 10H), 2.13~2.21 (m, 2H), 3.47 (m, 1H), 3.54 (m, 2H), 3.73 m, 1H), 4.13 (m, 2H), 4.48 (m, 2H), 7.26~7.35 (m, 5H).
(Step 2) (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,2'-morpholine]-5'-one
The Step 1 compound was reacted according to the same procedures as Steps 3 and 4 of Example 204 to give the title compound.
1H NMR (300 MHz, CDCl3) 1.53~2.05 (m, 11H), 2.32 (m. 1H), 2.84 (m, 1H), 3.40 (m, 1H), 3.77 (m, 1H), 4.08 (m, 1H), 6.51~6.67 (m, 2H), 7.09 (m, 1H), 7.23~7.45 (m, 4H), 7.80 (m, 1H), 8.74(m, 1H).
Figure PCTKR2011004607-appb-I000176
<Example 226> (±)-(1S,3aR,7aR)-2-cyano-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl methanesulfonate
(Step 1) (±)-(1S,3aR,7aR)-5,5-difluoro-1-(p-methoxybenzyloxymethyl)hexahydro-1H-inden-2(3H)-one
The solution of (±)-(1S,3aR,7aR)-5,5-difluoro-1-(hydroxymethyl)hexahydro-1H-inden-2(3H)-one (701 mg, 3.43 mmol) in DMF (10 mL) was stirred at room temperature, during which NaH (206 mg, 5.15 mmol) was added. The yellow suspension was stirred for 1 h, p-methoxybenzyl chloride (558 μL, 4.12 mmol) was added, and the mixture was stirred for 6 h. Distilled water (2 mL) was added to the mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with Et2O (3 × 10 mL). The organic layers were combined and washed with saturated aqueous NH4Cl solution (5 mL) and saturated aqueous sodium chloride solution (5 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to give the title compound (1.11 g, 83%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.14 (m, 1H), 1.55-2.07 (m, 7H), 2.22 (m, 1H), 2.37-2.51 (m, 2H), 3.61 (dd, J = 10.5, 3.6 Hz, 1H), 3.72 (dd, J = 10.5, 4.5 Hz, 1H), 3.80 (s, 3H), 4.38 (d, J = 11.7 Hz, 1H), 4.44 (d, J = 11.7 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H).
(Step 2) (±)-(1S,3aR,7aR)-2-hydroxy-5,5-difluoro-1-(p-methoxybenzyloxymethyl)octahydro-1H-indene-2-carbonitrile
The solution of Step 1 compound (302 mg, 0.931 mmol) in CH2Cl2 (3 mL) was stirred at room temperature, during which KCN (2.79 mmol) and a catalytic amount of 18-crown-6 were added. After stirring for 30 min, trimethylsilyl cyanide was added to the mixture. After stirring for 12 h, conc. hydrochloric acid (1 mL) was added to the mixture, which was then stirred for 1 h. To the mixture was added saturated aqueous NaHCO3 solution (5 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The organic layers were combined, washed with saturated aqueous NaHCO3 solution (3 mL), dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1→4:1) to give the title compound (243 mg, 74%) as a mixture of pale yellow liquid.
1H NMR (300 MHz, CDCl3) δ 1.17-1.51 (m, 3H), 1.53-1.77 (m, 3H), 1.97-2.36 (m, 5H), 3.66 (dd, J = 14.0, 9.0 Hz, 1H), 3.80 (m, 1H), 3.81 (s, 3H), 4.22 (br s, 1H), 4.45 (d, J = 11.4 Hz, 1H), 4.60 (d, J = 11.4 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 7.27 (d, J = 8.7 Hz, 2H).
(Step 3) (±)-(1S,3aR,7aR)-2-cyano-5,5-difluoro-1-(hydroxymethyl)octahydro-1H-inden-2-yl methanesulfonate
The solution of Step 2 compound (243 mg, 0.692 mmol) in CH2Cl2 (3 mL) was stirred at room temperature, during which CH3SO2Cl (107 μL, 1.38 mmol), pyridine (139 μL, 2.77 mmol) and N,N,-dimethylaminopyridine (42.3 mg, 0.346 mmol) were added. After stirring for 72 h, distilled water (1 mL) was added to the mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The organic layers were combined, washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (256 mg) as a yellow liquid, which was then used in the next reaction without further purification.
The solution of the mesylate (256 mg) in CH2Cl2/H2O (10:1, 5 mL) was stirred at room temperature, during which 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (677 mg, 2.98 mmol) was added. After stirring for 12 h, saturated aqueous NaHCO3 solution (3 mL) was added to the mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The organic layers were combined, washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound (107 mg, 2 Step Yield 50%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 1.40-1.85 (m, 4 H), 1.94-1.85 (m, 6H), 2.72 (dd, J = 12.9, 4.2 Hz, 1H), 3.22 (s, 3H), 3.89 (dd, J = 11.2, 5.8 Hz, 1H), 4.11 (dd, J = 11.2, 4.5 Hz, 1H).
(Step 4) (±)-(1S,3aR,7aR)-2-cyano-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl methanesulfonate
The Step 3 compound (72.0 mg, 0.233 mmol) was reacted according to the same procedures as Step 10 of Preparation 3 and Example 1 to give 20 mg of the title compound (2 Step Yield 18%) as a pale yellow liquid.
1H NMR (300 MHz, CDCl3) δ 1.36-1.83 (m, 5H), 1.95 (m, 1H), 2.15-2.29 (m, 2H), 2.36 (m, 1H), 2.85-2.96 (m, 2H), 3.19 (s, 3H), 6.74 (d, J = 15.6 Hz, 1H), 6.83 (dd, J = 15.6, 8.4 Hz, 1H), 7.11 (t, J = 8.7 Hz, 1H), 7.26-7.49 (m, 4H), 7.85 (dd, J = 8.0, 2.1 Hz, 1H), 8.80 (d, J = 1.8 Hz, 1H).
<Example 227> (±)-N-{(1S,3aR,7aR)-2-cyano-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methanesulfonamide
(Step 1) (±)-(1S,3aR,7aR)-2-amino-5,5-difluoro-1-(p-methoxybenzyloxymethyl)octahydro-1H-indene-2-carbonitrile
The solution of Step 1 compound of Example 226 (624 mg, 1.92 mmol) in MeOH (3 mL) was stirred at room temperature, during which KCN (376 mg, 5.77 mmol), NH4Cl (293 mg, 5.77 mmol) and NH4OH (3 mL) were added. The reaction mixture was stirred for 4 days at room temperature. The mixture was diluted with ethyl acetate (3 mL) and extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, washed with saturated aqueous sodium chloride solution (2 × 5 mL), dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to give the title compound (511 mg, 76%) as a pale yellow liquid.
1H NMR (300 MHz, CDCl3) δ 1.15-1.44 (m, 2H), 1.46-1.82 (m, 3H), 1.87-2.33 (m, 6H), 3.58 (dd, J = 10.6, 9.3 Hz, 1H), 3.73 (dd, J = 9.3, 4.5 Hz, 1H), 3.80 (s, 3H), 4.43 (d, J = 11.1 Hz, 1H), 4.57 (d, J = 11.1 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H).
(Step 2) (±)-N-[(1S,3aR,7aR)-2-cyano-5,5-difluoro-(1-hydroxymethyl)octahydro-1H-inden-2-yl]methanesulfonamide
The Step 1 compound was reacted according to the same procedure as Step 3 of Example 226 to give the title compound as a white solid.
1H NMR (300 MHz, CDCl3) δ 1.22-1.59 (m, 3H), 1.61-1.86 (m, 3H), 1.93-2.40 (m, 4H), 2.50 (br s, 1H), 2.81 (dd, J = 13.5, 7.2 Hz, 1H), 3.94-4.08 (m, 2H), 5.77 (br s, 1H).
(Step 3) (±)-N-{(1S,3aR,7aR)-2-cyano-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methanesulfonamide
The solution of oxalyl chloride (48.5 μL, 0.556 mmol) in CH2Cl2 (2 mL) was stirred at -78 ℃, during which the solution of anhydrous DMSO (72.5 μL, 1.02 mmol) in CH2Cl2 (1 mL) was added. After stirring for 20 min, the solution of Step 2 compound (143 mg, 0.464 mmol) in CH2Cl2 (1 mL) was added to the mixture and stirred for 30 min at -78 ℃. To the mixture was added Et3N (323 μL, 2.32 mmol) and stirred for 30 min at 0 ℃. Saturated aqueous NH4Cl solution (3 mL) was added to the mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The organic layers were combined, washed with brine (5 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was filtered through a silica gel pad using Et2O (50 mL). The filtrate was concentrated under reduced pressure to give a pale yellow aldehyde (52 mg), which was reacted without further purification according to the same procedure as Example 1 to give the title compound (46 mg, 2 Step Yield 21%) as a pale yellow liquid.
1H NMR (300 MHz, CDCl3) δ 1.23-1.44 (m, 3H), 1.51-1.83 (m, 3H), 1.90 (m, 1H), 2.18-2.34 (m, 2H), 2.58 (dd, J = 11.1, 9.0 Hz, 1H), 2.83 (dd, J = 14.2, 7.8 Hz, 1H), 3.17 (s, 3H), 5.31 (br s, 1H), 6.75 (d, J = 15.6 Hz, 1H), 6.85 (dd, J = 15.6, 9.0 Hz, 1H), 7.09 (td, J = 8.4, 2.7 Hz, 1H), 7.26-7.49 (m, 4H), 7.85 (dd, J = 8.1, 1.8 Hz, 1H), 8.79 (d, J = 2.1 Hz, 1H).
Figure PCTKR2011004607-appb-I000177
<Example 228> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro-[indene-2,4'-oxazolidin]-2'-one
(Step 1) (±)-(1S,3aR,7aR)-2-azido-1-(benzyloxymethyl)-5,5-difluorooctahydro-1H-indene-2-carbonitrile
The solution of NaN3 (1.64 g, 25.1 mmol) in toluene/water (1:1, 8.2 mL) was stirred at 0 ℃, during which triflic anhydride (2.69 mL, 12.6 mmol) was slowly added. After stirring for 30 min, the reaction vessel was warmed to room temperature and the mixture was stirred for 2 h. Saturated aqueous NaHCO3 solution (5 mL) was added to the mixture and stirred until no more gas was developed. The reaction mixture was extracted with toluene (2 × 4.1 mL) and the organic layers were combined to give triflic azide.
The solution of the amine (573 mg, 1.79 mmol) in H2O (2.32 mL) was stirred at room temperature, during which NaHCO3 (601 mg, 7.16 mmol) and CuSO4(II)·5 hydrate (22.3 mg, 0.0895 mmol) were added. After stirring for 5 min, the solution of triflic azide (3.94 mL, 1.0 M toluene, 3.94 mmol) and methanol (15.5 mL) were added. The reaction mixture was stirred until its color was changed from blue to green, and then concentrated under reduced pressure. The concentrate was diluted with ethyl acetate (3 mL) and extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to give the title compound (440 mg, 71%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.37-1.60 (m, 4H), 1.82-1.92 (m, 3H), 2.08-2.33 (m, 4H), 3.59 (dd, J = 9.7, 8.6 Hz, 1H), 3.72 (dd, J = 9.7, 4.3 Hz, 1H), 4.53 (d, J = 11.6 Hz, 1H), 4.63 (d, J = 11.6 Hz, 1H), 7.28-7.38 (m, 5H).
(Step 2) (±)-(1S,3aR,7aR)-1-(benzyloxymethyl)-5,5-difluorooctahydrospiro-[indene-2,4'-oxazolidin]-2'-one
The solution of Step 1 compound (440 mg, 1.27 mmol) in THF (3 mL) was stirred at -78 ℃, during which diisobutylaluminum hydride (2.54 mL, 1.0 M hexane solution, 2.54 mmol) was added. After stirring for 2 h, the reaction vessel was warmed to room temperature and the mixture was stirred for 30 min. H2O (1 mL) was added to the mixture to stop the reaction. conc. Sulfuric acid (200 μL) and H2O (1 mL) were added and stirred for 30 min at room temperature. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The organic layers were combined, washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give an aldehyde (368 mg) as a colorless liquid, which was then used in the next reaction without further purification.
The solution of the aldehyde (368 mg) in THF (3 mL) was stirred at 0 ℃, LiAlH4 (96.3 mg, 2.54 mmol) was slowly added, and the mixture was stirred for 2 h. H2O (1 mL) was added to the mixture to stop the reaction. 2 N aqueous NaOH solution (2 mL) was added and stirred for 30 min. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (5 × 10 mL). The organic layers were combined, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give an aminoalcohol (26 mg) as a pale yellow liquid, which was then used in the next reaction without further purification.
The aminoalcohol (256 mg), diethyl carbonate (1.53 mL, 11.2 mmol) and K2CO3 (877 mg, 6.35 mmol) were introduced to a reaction vessel at room temperature and heated to 140 ℃. After stirring for 12 h, the mixture was diluted with CH2Cl2 (3 mL) and H2O (2 mL). The reaction mixture was extracted with CH2Cl2 (3 × 10 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound (87 mg, 3 Step Yield 20%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.22-1.56 (m, 5H), 1.58-1.86 (m, 3H), 2.08-2.34 (m, 3H), 3.54 (dd, J = 10.3, 4.5 Hz, 1H), 3.66 (dd, J = 10.3, 2.7 Hz, 1H), 4.04 (d, J = 9.3 Hz, 1H), 4.44 (d, J = 11.7 Hz, 1H), 4.52 (d, J = 11.7 Hz, 1H), 4.63 (d, J = 9.3 Hz, 1H), 6.36 (br s, 1H), 7.26-7.43 (m, 5H).
(Step 3) (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro-[indene-2,4'-oxazolidin]-2'-one
The Step 2 compound (56.1 mg, 0.214 mmol) was reacted according to the same procedure as Step 4 of Example 204 to give the title compound (43 mg, 2 Step Yield 47%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 1.21-1.46 (m, 3H), 1.52-1.87 (m, 4H), 1.96-2.13 (m, 2H), 2.20-2.36 (m, 2H), 2.90 (s, 3H), 4.19 (d, J = 8.7 Hz, 1H), 4.25 (d, J = 8.7 Hz, 1H), 6.60 (d, J = 15.9 Hz, 1H), 6.70 (dd, J = 15.9, 7.8 Hz, 1H), 7.09 (td, J = 8.1, 1.5 Hz, 1H), 7.26-7.48 (m, 4H), 7.82 (dd, J = 8.1, 2.4 Hz, 1H), 8.76 (d, J = 1.8 Hz, 1H).
<Example 229> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-3'-methyloctahydrospiro-[indene-2,4'-oxazolidin]-2'-one
The Example 228 compound (20.1 mg, 0.0467 mmol) was reacted according to the same procedure as Example 207 to give the title compound (15 mg, Yield 77%) as a pale yellow solid.
1H NMR (300 MHz, CDCl3) δ 1.20-1.47 (m, 2H), 1.51-1.85 (m, 5H), 1.92-2.02 (m, 2H), 2.20 (dd, J = 11.4, 7.8 Hz, 1H), 2.33 (dd, J = 14.1, 8.1 Hz, 1H), 2.76 (s, 3H), 2.81 (s, 3H), 3.21 (d, J = 8.7 Hz, 1H), 3.29 (d, J = 8.7 Hz, 1H), 6.55 (d, J = 15.9 Hz, 1H), 6.68 (dd, J = 15.9, 7.8 Hz, 1H), 7.09 (td, J = 8.4, 2.4 Hz, 1H), 7.26-7.48 (m, 4H), 7.81 (dd, J = 8.1, 2.4 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H).
<Example 230> (±)-(1'S,3a'R,7a'R)-5',5'-difluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-3H-spiro[furan-2,2'-inden]-5(4H)-one
Figure PCTKR2011004607-appb-I000178
(Step 1) (±)-(1S,3aR,7aR)-2-allyl-1-(benzyloxymethyl)-5,5-difluorooctahydro-1H-inden-2-ol
The solution of ketone (310 mg, 1.05 mmol) in THF (3 mL) was stirred at -78 ℃, during which allyl magnesium bromide (2.10 mL, 1.0 M in Et2O, 2.10 mmol) was added. After stirring for 10 min, the reaction vessel was warmed to 0 ℃ and the mixture was stirred for 2 h. Saturated aqueous NH4Cl solution (3 mL) was added to the mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to give the title compound (276 mg, 78%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.19-1.56 (m, 4H), 1.56-1.82 (m, 4H), 2.07 (dd, J = 7.0, 4.5 Hz, 1H), 2.10-2.25 (m, 2H), 2.29 (dd, J = 13.5, 7.5 Hz, 1H), 2.40 (dd, J = 13.5, 6.9 Hz, 1H), 2.95 (br s, 1H), 3.63 (m, 2H), 4.45 (d, J = 11.7 Hz, 1H), 4.56 (d, J = 11.7 Hz, 1H), 5.09 (d, J = 17.4 Hz, 1H), 5.10 (d, J = 10.8 Hz, 1H), 5.82-5.96 (m, 1H), 7.26-7.38 (m, 5H).
(Step 2) (±)-(1S,3aR,7aR)-1-(benzyloxymethyl)-5,5-difluoro-2-(hydroxypropyl)octahydro-1H-inden-2-ol
The solution of Step 1 compound (276 mg, 0.820 mmol) in THF (2 mL) was stirred at 0 ℃, during which borane-methylsulfide complex (1.23 mL, 2.0 M in THF, 2.46 mmol) was slowly added. After stirring for 10 min, the reaction vessel was warmed to room temperature and the mixture was stirred for 2 h. EtOH (1 mL) was added to the reaction vessel to stop the reaction. To the mixture were added 3 N NaOH (2 mL) and 30% H2O2 (2 mL), which was then stirred under reflux for 2 h. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound (206 mg, 71%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.18-1.53 (m, 5H), 1.54-1.83 (m, 7H), 2.05-2.32 (m, 3H), 2.45 (br s, 1H), 3.58-3.71 (m, 4H), 4.46 (d, J = 12.0 Hz, 1H), 4.57 (d, J = 12.0 Hz, 1H), 7.26-7.39 (m, 5H).
(Step 3) (±)-(1'S,3a'R,7a'R)-1'-(benzyloxymethyl)-5',5'-difluorooctahydro-3H-spiro[furan-2,2'-inden]-5(4H)-one
The solution of Step 2 compound (206 mg, 0.581 mmol) in CH2Cl2 (5 mL) was stirred at room temperature, during which pyridium chlorochromate (376 mg, 1.74 mmol) was added. After the dark brown suspension was stirred for 6 h, a celite 545 (200 mg) was added to the mixture and stirred for 30 min. The reaction mixture was filtered through a celite 545 pad using CH2Cl2 (30 mL). The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to give the title compound (156 mg, 76%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 1.18-1.54 (m, 3H), 1.57-1.92 (m, 5H), 2.08-2.29 (m, 4H), 2.30-2.64 (m, 3H), 3.56 (d, J = 6.3 Hz, 1H), 3.57 (d, J = 7.8 Hz, 1H), 4.39 (d, J = 11.7 Hz, 1H), 4.48 (d, J = 11.7 Hz, 1H), 7.26-7.36 (m, 5H).
(Step 4) (±)-(1'S,3a'R,7a'R)-5',5'-difluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-3H-spiro[furan-2,2'-inden]-5(4H)-one
The Step 3 compound was reacted according to the same procedures as Steps 3 and 4 of Example 204 to give the title compound as a yellow solid.
1H NMR (300 MHz, CDCl3) δ 1.29 (m, 1H), 1.54-1.79 (m, 4H), 1.81-1.95 (m, 3H), 2.13-2.36 (m, 6H), 2.45-2.53 (m, 2H), 6.63 (m, 2H), 7.09 (tdd, J = 8.1, 2.4, 0.9 Hz, 1H), 7.24-7.48 (m, 4H), 7.81 (dd, J = 8.1, 2.4 Hz, 1H), 8.74 (dd, J = 2.4, 0.6 Hz, 1H).
Figure PCTKR2011004607-appb-I000179
<Example 231> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2',2'-dimethyl-3'-(methylsulfonyl)octahydrospiro[indene-2,4'-oxazolidine]
(Step 1) (±)-(1R,3aR,7aR)-1-(benzyloxymethyl)-5,5-difluoro-2-{trichloromethyl)octahydro-1H-inden-2-ol
The solution of ketone (232 mg, 0.788 mmol) in THF (3 mL) was stirred at room temperature, during which CHCl3 (159 μL, 1.97 mmol) was added. After stirring for 5 min, the reaction vessel was cooled to -78 ℃. Lithium hexamethyldisilazide (1.58 mL, 1.0 M THF solution, 1.58 mmol) was added and stirred for 30 min. The reaction vessel was warmed to 0 ℃, and saturated aqueous NH4Cl solution (1 mL) was added to the mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, washed with saturated aqueous sodium chloride solution (3 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 40:1) to give the title compound (264 mg, 81%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.17-1.55 (m, 2H), 1.58-1.98 (m, 4H), 2.01-2.39 (m, 4H), 2.67 (dd, J = 13.0, 6.5 Hz, 1H), 3.73 (dd, J = 10.0, 2.4 Hz, 1H), 4.17 (dd, J = 10.0, 3.3 Hz, 1H), 4.46 (d, J = 11.7 Hz, 1H), 4.61 (d, J = 11.7 Hz, 1H), 5.44 (s, 1H), 7.25-7.38 (m, 5H).
(Step 2) (±)-(1S,3aR,7aR)-methyl-2-azido-1-(benzyloxymethyl)-5,5-difluorooctahydro-1H-indene-2-carboxylate
The solution of Step 1 compound (264 mg, 0.638 mmol) in MeOH (3 mL) was stirred at room temperature, during which NaN3 (124 mg, 1.91 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (477 μL, 3.19 mmol) were added. After stirring for 24 h, distilled water (1 mL) was added to the mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 40:1) to give the title compound (203 mg, 84%) as a pale yellow liquid.
1H NMR (300 MHz, CDCl3) δ 1.29-1.64 (m, 4H), 1.66-1.96 (m, 4H), 2.08-2.36 (m, 3H), 3.44 (dd, J = 9.3, 8.7 Hz, 1H), 3.58 (dd, J = 9.3, 5.1 Hz, 1H), 3.65 (s, 3H), 4.40 (d, J = 12.0 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 7.25-7.36 (m, 5H).
(Step 3) (±)-(1S,3aR,7aR)-methyl-1-(benzyloxymethyl)-5,5-difluoro-2-(methylsulfonamido)octahydro-1H-indene-2-carboxylate
The solution of Step 2 compound (203 mg, 0.535 mmol) in THF/H2O (10:1, 3 mL) was stirred at room temperature, during which PPh3 (702 mg, 2.67 mmol) was added. The reaction mixture was heated to 70 ℃ and stirred for 24 h. The reaction vessel was cooled, and distilled water (1 mL) and ethyl acetate (2 mL) were added thereto. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (5 × 10 mL). The organic layers were combined, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a pale yellow amine (232 mg), which was then used in the next reaction without further purification.
The solution of the amine (232 mg) in CH2Cl2 (2 mL) was stirred at 0 ℃, during which methanesulfonyl chloride (82.8 μL, 1.07 mmol) and NEt3 (149 μL, 1.07 mmol) were added. After stirring for 2 h, distilled water (1 mL) was added to the mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound (185 mg, 2 Step Yield 76%) as a pale yellow liquid.
1H NMR (300 MHz, CDCl3) δ 1.28-1.53 (m, 2H), 1.56-1.82 (m, 4H), 1.92-2.46 (m, 5H), 3.01 (s, 3H), 3.25 (dd, J = 9.6, 9.6 Hz, 1H), 3.59 (dd, J = 9.6, 3.9 Hz, 1H), 3.71 (s, 3H), 4.41 (s, 2H), 5.47 (br s, 1H), 7.26-7.36 (m, 5H).
(Step 4) (±)-(1S,3aR,7aR)-1-(benzyloxymethyl)-5,5-difluoro-2',2'-dimethyl-3'-(methylsulfonyl)octahydrospiro[indene-2,4'-oxazolidine]
The solution of Step 3 compound (92.5 mg, 0.203 mmol) in THF (2 mL) was stirred at 0 ℃, during which LiAlH4 (15.4 mg, 0.406 mmol) was slowly added and stirred for 1 h. H2O (1 mL) was added to the mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 × 10 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give an aminoalcohol (63 mg) as a pale yellow liquid, which was then used in the next reaction without further purification.
The solution of the aminoalcohol (63 mg) in CH2Cl2 (2 mL) was stirred at room temperature in a reaction vessel, during which 2,2-dimethoxypropane (49.7 μL, 0.406 mmol) and a catalytic amount of p-toluenesulfonic acid were added. After stirring for 6 h, the reaction mixture was neutralized by adding saturated aqueous NaHCO3 solution (1 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to give the title compound (47 mg, 2 Step Yield 52%) as a pale yellow liquid.
1H NMR (300 MHz, CDCl3) δ 1.03 (m, 1H), 1.24-1.74 (m, 4H), 1.56 (s, 3H), 1.58 (s, 3H), 1.90-2.37 (m, 5H), 2.63 (dd, J = 13.8, 8.1 Hz, 1H), 2.94 (s, 3H), 3.65 (m, 3H), 4.26 (d, J = 9.6 Hz, 1H), 4.43 (d, J = 11.7 Hz, 1H), 4.54 (d, J = 11.7 Hz, 1H), 7.27-7.38 (m, 5H).
(Step 5) (±)-(1S,3aR,7aR)-1-(hydroxymethyl)-5,5-difluoro-2',2'-dimethyl-3'-(methylsulfonyl)octahydrospiro[indene-2,4'-oxazolidine]
The Step 4 compound (47.2 mg, 0.106 mmol) was reacted according to the same procedure as Step 3 of Example 204 to give the title compound (35 mg, 83%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 1.25-1.59 (m, 4H), 1.57 (s, 3H), 1.71 (s, 9H), 1.84 (m, 1H), 2.07-2.39 (m, 5H), 2.66 (dd, J = 13.7, 7.8 Hz, 1H), 3.10 (s, 3H), 3.70 (d, J = 9.9 Hz, 1H), 3.85 (m, 2H), 4.33 (d, J = 9.9 Hz, 1H).
(Step 6) (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2',2'-dimethyl-3'-(methylsulfonyl)octahydrospiro[indene-2,4'-oxazolidine]
The solution of Step 5 compound (35.0 mg, 0.0990 mmol) in CH2Cl2 (1 mL) was stirred at room temperature, during which NEt3 (41.4 μL, 0.297 mmol) was added. The reaction vessel was cooled to 0 ℃, and the solution of sulfur trioxide-pyridine complex (47.3 mg, 0.297 mmol) in DMSO (1 mL) was added. After stirring for 2 h, cold saturated aqueous sodium chloride solution (1 mL) was added to the mixture to stop the reaction. The reaction mixture was extracted with CH2Cl2 (3 × 10 mL). The organic layers were combined, washed with brine (2 × 5 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a colorless aldehyde (33 mg), which was then used in the next reaction without further purification.
The solution of Preparation 15 compound (64.0 mg, 0.198 mmol) in THF (1 mL) was stirred under nitrogen atmosphere at 0 ℃, during which n-BuLi (79.2 μL, 2.5 M in hexanes, 0.198 mmol) was added. After stirring the dark brown reaction mixture for 20 min, the solution of aldehyde (33 mg) in THF (1 mL) was added. The deep yellow reaction mixture was stirred for 1 h at 0 ℃, and saturated aqueous NH4Cl solution (1 mL) was added to the mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to give the title compound (37 mg, 2 Step Yield 72%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.11 (m, 1H), 1.23-1.71 (m, 4H), 1.57 (s, 3H), 1.61 (s, 3H), 1.86 (m, 1H), 2.06-2.38 (m, 3H), 2.75 (dd, J = 13.5, 8.1 Hz, 1H), 2.89 (dd, J = 12.0, 9.0 Hz, 1H), 3.12 (s, 3H), 3.89 (d, J = 9.6 Hz, 1H), 4.24 (d, J = 9.6 Hz, 1H), 6.62 (d, J = 15.6 Hz, 1H), 6.76 (dd, J = 15.6, 9.0 Hz, 1H), 7.09 (t, J = 8.4 Hz, 1H), 7.22-7.48 (m, 4H), 7.81 (dd, J = 8.1, 2.4 Hz, 1H), 8.77 (d, J = 2.1 Hz, 1H).
<Example 232> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-3'-(methylsulfonyl)octahydrospiro[indene-2,4'-oxazolidine]
The same procedure as Example 231 was carried out except that dimethoxymethane was used instead of 2,2-dimethoxypropane in Step 4 to give the title compound.
<Example 233> (±)-{(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(hydroxymethyl)octahydro-1H-inden-2-yl}methanesulfonamide
The solution of Example 231 compound (34.1 mg, 0.0653 mmol) in THF (1 mL) was stirred at room temperature, during which conc. hydrochloric acid (1 mL) was added. After stirring for 6 h, the reaction mixture was neutralized by adding saturated aqueous NaHCO3 solution (5 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (5 × 10 mL). The organic layers were combined, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to give the title compound (21 mg, 68%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.12-1.44 (m, 2H), 1.52-1.86 (m, 4H), 2.02-2.38 (m, 3H), 2.42 (dd, J = 13.9, 7.3 Hz, 1H), 2.73 (dd, J = 9.1, 9.1 Hz, 1H), 3.11 (s, 3H), 3.56 (d, J = 9.6 Hz, 1H), 3.85 (d, J = 9.6 Hz, 1H), 4.98 (br s, 1H), 6.65 (d, J = 15.5 Hz, 1H), 6.79 (dd, J = 15.5, 9.1 Hz, 1H), 7.09 (tdd, J = 8.4, 2.4, 1.1 Hz, 1H), 7.22-7.48 (m, 4H), 7.82 (dd, J = 8.1, 2.4 Hz, 1H), 8.75 (d, J = 1.8 Hz, 1H).
<Example 234> (±)-{(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(fluoromethyl)octahydro-1H-inden-2-yl}methanesulfonamide
The solution of Example 233 compound (18.2 mg, 0.0379 mmol) in CH2Cl2 (1 mL) was stirred at 0 ℃, during which diethylaminosulfur trifluoride (10.0 μL, 0.0757 mmol) was added. After stirring for 5 h, saturated aqueous NaHCO3 solution (1 mL) was added to the mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound (12 mg, 65%) as a pale yellow liquid.
1H NMR (300 MHz, CDCl3) δ 1.23-1.65 (m, 4H), 1.72-1.95 (m, 2H), 2.04-2.44 (m, 3H), 2.56 (d, J = 5.1 Hz, 2H), 2.58 (m, 1H), 2.83 (m, 1H), 3.05 (s, 3H), 6.50 (d, J = 3.9 Hz, 2H), 7.09 (t, J = 8.4 Hz, 1H), 7.22-7.48 (m, 4H), 7.81 (dd, J = 8.1, 2.4 Hz, 1H), 8.76 (d, J = 1.8 Hz, 1H).
<Example 235> (±)-(1S,3aS,5S,6S,7aR)-6-fluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-hydroxyoctahydrospiro[indene-2,5'-oxazolidin]-2'-one
Figure PCTKR2011004607-appb-I000180
(Step 1) (±)-(1R,3aS,5S,6S,7aR)-1-(benzyloxymethyl)-6-fluoro-5-hydroxyhexahydro-1H-inden-2-(3H)-one
The solution of epoxide (447 mg, 1.64 mmol) in THF (3 mL) was stirred at room temperature, during which HF-pyridine complex (1 mL) was added. After stirring for 3 h, the reaction mixture was neutralized by adding saturated aqueous NaHCO3 solution (15 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 15 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to give the title compound (182 mg, 38%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.62-1.95 (m, 3H), 2.02-2.11 (m, 4H), 2.27-2.43 (m, 2H), 3.66 (m, 2H), 4.19 (m, 2H), 4.46 (d, J = 12.3 Hz, 1H), 4.53 (d, J = 12.3 Hz, 1H), 4.65-4.80 (m, 1H), 7.25-7.37 (m, 5H).
(Step 2) (±)-(1S,3aS,5S,6S,7aR)-6-fluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-hydroxyoctahydrospiro[indene-2,5'-oxazolidin]-2'-one
The Step 1 compound was reacted according to the same procedures as Step 7 of Preparation 7, Example 204 and Step 5 of Preparation 5 in the order to give the title compound as a white solid.
1H NMR (300 MHz, CDCl3) δ 144-1.90 (m, 4H), 1.92-2.06 (m, 3H), 2.13 (m, 1H), 2.29 (dd, J = 13.7, 7.4 Hz, 1H), 3.55 (d, J = 8.8 Hz, 1H), 3.59 (d, J = 8.8 Hz, 1H), 4.16 (m, 1H), 4.57-4.77 (m, 1H), 4.79 (br s, 1H), 6.63 (m, 2H), 7.09 (tdd, J = 7.8, 2.5, 1.0 Hz, 1H), 7.26-7.55 (m, 4H), 7.82 (dd, J = 8.3, 2.4 Hz, 1H), 8.74 (d, J = 1.7 Hz, 1H).
Figure PCTKR2011004607-appb-I000181
<Example 236> (±)-(1S,3aS,5S,6S,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5,6-dihydroxyoctahydrospiro[indene-2,5'-oxazolidin]-2'-one
(Step 1) (±)-(1'R,3a'S,5'S,6'S,7a'R)-1'-(benzyloxymethyl)octahydrospiro[(1,2)dioxolane-2,2'-inden]-5',6'-diol
The solution of epoxide (1.00 g, 3.16 mmol) in CH2Cl2 (10 mL) was stirred at room temperature, during which HF (1 mL) was added. After stirring for 6 h, the reaction mixture was neutralized by adding saturated aqueous NaHCO3 solution (10 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 × 15 mL). The organic layers were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to give the title compound (740 mg, 70%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.50-1.86 (m, 4H), 1.90-2.11 (m, 4H), 2.36 (dd, J = 17.1, 5.7 Hz, 1H), 3.38-3.71 (m, 4H), 3.73-4.04 (m, 4H), 4.46 (d, J = 12.0 Hz, 1H), 4.52 (d, J = 12.0 Hz, 1H), 7.26-7.36 (m, 5H).
(Step 2) (±)-(1S,3aS,5S,6S,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5,6-dihydroxyoctahydrospiro[indene-2,5'-oxazolidin]-2'-one
The Step 1 compound was reacted according to the same procedures as Step 7 of Preparation 7, Example 204 and Step 5 of Preparation 5 in the order to give the title compound as a white solid.
1H NMR (300 MHz, CDCl3) δ 1.58 (m, 1H), 1.72-1.91 (m, 3H), 1.95-2.14 (m, 3H), 2.17-2.28 (m, 2H), 2.81 (br s, 1H), 2.92 (br s, 1H), 3.51 (d, J = 8.7 Hz, 1H), 3.56 (d, J = 8.7 Hz, 1H), 3.93 (m, 2H), 5.74 (br s, 1H), 6.64 (m, 2H), 7.10 (t, J = 8.4 Hz, 1H), 7.12-7.49 (m, 4H), 7.81 (dd, J = 8.1, 2.4 Hz, 1H), 8.73 (d, J = 2.1 Hz, 1H).
<Example 237> (±)-(1aR,2aR,3S,5aS,6aS)-3-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indeno-[5,6-b]oxirane-4,5'-oxazolidin]-2'-one
The solution of Example 236 compound (15.1 mg, 0.0353 mmol) in CH2Cl2 (1 mL) was stirred at 0 ℃, during which diethylaminosulfur trifluoride (46.7 μL, 0.353 mmol) was added. After stirring for 1 h, saturated aqueous NaHCO3 solution (2 mL) was added to the mixture to stop the reaction. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1 → 2:1) to give the title compound (3.1 mg, 21%) as a colorless liquid.
1H NMR (300 MHz,CDCl3) δ 1.42-1.74 (m, 4H), 1.95-2.09 (m, 2H), 2.13-2.30 (m, 2H), 2.43 (m, 1H), 3.17 (dd, J = 5.7, 3.6 Hz, 1H), 3.20 (m, 1H), 3.55 (s, 2H), 4.75 (br s, 1H), 6.63 (m, 2H), 7.10 (t, J = 8.4 Hz, 1H), 7.29-7.50 (m, 4H), 7.82 (dd, J = 8.1, 2.4 Hz, 1H), 8.75 (d, J = 2.1 Hz, 1H).
<Example 238> (±)-(1aS,2aR,3S,5aS,6aR)-3-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indeno-[5,6-b]oxirane-4,5'-oxazolidin]-2'-one
The Example 236 compound was reacted according to the same procedure as Example 237 to give the title compound (6.5 mg, 33%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.25-1.79 (m, 4H), 1.87-2.17 (m, 3H), 2.23-2.44 (m, 2H), 3.19 (m, 2H), 3.53 (d, J = 8.7 Hz, 1H), 3.57 (d, J = 8.7 Hz, 1H), 4.78 (br s, 1H), 6.58 (dd, J = 15.9, 8.4 Hz, 1H), 6.68 (d, J = 15.9 Hz, 1H), 7.10 (t, J = 8.1 Hz, 1H), 7.30-7.55 (m, 4H), 7.83 (dd, J = 8.1, 1.8 Hz, 1H), 8.75 (d, J = 1.8 Hz, 1H).
<Example 239> (±)-(1S,3aR,5R,6R,7aR)-5,6-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one
The Example 236 compound was reacted according to the same procedure as Example 237 to give the title compound.
Figure PCTKR2011004607-appb-I000182
<Example 240> (±)-(1'S,3a'S,5'S,6'S,7a'R)-6'-fluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-ol
The compound of Step 7 of Preparation 3 was reacted according to the same procedures as Step 2 of Preparation 5, Step 1 of Example 235, Step 8 of Preparation 3, Step 5 of Preparation 5, Steps 9 and 10 of Preparation 3 and Example 1 in the order to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.53~2.13 (m, 10H), 2.44 (m, 1H), 3.73~4.15 (m, 5H), 4.60~4.75 (m, 1H), 6.55~6.76 (m, 2H), 7.08 (m, 1H), 7.28~7.47 (m, 4H), 7.81 (dd, 1H, J = 2.4, 2.4 Hz), 8.75(d, 1H, J = 1.8 Hz)
<Example 241> (±)-2-{(E)-2-{(3'S,3a'R,5'S,6'S,7a'S)-5'-fluoro-6'-methoxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-3'-yl}vinyl}-5-(3-fluorophenyl)pyridine
The Example 240 compound was reacted according to the same procedure as Example 7 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.42~1.80 (m, 5H), 2.06 (m, 3H), 2.42 (m, 1H), 3.37 (s, 3H), 3.57 (m, 1H), 3.74~3.99 (m, 4H), 4.67~4.82 (m, 1H), 6.53~6.76 (m, 2H), 7.09 (m, 1H), 7.28~7.47 (m, 4H), 7.80 (dd, 1H, J = 2.4, 2.4 Hz), 8.76 (d, 1H, J = 2.1 Hz)
<Example 242> (±)-(1'S,2S,3a'S,7a'R)-5',5'-difluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-3H-spiro[furan-2,2'-inden]-5(4H)-one
Figure PCTKR2011004607-appb-I000183
(±)-(1R,3aS,7aR)-1-(benzyloxymethyl)-5,5-difluorohexahydro-1H-inden-2(3H)-one was reacted according to the same procedure as Example 230 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.60~2.20 (m, 10H), 2.38~2.54 (m, 4H), 3.00 m, 1H), 6.58~6.79 (m, 2H), 7.11 (m, 1H), 7.25~7.49 (m, 4H), 7.83 (m, 1H), 8.78 (s, 1H).
<Example 243> (±)-(1'S,2R,3a'S,7a'R)-5',5'-difluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-3H-spiro[furan-2,2'-inden]-5(4H)-one
Figure PCTKR2011004607-appb-I000184
The same procedure as Example 242 was carried out to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.54~1.90 (m, 7H), 2.05~4.13 (m, 8H), 6.52~6.71 (m, 2H), 7.10 m, 1H), 7.26~7.48 (m, 4H), 7.82 (dd, 1H, J = 2.4, 2.4 Hz), 8.76 (d, 1H, J = 1.8 Hz)
Figure PCTKR2011004607-appb-I000185
<Example 244> (±)-(1'S,3a'R,5'S,6'S,7a'R)-6'-fluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-ol
(±)-(3aR,7aR)-methyl 2-oxo-2,3,3a,4,7,7a-hexahydro-1H-indene-1-carboxylate was reacted according to the same procedure as Example 240 to give the title compound.
<Example 245> (±)-2-{(E)-2-{(3'S,3a'R,5'S,6'S,7a'R)-5'-fluoro-6'-methoxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-3'-yl}vinyl}-5-(3-fluorophenyl)pyridine
The Example 244 compound was reacted according to the same procedure as Example 7 to give the title compound.
<Example 246> (±)-(1'S,3a'R,6'S,7a'R)-6'-fluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'(1'H)-one
The Example 244 compound was reacted according to the same procedure as Step 4 of Preparation 5 to give the title compound.
<Example 247> (±)-2-{(E)-2-{(1'S,3a'S,5'R,6'S,7a'R)-5',6'-difluorooctahydrospiro[(1,3)dioxolane-2,2'-inden]-1’-yl}vinyl}-5-(3-fluorophenyl)pyridine
The Example 244 compound was reacted according to the same procedure as Example 189 to give the title compound.
<Example 248> (-)-(1R,2S,3aS,7aS)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one
Figure PCTKR2011004607-appb-I000186
The Preparation 16 compound was reacted according to the same procedures as Steps 8 and 9 of Preparation 3, Step 1 of Preparation 7, Step 3 of Preparation 5, Example 184 and Example 187 to give (-)-(1S,3aS,7aS)-1-(benzyloxymethyl)-5,5-difluorohexahydro-1H-inden-2(3H)-one, which was then reacted according to the same procedure as Example 204 to give the title compound as a white solid.
1H NMR (300 MHz, CDCl3) δ 1.29 (m, 1H), 1.57-1.80 (m, 4H), 1.89 (m, 1H), 2.03 (dd, J = 14.0, 10.0 Hz, 1H), 2.11-2.23 (m, 2H), 2.33 (m, 2H), 3.58 (s, 2H), 4.99 (br s, 1H), 6.65 (m, 2H), 7.09 (t, J = 8.7 Hz, 1H), 7.25-7.49 (m, 4H), 7.81 (dd, J = 8.1, 2.4 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H).
<Example 249> (-)-(1R,2R,3aS,7aS)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5’-oxazolidin]-2’-one
Figure PCTKR2011004607-appb-I000187
The same procedure as Example 248 was carried out to give the title compound as a white solid.
1H NMR (300 MHz, CDCl3) δ 1.23-1.79 (m, 5H), 1.89-2.10 (m, 2H), 2.12-2.42 (m, 2H), 2.50 (dd, J = 13.5, 6.3 Hz, 1H), 2.72 (dd, J = 11.0, 8.7 Hz, 1H), 3.37 (d, J = 9.3 Hz, 1H), 3.78 (d, J = 9.3 Hz, 1H), 4.83 (br s, 1H), 6.62 (dd, J = 15.6 Hz, 1H), 6.73 (dd, J = 15.6, 8.7 Hz, 1H), 7.09 (td, J = 7.8, 1.5 Hz, 1H), 7.26-7.37 (m, 3H), 7.44 (dd, J = 7.8, 6.0 Hz, 1H), 7.83 (dd, J = 8.1, 2.4 Hz, 1H), 8.76 (d, J = 2.1 Hz, 1H).
Figure PCTKR2011004607-appb-I000188
<Example 250> (±)-5-(3-Fluorophenyl)-2-{(E)-2-[(3a'R,4a'R,5'S,7a'S,8a'S)- octahydrospiro[(1,3)dioxolane-2,6'-indeno(5,6-d)(1,3)dioxol]-5’-yl]vinyl}pyridine
(Step 1) (±)-(1'S,3a'S,5'S,6'R,7a'R)-methyl 5',6'- dihydroxyoctahydrospiro[(1,3)dioxolane-2,2'-indene]-1'-carboxylate
The compound of Step 7 of Preparation 3 (2.5 g, 10.5 mmol) was dissolved in a solvent mixture of t-butanol : acetone : water (12.5 mL : 5 mL : 5 mL). N-methylmorpholine-N-oxide (3.6 g, 31.47 mmol) was added, and then OsO4 (0.16 mL, 0.41 mmol) was added. After stirring for 1 h at room temperature, the reaction was stopped by Na2SO3. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to give the title compound (350 mg, 12%).
(Step 2) (±)-(1'S,3a'S,5'S,6'R,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-indene]-5',6'-diol
The Step 1 compound was reacted according to the same procedures as Step 5 of Preparation 5, Steps 9 and 10 of Preparation 3, Example 1 and Step 3 of Example 62 in the order to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.45 (m, 1H), 1.78-1.93 (m, 3H), 2.04-2.20 (m, 4H), 2.49 (m, 1H), 3.66 (m, 1H), 3.74-4.05 (m, 5H), 6.57 (d, 1H, J = 15.7 Hz), 6.75 (dd, 1H, J = 9.3, 15.8 Hz), 7.12 (m, 1H), 7.28-7.45 (m, 4H), 7.80 (dd, 1H, J = 2.4, 8.1 Hz), 8.79 (d, 1H, J = 1.9 Hz).
(Step 3) (±)-5-(3-Fluorophenyl)-2-{(E)-2-[(3a'R,4a'R,5'S,7a'S,8a'S)- octahydrospiro[(1,3)dioxolane-2,6'-indeno(5,6-d)(1,3)dioxol]-5’-yl]vinyl}pyridine
The Step 2 compound (30 mg, 0.07 mmol) was dissolved in anhydrous DMF (2 mL), NaH (7.29 mg, 0.28 mmol) was added thereto and stirred for 1 h at room temperature. CH2Br2 (0.01 mL, 0.16 mmol) was added and stirred for further 1 h at room temperature. NH4Cl was added to stop the reaction. The mixture was extracted with ether and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound(10 mg, 29%).
1H NMR (300 MHz, CDCl3) δ1.11-1.50 (m, 5H), 1.82 (m, 1H), 1.97-2.19 (m, 2H), 2.44 (m, 1H), 3.74-4.14 (m, 6H), 5.00 (s, 1H), 5.21 (s, 1H), 6.55 (d, 1H, J = 15.9 Hz), 6.73 (dd, 1H, J = 9.3, 15.9 Hz), 7.08 (m, 1H), 7.29~7.47 (m, 4H), 7.80 (dd, 1H, J = 2.7, 8.4 Hz), 8.76 (d, 1H, J = 2.1 Hz).
<Example 251> (±)-5-(3-Fluorophenyl)-2-{(E)-2-[(3a'S,4a'R,5'S,7a'S,8a'R)- octahydrospiro[(1,3)dioxolane-2,6'-indeno(5,6-d)(1,3)dioxol]-5’-yl]vinyl}pyridine
(±)-(1'S,3a'S,5'R,6'S,7a'R)-methyl 5',6'-dihydroxyoctahydrospiro[(1,3)dioxolane-2,2'-indene]-1'-carboxylate was reacted according to the same procedures as Steps 2 and 3 of Example 250 to give the title compound.
1H NMR (300 MHz, CDCl3) δ1.25 (m, 1H), 1.39-1.49 (m, 3H), 1.58-1.75 (m, 2H), 2.02-2.13 (m, 2H), 2.35-2.40 (m, 2H), 3.73-3.90 (m, 5H), 4.16 (m, 1H), 4.95 (s, 1H), 5.17 (s, 1H), 6.56 (d, 1H, J = 15.9 Hz), 6.71 (dd, 1H, J = 9.3, 15.9 Hz), 7.08 (m, 1H), 7.29-7.47 (m, 4H), 7.85 (dd, 1H, J = 2.1, 8.1 Hz), 8.75 (d, 1H, J = 2.1 Hz).
Figure PCTKR2011004607-appb-I000189
<Example 252> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,4’-oxazolidin]-2'-thione
(Step 1) (±)-{(1S,3aR,7aR)-2-amino-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methanol
The solution of (±)-(1S,3aR,7aR)-t-butyl 5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2',2'-dimethyloctahydrospiro[indene-2,4’-oxazolidine]-3'-carboxylate (41.4 mg, 0.0763 mmol) in CH2Cl2 (1 mL) was stirred, during which CF3COOH (113 μL, 1.53 mmol) was added. The mixture was stirred for 1.5 h and neutralized by adding saturated aqueous NaHCO3 solution (3 mL) thereto. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The organic layers were combined and washed with saturated aqueous NaHCO3 solution (2 × 3 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (CHCl3:MeOH = 5:1) to give the title compound(17.3 mg, 56%).
1H NMR (300 MHz, CDCl3) δ 1.21-1.34 (m, 2H), 1.35 (s, 3H), 1.36 (s, 3H), 1.42-1.62 (m, 2H), 1.83-1.96 (m, 3H), 2.11-2.33 (m, 4H), 3.60 (d, J = 8.7 Hz, 1H), 3.98 (d, J = 8.7 Hz, 1H), 6.56 (d, J = 15.6 Hz, 1H), 6.69 (dd, J = 15.6, 9.0 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 7.26-7.37 (m, 3H), 7.43 (dd, J = 7.8, 6.0 Hz, 1H), 7.81 (dd, J = 8.1, 2.1 Hz, 1H), 8.76 (d, J = 2.1 Hz, 1H).
(Step 2) (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,4’-oxazolidin]-2'-thione
The solution of aminoalcohol compound obtained in Step 1 (4.40 mg, 0.0109 mmol) in THF (100 μL) was stirred at room temperature, during which 1,1'-thiocarbonyldiimidazole (5.84 mg, 0.0327 mmol) was added. After stirring for 18 h, the reaction mixture was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to give the title compound (3.3 mg, 69%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 1.25-1.68 (m, 4H), 1.74-2.00 (m, 3H), 2.17-2.41 (m, 4H), 4.05 (d, J = 9.3 Hz, 1H), 4.58 (d, J = 9.3 Hz, 1H), 5.11 (br s, 1H), 6.63 (d, J = 15.6 Hz, 1H), 6.76 (dd, J = 15.6, 8.4 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 7.26-7.37 (m, 3H), 7.43 (dd, J = 8.4, 6.0 Hz, 1H), 7.82 (dd, J = 8.1, 2.4 Hz, 1H), 8.76 (d, J = 2.1 Hz, 1H).
<Example 253> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,4’-oxazolidin]-2'-imine
The solution of aminoalcohol compound obtained in Step 1 of Example 252 (5.60 mg, 0.0139 mmol) in THF (200 μL) was stirred at room temperature, during which K2CO3 (3.04 mg, 0.0278 mmol) was added. The reaction solution was cooled to 0 ℃. The solution of BrCN (2.95 mg, 0.0278 mmol) in THF (200 μL) was added thereto and stirred for 15 h. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to give the title compound (3.2 mg, 54%) as a colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.25-1.75 (m, 4H), 1.92-2.08 (m, 2H), 2.17-2.42 (m, 3H), 2.59 (dd, J = 15.0, 7.8 Hz, 1H), 2.74 (dd, J = 11.4, 6.6 Hz, 1H), 4.09 (d, J = 9.3 Hz, 1H), 4.60 (d, J = 9.3 Hz, 1H), 5.96 (br s, 1H), 6.76 (m, 2H), 7.10 (t, J = 8.1 Hz, 1H), 7.26-7.37 (m, 3H), 7.44 (dd, J = 8.1, 6.0 Hz, 1H), 7.84 (dd, J = 8.1, 2.1 Hz, 1H), 8.77 (d, J = 2.4 Hz, 1H).
<Example 254> (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(2-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5’-oxazolidin]-2’-one
(±)-(1S,3aR,7aR)-5,5-difluoro-2'-oxooctahydrospiro[indene-2,5'-oxazolidine]-1-carbaldehyde and diethyl [5-(2-fluorophenyl)pyridin-2-yl]methylphosphonate were reacted according to the same procedure as Example 1 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.23-2.36 (m, 11H), 3.58 (m, 2H), 5.15(brs, 1H), 6.65 (m, 2H), 7.15-7.49 (m, 5H), 7.85 (m, 1H), 8.71 (m, 1H).
<Example 255> (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(2-methoxyphenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5’-oxazolidin]-2’-one
(±)-(1S,3aR,7aR)-5,5-difluoro-2'-oxooctahydrospiro[indene-2,5'-oxazolidine]-1-carbaldehyde and diethyl [5-(2-methoxyphenyl)pyridin-2-yl]methylphosphonate were reacted according to the same procedure as Example 1 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 0.88-2.35 (m, 11H), 3.57 (m, 2H), 3.81 (s, 3H), 5.25 (brs, 1H), 6.61 (m, 2H), 7.03 (m, 2H), 7.30-7.45(m, 3H), 7.81 (dd, 1H, J = 2.1, 2.1 Hz), 8.76(d, 1H, J = 1.8 Hz).
Figure PCTKR2011004607-appb-I000190
<Example 256> (±)-(1S,3aR,7aR)-5,5-difluoro-1-[(E)-2-(5-hydroxypyridin-2-yl)vinyl]octahydrospiro[indene-2,5’-oxazolidin]-2’-one
(±)-(1S,3aR,7aR)-5,5-difluoro-2'-oxooctahydrospiro[indene-2,5'-oxazolidine]-1-carbaldehyde and diethyl [5-(triisopropylsilyloxy)pyridin-2-yl]methylphosphonate were reacted according to the same procedures as Example 1 and Step 3 of Example 62 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.58-1.82 (m, 10H), 2.02-2.32 (m, 5H), 3.55 (m, 1H), 5.32 (brs, 1H), 6.30-6.59 ( m, 2H), 7.10 (m, 1H), 8.10 (m, 1H).
<Example 257> (±)-(1S,3aR,7aR)-1-{(E)-2-[5-(benzyloxy)pyridin-2-yl]vinyl} -5,5-difluorooctahydrospiro[indene-2,5’-oxazolidin]-2’-one
In anhydrous THF (1 mL) was dissolved the Example 256 compound (7 mg, 0.018 mmol). K2CO3 (3 mg, 0.021 mmol) and benzyl bromide (0.002 mL, 0.019 mmol) were added and stirred for 24 h at 50 ℃. After completion of the reaction, the mixture was extracted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4, filtered and concentrated. The concentrated was purified by silica gel column chromatography (hexane:ethyl acetate = 1:2) to give the title compound (2.3 mg, 29%).
1H-NMR (300MHz, CDCl3) δ 0.84-2.27 (m, 7H), 2.32 (m, 2H), 3.59 (m, 2H), 4.77( brs, 1H), 5.11 (s, 2H), 6.35-6.91 (m, 2H), 7.11-7.44 (m, 7H), 8.30(m, 1H).
<Example 258> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(2-morpholinoethoxy)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5’-oxazolidin]-2’-one
In anhydrous THF (1 mL) was dissolved the Example 256 compound (10 mg, 0.026 mmol). K2CO3 (16 mg, 0.116 mmol), NaI (5 mg, 0.039 mmol) and chloroethyl morpholine hydrochloride (7 mg, 0.039 mmol) were added and stirred for 4 h at 60 ℃. After completion of the reaction, the mixture was extracted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO4, filtered and concentrated. The concentrate was purified by silica gel column chromatography (hexane:ethyl acetate = 1:2) to give the title compound (3.8 mg, 32%).
1H-NMR (300MHz, CDCl3)δ 0.82-2.04( m, 10H), 2.58 (m, 5H), 2.81 (m, 2H), 3.55 (s, 1H), 3.72 (m, 5H), 4.15 (m, 2H), 4.81 (brs, 4H), 6.35-6.59 (m, 2H), 7.14 (m, 1H), 7.36 (m, 1H), 8.24 (m, 1H).
<Example 259> (+)-(1S,2R,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5’-oxazolidin]-2’-one
(+)-(1R,3aR,7aR)-1-(benzyloxymethyl)-5,5-difluorohexahydro-1H-inden-2(3H)-one was reacted according to the same procedure as Example 248 to give the title compound as a white solid.
1H NMR (300 MHz, CDCl3) δ 1.29 (m, 1H), 1.57-1.80 (m, 4H), 1.89 (m, 1H), 2.03 (dd, J = 14.0, 10.0 Hz, 1H), 2.11-2.23 (m, 2H), 2.33 (m, 2H), 3.58 (s, 2H), 4.99 (br s, 1H), 6.65 (m, 2H), 7.09 (t, J = 8.7 Hz, 1H), 7.25-7.49 (m, 4H), 7.81 (dd, J = 8.1, 2.4 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H).
Figure PCTKR2011004607-appb-I000191
<Example 260> (+)-Ethyl {(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxyoctahydrospiro-1H-inden-2-yl}methylcarbamate
(+)-Ethyl [(1S,3aR,7aR)-5,5-difluoro-1-formyl-2-hydroxyoctahydro-1H-inden-2-yl]methylcarbamate was reacted according to the same procedure as Example 1 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 0.82-1.84 (m, 10H), 2.04-2.29 (m, 4H), 2.73 (brs, 1H), 3.32 (m, 2H), 4.08 (m. 2H), 5.20 (brs, 1H), 6.56-6.90 (m, 2H), 7.12 (m, 1H), 7.28-7.45 (m, 4H), 7.81 (m, 1H), 8.76 (d, 1H, J= 1.8 Hz).
<Example 261> (+)-Ethyl {(1S,3aR,7aR)-2,5,5-trifluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro-1H-inden-2-yl}methylcarbamate
The Example 260 compound was reacted according to the same procedure as Example 189 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 0.82-2.71 (m, 13H), 3.34-3.78 (m, 3H), 4.15 (m, 2H), 4.93 (brs, 1H), 6.60 (m, 2H), 7.12 (m, 1H), 7.26-7.61 (m, 4H), 7.70 (m, 1H), 8.77 (m, 1H).
Figure PCTKR2011004607-appb-I000192
<Example 262> (±)-(4aR,5S,7aR)-t-butyl-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-hydroxy-6-methylhexahydro-1H-cyclopenta[c]pyridine-2(3H)-carboxylate
The compound of Step 8 of Example 200 was reacted according to the same procedures as Steps 8~11 of Example 171 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 1.22 (d, J = 8.11 Hz, 3H), 1.48 (s, 9H), 1.65-1.83 (m, 2H), 2.01-2.03 (m, 2H), 2.35-2.42 (m, 2H), 3.08 (q, J = 6.02 Hz, 1H), 3.35-3.36 (m, 2H), 3.39 (m, 1H), 3.54 (m, 1H), 6.69 (m, 1H), 6.81 (m, 1H), 7.21-7.27 (m, 2H), 7.34-7.46 (m, 2H), 7.80 (m, 1H), 8.75 (s, 1H).
<Example 263> (±)-(4aR,5S,7aR)-t-butyl 6-(carbamoyloxy)-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-methylhexahydro-1H-cyclopenta[c]pyridine-2(3H)-carboxylate
The Example 262 compound (48 mg, 0.106 mmol) was reacted according to the same procedure as Example 65 to give the title compound (50 mg, 91%) as a yellow solid.
1H NMR (300 MHz, CDCl3) δ 1.24 (s, 3H), 1.50 (s, 9H), 1.85-1.87 (m, 2H), 2.01-2.02 (m, 2H), 2.42 (m, 1H), 2.49 (m, 1H), 2.90 (t, J = 5.51 Hz, 2H), 3.36-3.45 (m, 2H), 3.54 (m, 1H), 4.52 (s, 2H), 6.62 (m, 1H), 6.78 (m, 1H), 7.09 (m, 1H), 7.25 (s, 1H), 7.38 (d, J = 1.2 Hz, 2H), 7.48 (m, 1H), 7.83 (m, 1H), 8.81 (d, J = 1.2 Hz, 1H).
<Example 264> (±)-(4aR,5S,7aR)-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-methyloctahydro-1H-cyclopenta[c]pyridin-6-ylcarbamate
The Example 263 compound (50 mg, 0.101 mmol) was dissolved in CH2Cl2 (2 mL). CF3COOH (50㎕) was added at 0 ℃ and stirred for 1 h at room temperature. The mixture was neutralized by 1 N NaOH, extracted with CH2Cl2 and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over Na2SO4, filtered and concentrated. The concentrate was purified by silica gel column chromatography (CH2Cl2:MeOH = 10:1) to give the title compound (36 mg, 90%) as a pale yellow solid.
1H-NMR (300MHz, CDCl3) δ 2.01 (m, 1H), 2.41 (m, 1H), 2.48 (m, 1H), 2.53 (m, 1H), 2.71-2.86 (m, 3H), 2.96 (q, J = 6.2Hz, 1H), 4.58 (s, 2H), 6.57 (m, 1H), 6.77 (m, 1H), 7.11 (m, 1H), 7.28 (m, 1H), 7.32 (d, J = 6.0Hz, 2H), 7.43 (m, 1H), 7.83 (dd, J = 5.3 Hz, 1H), 8.77 (d, J = 0.9Hz, 1H).
<Example 265> (±)-(4aR,5S,7aR)-2-carbamoyl-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-methyloctahydro-1H-cyclopenta[c]pyridin-6-yl carbamate
The Example 264 compound (10 mg, 0.025 mmol) was dissolved in CH2Cl2 (1 mL). NEt3 (5 ㎕, 0.038 mmol) and triethylsilylisocyanate were added and stirred for 1 h at room temperature. The mixture was diluted with CH2Cl2 and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over Na2SO4, filtered and concentrated. The concentrate was purified by silica gel column chromatography (CH2Cl2:MeOH = 15:1) to give the title compound (10 mg, 90%) as a white solid.
1H-NMR(300MHz, CDCl3) δ 1.19(s, 3H), 1.94-2.02 (m, 2H), 2.21 (m, 1H), 2.27 (m, 1H), 2.42 (m, 1H), 2.98-3.12 (m, 2H), 3.32 (m, 1H), 3.44 (m, 1H), 3.78 (m, 1H), 4.35 (s, 1H), 4.51-4.53 (m, 2H), 6.58 (m, 1H), 6.80 (m, 1H), 7.10 (m, 1H), 7.28 (m, 1H), 7.33-7.37 (m, 2H), 7.43 (m, 1H), 7.84 (m, 1H), 8.77(d, J = 1.1 Hz, 1H).
<Example 266> (±)-(4aR,5S,7aR)-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-formyl-6-methyloctahydro-1H-cyclopenta[c]pyridin-6-ylcarbamate
(CH3CO)2O (3.6㎕, 0.038mmol) and HCOOH (1.5㎕, 0.038mmol) were stirred for 2 h at 50 ℃ and added to the solution of Example 264 compound (10㎎, 0.025mmol) in THF (1㎖). After stirring for 20 min at room temperature, the mixture was diluted with CH2Cl2 and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over Na2SO4, filtered and concentrated. The concentrate was purified by silica gel column chromatography (CH2Cl2:MeOH = 12:1) to give the title compound (10 mg, 90%) as a white solid.
1H-NMR(300MHz, CDCl3) δ 1.19 (s, 3H), 2.00-2.09 (m, 2H), 2.27 (t, J = 1.4 Hz, 1H), 2.45-2.58 (m, 2H), 3.04-3.25 (m, 2H), 3.31-3.52 (m, 3H), 4.16 (m, 1H), 4.53-4.57 (m, 2H), 6.57 (m, 1H), 6.79 (m, 1H), 7.10 (m, 1H), 7.28 (m, 1H), 7.32 (d, J = 11.9 Hz, 1H), 7.45 (m, 1H), 7.84 (m, 1H), 8.09 (s, 1H), 8.79(s, 1H).
Figure PCTKR2011004607-appb-I000193
<Example 267> (±)-(4aR,5S,7aR)-t-butyl 5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5'-oxooctahydro-3'H-spiro(cyclopenta[c]pyridine-6,2'-furan)-2(1H)-carboxylate
The compound of Step 8 of Example 200 was reacted according to the same procedures as Steps 1~3 of Example 230 and Steps 9~11 of Example 171 to give the title compound as a pale yellow oil.
1H NMR (300 MHz, CDCl3) δ 1.47 (s, 9H), 1.60 (m, 1H), 1.82 (m, 1H), 1.99-2.07 (m, 4H), 2.21 (m, 1H), 2.43 (m, 1H), 2.50-2.54 (m, 2H), 2.96 (m, 1H), 3.15 (t, J = 8.2 Hz, 1H), 3.32 (m, 1H), 3.51 (m, 1H), 3.77 (m, 1H), 4.15 (m, 1H), 6.65-6.74 (m, 2H), 7.10 (m, 1H), 7.35-7.37 (m, 2H), 7.45 (m, 1H), 7.83 (d, J = 4.5 Hz, 1H), 8.77(s, 1H).
<Example 268> (±)-(4aR,5S,7aR)-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-methyloctahydrocyclopenta[c]pyran-6-yl carbamate
The Example 171 compound (3 mg, 0.0084 mmol) was reacted according to the same procedure as Example 65 to give the title compound (1.2 mg, 36%).
1H NMR (300 MHz, CDCl3) δ 1.61 (s, 3H), 2.0 (brs, 2H), 2.38 (m, 3H), 2.77 (m, 1H), 3.20 (t, J = 5.0 Hz, 1H), 3.50 (t, J = 5.0 Hz, 1H), 3.73 (brs, 2H), 4.60 (brs, 2H), 6.61 (d, J = 17.6, 1H), 6.79 (m, 1H), 7.07 (t, J = 7.5 Hz, 1H), 7.23-7.47 (m, 4H), 7.83 (d, J = 2.5 Hz, 1H), 8.78 (s, 1H).
Figure PCTKR2011004607-appb-I000194
<Example 269> (±)-t-Butyl (1'S,3a'S,7a'R)-1'-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-oxodecahydro-3H-spiro(furan-2,2'-inden)-5'-ylcarbamate
(±)-t-Butyl (1'R,3a'S,7a'R)-1'-(benzyloxymethyl)-5-oxooctahydro-3H-spiro(furan-2,2'-inden)-5'-ylcarbamate was reacted according to the same procedure as Example 230 to give the title compound.
1H NMR (300 MHz, CDCl3) δ 0.8-1.35 (m, 5H), 1.45 (s, 9H), 1.8-2.6 (m, 10H), 3.5 (brs, 1H), 4.45 (d, 1H, J =8.1, Hz), 6.6 (m, 1H), 7.09 (m, 1H), 7.28-7.49 (m, 4H), 7.82 (d, 1H, J =8.1 Hz), 8.78 (s, 1H).
<Example 270> (±)-(1'S,3a'S,7a'R)-5'-amino-1'-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-3H-spiro(furan-2,2'-inden)-5(4H)one
The Example 269 compound (100 mg, 0.197 mmol) was reacted according to the same procedure as Example 264 to give the title compound (65 mg, 82%).
1H NMR (300 MHz, CDCl3) δ 0.9-1.9 (m, 10H), 2.24 (m, 4H), 2.5 (m, 2H), 6.62 (s, 2H), 7.09 (m 1H), 7.29-7.5 (m, 4H), 7.8 (d, 1H, J = 8.4 Hz), 8.74 (s, 1H).
Table 1
Figure PCTKR2011004607-appb-T000001
Figure PCTKR2011004607-appb-I000195
Figure PCTKR2011004607-appb-I000196
Figure PCTKR2011004607-appb-I000197
Figure PCTKR2011004607-appb-I000198
Figure PCTKR2011004607-appb-I000199
In addition, the compounds of formula (1) of the present invention were tested for their pharmacological effects according to the following experiment.
<Experiment > Antagonistic action against thrombin receptor
(1) Preparation of platelet membrane
20 unit of platelet concentrate (Red Cross Blood Services, Daejeon) was centrifuged for 20 min at 100 g to remove red blood cells. The supernatant was collected and centrifuged for 15 min (3,000 g). The resulting precipitate was mixed well with Buffer A (200 mL) (10 mM Tris Cl, pH 7.5, 5 mM EDTA, 150 mM NaCl) and centrifuged for 10 min at 4400 g. The resulting precipitate was mixed well with Buffer A (200 mL) and centrifuged again for 10 min at 4400 g. The resulting precipitate was mixed well with Buffer B (30 mL) (10 mM Tris Cl, pH 7.5, 5 mM EDTA). Then, the mixture was homogenized twenty (20) times using a Dounce homogenizer and centrifuged for 20 min at 41000 g. The resulting precipitate was mixed well with Buffer C (40 mL) (20 mM Tris Cl, pH 7.5, 1 mM EDTA, (0.1 mM DTT)). This mixture was divided in 5-mL portions, quickly cooled by liquid nitrogen and stored at -80 ℃.
The portions stored at -80 ℃ were dissolved, homogenized five (5) times using a Dounce homogenizer and centrifuged for 20 min at 41000 g. The resulting precipitate was mixed well with Buffer D (20 mL) (10 mM Tris ethanolamine HCl, pH 7.4, 5 mM EDTA) and centrifuged for 20 min at 41000 g (three times repeat). Then, the resulting precipitate was mixed well with Buffer E (20 mL) (50 mM Tris Cl, pH 7.5, 10 mM MgCl2, 1 mM EGTA, (1% DMSO)). This mixture was divided in 250-㎕ portions, quickly cooled by liquid nitrogen and stored at -80 ℃.
Blood within 48 h after the blood collection must be used and the blood should be kept at 4 ℃ after it is washed with Buffer A.
(2) Evaluation of Antagonistic Effect
First, the buffer for binding reaction (39 ㎕) was distributed into the reaction plate (Nunc 96 well plate # 269620). The human platelet membrane was diluted with the buffer for binding reaction (50 mM Tris HCl, pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.1% BSA) to prepare 2X concentration (the final 1X concentration: 0.15 mg/mL), and 50 ㎕ each was added to the reaction plate. The Example compound was diluted with DMSO to prepare 10X solution, and 10 ㎕ each was added to the reaction plate and mixed by pipetting. To the positive control was added DMSO (10 ㎕) and to the nonselective binding control was added 10X unlabeled haTRAP (10 ㎕) (hexaamino acid thrombin receptor antagonistic peptide; final concentration 100 μM). The radio-labeled ligand ([3H]-haTRAP) was diluted with DMSO to prepare 100X concentration, and 1 ㎕ each was added to the reaction plate and mixed by pipetting (the final concentration of the radio-labeled ligand was decided as the concentration showing the binding of 60% Bmax in the saturation experiment). Then, the reaction plate was treated in a plate stirrer (Heidolph, Titramax 1000) for 15 sec at 900 rpm to mix and incubated for 60 min at 30 ℃. During the incubation, the unifilter GF/C plate (Perkin Elmer, # 6005174) was previously wetted with 0.1% polyethyleneimine (100 ㎕). After completion of the reaction, the unifilter GF/C plate was located in a Milipore Vacuum Manifold. The reaction mixture was transferred and combined using a pipette and washed six (6) times with cooled washing buffer (100 ㎕) (50 mM Tris HCl, pH 7.5, 10 mM MgCl2, 1 mM EGTA). The unifilter GF/C plate was dried at room temperature. Microscint-20 scintillation cocktail solution (Perkin Elmer, # 6013621) (40 ㎕) was added to each well and its radioactivity was measured by Packard TOPCOUNT scintillation counter to calculate the IC50 value.
The antagonistic effect against PAR-1 receptor was measured for the compounds of formula (1). As a result, the compounds of Example 1, 37, 39, 46, 49, 53, 55, 61, 62, 65, 67, 71, 72, 73, 74, 76, 77, 87, 96, 98, 122, 147, 152, 156, 157, 159, 162, 165, 166, 167, 168, 179, 180, 181, 193, 203, 204, 206, 212, 213, 214, 215, 216, 218, 230, 232, 238, 243, 248, 254, 255 and 269 showed very excellent antagonistic effects against PAR-1, i.e., IC50 values of 0.050 μM or less. The IC50 values for the individual compounds are represented in the following Table 2.
Table 2
Figure PCTKR2011004607-appb-T000002

Claims (11)

  1. [6+5] fused bicycle compounds of formula (1)
    Figure PCTKR2011004607-appb-I000200
    in which
    Figure PCTKR2011004607-appb-I000201
    denotes a double or single bond,
    A, E and G independently of one another are selected from carbon, nitrogen and oxygen atoms, and the type of bond and the number of substituent are decided depending on the type of atom,
    R1 and R2 independently of one another represent
    hydrogen, halogen or cyano,
    5- to 6-membered heteroaryl which has 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms and is optionally mono- or disubstituted by the substituents selected from oxo, C1-C4-alkyl, C1-C4-alkylsulfonyl and C1-C4-alkylcarbonyl,
    saturated or partially unsaturated 5- to 6-membered heterocycle which has 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms and is optionally mono- or disubstituted by the substituents selected from oxo, C1-C4-alkyl, C1-C4-alkylsulfonyl and C1-C4-alkylcarbonyl,
    (CH2)mRa, (CH2)mOC(O)Ra, (CH2)mORa, (CH2)mOC(S)Ra, (CH2)mOC(O)NRaRb, (CH2)mOC(S)NRaRb, (CH2)mOS(O)mRa, (CH2)mS(O)mRa, (CH2)mS(O)mNRaRb, (CH2)mOS(O)mNRaRb, C(O)NRaRb, (CH2)mC(O)ORa, (CH2)mC(O)Ra, O(CH2)mRa, NRaRb, N(Ra)C(O)Rb, N(Ra)C(O)NRaRb, (CH2)mN(Ra)C(O)ORb, or (CH2)mN(Ra)S(O)mRb, wherein m denotes a number of 0 to 2, Ra and Rb independently of one another represent hydrogen, halogen, hydroxy, C1-C4-alkyl, C3-C6-cycloalkyl, optionally halogen-substituted C6-C10-aryl, C1-C4-alkylcarbonyl, C1-C4-alkylsulfonyl, C1-C4-alkoxy-C1-C4-alkyl or hydroxy-C1-C4-alkyl, or represent 4- to 7-membered heteroaryl or heterocycle which contains 1 to 3 heteroatoms selected from nitrogen and oxygen atoms and is optionally substituted by C1-C4-alkyl, or Ra and Rb together with the atoms to which they are attached represent 4- to 7-membered heteroaryl or heterocycle which contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms and is optionally substituted by oxo or C1-C4-alkyl, or
    R1 and R2 together represent oxo or hydroxyimino, or together with the atoms to which they are attached form a cycle B (
    Figure PCTKR2011004607-appb-I000202
    ), wherein the cycle B represents 4- to 7-membered saturated heterocycle which contains 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms and is optionally mono- to trisubstituted by the substituents selected from oxo, C1-C4-alkyl, C1-C4-alkylsulfonyl and C1-C4-alkylcarbonyl,
    R3 and R4 independently of one another represent hydrogen or C1-C4-alkyl, or
    R3 and R4 together represent oxo,
    R5 and R6 independently of one another represent hydrogen, halogen, cyano or amino, represent NRaRb, (CH2)mORa, O(CH2)mRa, (CH2)mC(O)ORa, (CH2)mOC(O)NRaRb, N(Ra)C(O)Rb, N(Ra)C(O)ORb or (CH2)mN(Ra)S(O)mRb (wherein m, Ra and Rb are as defined above), or represent 5- to 6-membered heteroaryl or heterocycle which contains 1 to 3 heteroatoms selected from nitrogen and oxygen atoms,
    R5 and R6 together represent dioxolanyl, oxo or hydroxyimino,
    R7 and R8 independently of one another represent hydrogen, halogen, O(CH2)mRa, NRaRb or N(Ra)C(O)ORb, wherein m, Ra and Rb each are as defined above,
    R7 and R8 together represent dioxolanyl, and
    Het represents monocyclic, bicyclic or tricyclic 5- to 14-membered heteroaryl or heterocycle which is optionally substituted by 1 to 4 R1 and contains 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms, wherein oxygen and sulfur atoms cannot exist adjacently, pharmaceutically acceptable salts or isomers thereof.
  2. The compounds of Claim 1 wherein the cycle
    Figure PCTKR2011004607-appb-I000203
    is selected from the structures of
    Figure PCTKR2011004607-appb-I000204
    Figure PCTKR2011004607-appb-I000205
    and
    Figure PCTKR2011004607-appb-I000206
  3. The compounds of Claim 1 wherein Het represents 5- to 6-membered heteroaryl which is optionally substituted by C6-C10-aryl and contains 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur atoms, wherein the oxygen and sulfur atoms cannot exist adjacently and C6-C10-aryl may be optionally substituted by halogen.
  4. The compounds of Claim 3 wherein Het represents (3-fluorophenyl)pyridine.
  5. The compounds of Claim 1 wherein
    the cycle
    Figure PCTKR2011004607-appb-I000207
    is selected from the structures of
    Figure PCTKR2011004607-appb-I000208
    Figure PCTKR2011004607-appb-I000209
    and
    Figure PCTKR2011004607-appb-I000210
    R1 and R2 independently of one another represent
    hydrogen, halogen or cyano,
    5- to 6-membered heteroaryl which has 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms and is optionally mono- or disubstituted by the substituents selected from oxo, C1-C4-alkyl, C1-C4-alkylsulfonyl and C1-C4-alkylcarbonyl,
    saturated or partially unsaturated 5- to 6-membered heterocycle which has 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms, and is optionally mono- or disubstituted by the substituents selected from oxo, C1-C4-alkyl, C1-C4-alkylsulfonyl and C1-C4-alkylcarbonyl,
    (CH2)mRa, (CH2)mOC(O)Ra, (CH2)mORa, (CH2)mOC(S)Ra, (CH2)mOC(O)NRaRb, (CH2)mOC(S)NRaRb, (CH2)mOS(O)mRa, (CH2)mS(O)mRa, (CH2)mS(O)mNRaRb, (CH2)mOS(O)mNRaRb, C(O)NRaRb, (CH2)mC(O)ORa, (CH2)mC(O)Ra, O(CH2)mRa, NRaRb, N(Ra)C(O)Rb, N(Ra)C(O)NRaRb, (CH2)mN(Ra)C(O)ORb, or (CH2)mN(Ra)S(O)mRb, wherein m denotes a number of 0 to 2, Ra and Rb independently of one another represent hydrogen, halogen, hydroxy, C1-C4-alkyl, C3-C6-cycloalkyl, optionally halogen-substituted C6-C10-aryl, C1-C4-alkylcarbonyl, C1-C4-alkylsulfonyl, C1-C4-alkoxy-C1-C4-alkyl or hydroxy-C1-C4-alkyl, or represent 5- to 6-membered heteroaryl or heterocycle which contains 1 to 3 heteroatoms selected from nitrogen and oxygen atoms and is optionally substituted by C1-C4-alkyl, or Ra and Rb together with the atoms to which they are attached represent 5- or 6-membered heteroaryl or heterocycle which contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms and is optionally substituted by oxo or C1-C4-alkyl, or
    R1 and R2 together represent oxo or hydroxyimino, or together with the atoms to which they are attached form a cycle B, wherein the cycle B is 5- to 6-membered saturated heterocycle which contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms and is optionally mono- or disubstituted by the substituents selected from oxo, C1-C4-alkyl, C1-C4-alkylsulfonyl and C1-C4-alkylcarbonyl,
    R3 and R4 independently of one another represent hydrogen or C1-C4-alkyl, or
    R3 and R4 together represent oxo,
    R5 and R6 independently of one another represent hydrogen, halogen, cyano or amino, represent NRaRb, (CH2)mORa, O(CH2)mRa, (CH2)mC(O)ORa, (CH2)mOC(O)NRaRb, N(Ra)C(O)Rb, N(Ra)C(O)ORb or (CH2)mN(Ra)S(O)mRb (wherein m, Ra and Rb are as defined above), or represent 5- to 6-membered heteroaryl or heterocycle which contains 1 to 3 heteroatoms selected from nitrogen and oxygen atoms,
    R5 and R6 together represent dioxolanyl, oxo or hydroxyimino,
    R7 and R8 independently of one another represent hydrogen, halogen, ORa, NRaRb or N(Ra)C(O)ORb, wherein Ra and Rb each are as defined above, or
    R7 and R8 together represent dioxolanyl, and
    Het represents 6-membered heteroaryl which is optionally substituted by C6-C10-aryl and contains 1 or 2 nitrogen atoms, wherein C6-C10-aryl may be optionally substituted by halogen.
  6. The compounds of Claim 1 which are selected from the following group:
    <Example 1> (±)-5-(3-fluorophenyl)-2-{(E)-2-[(1'S,3a'R,7a'R)-octahydrospiro[(1,3)-dioxolane-2,2'-inden]-1'-yl]vinyl}pyridine;
    <Example 2> (±)-5-(3-fluorophenyl)-2-{(E)-2-[(1'S,3a'S,7a'R)-octahydrospiro[(1,3)-dioxolane-2,2'-inden]-2-yl]vinyl}pyridine;
    <Example 3> (±)-(1S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}hexahydro-1H-inden-2(3H)-one;
    <Example 4> (±)-(1S,3aR,7aR, E)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}hexahydro-1H-inden-2(3H)-one oxime;
    <Example 5> (±)-(1S,3aR,7aR, Z)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}hexahydro-1H-inden-2(3H)-one oxime;
    <Example 6> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2(3H)-ol;
    <Example 7> (±)-5-(3-fluorophenyl)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-methoxyoctahydro-1H-inden-1-yl]vinyl}pyridine;
    <Example 8> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl acetate;
    <Example 9> (±)-5-(3-fluorophenyl)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(benzyloxy)octahydro-1H-inden-1-yl]vinyl}pyridine;
    <Example 10> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl methanesulfonate;
    <Example 11> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl phenylcarbamate;
    <Example 12> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl dimethylcarbamothioate;
    <Example 13> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl carboxylic acid;
    <Example 14> {(±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}(morpholin-4-yl)methanone;
    <Example 15> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-N-methyloctahydro-1H-indene-2-carboxamide;
    <Example 16> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-N,N-dimethyloctahydro-1H-indene-2-carboxamide;
    <Example 17> {(±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}(pyrrolidin-1-yl)methanone;
    <Example 18> {(±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}(piperidin-1-yl)methanone;
    <Example 19> {(±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}(4-methylpiperazin-1-yl)methanone;
    <Example 20> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-N-(methylsulfonyl)octahydro-1H-indene-2-carboxamide;
    <Example 21> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-indene-2-carboxamide;
    <Example 22> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-indene-2-carbonitrile;
    <Example 23> (±)-(1S,2S,3aR,7aR)-methyl-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-indene-2-carboxylate;
    <Example 24> (±)-(1S,2S,3aR,7aR)-ethyl-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-indene-2-carboxylate;
    <Example 25> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-N-(2-hydroxyethyl)octahydro-1H-indene-2-carboxamide;
    <Example 26> 2-{(±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-4,5-dihydrooxazole;
    <Example 27> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-N-hydroxyoctahydro-1H-indene-2-carboxamide;
    <Example 28> (±)-5-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-1,2,4-oxadiazole;
    <Example 29> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-indene-2-amine;
    <Example 30> (±)-methyl(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-ylcarbamate;
    <Example 31> (±)-ethyl(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-ylcarbamate;
    <Example 32> (±)-t-butyl-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-ylcarbamate;
    <Example 33> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(1H-tetrazol-5-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 34> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(1-methyl-1H-tetrazol-5-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 35> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(2-methyl-2H-tetrazol-5-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 36> (±)-3-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-5-methyl-1,2,4-oxadiazole;
    <Example 37> (±)-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methanol;
    <Example 38> (±)-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl acetate;
    <Example 39> (±)-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl methanesulfonate;
    <Example 40> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(methoxymethyl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 41> (±)-O-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl dimethylcarbothiolate;
    <Example 42> (±)-O-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl carbothiolate;
    <Example 43> (±)-O-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl methylcarbothiolate;
    <Example 44> (±)-1-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-3-methylurea;
    <Example 45> (±)-3-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-1,1-dimethylurea;
    <Example 46> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(4,5-dihydro-1H-imidazole-2-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 47> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methanesulfonamide;
    <Example 48> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}acetamide;
    <Example 49> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-N-methylacetamide;
    <Example 50> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}cyclopropanecarboxamide;
    <Example 51> (±)-O-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl acetyl(methyl)carbothiolate;
    <Example 52> (±)-4-{[(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl]methyl}morpholine;
    <Example 53> (±)-1-{{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl}-1H-imidazole;
    <Example 54> (±)-N-{{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl}methanesulfonamide;
    <Example 55> (±)-N-{{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl}-N-methylmethanesulfonamide;
    <Example 56> (±)-N-{{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl}sultam;
    <Example 57> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(pyrrolidin-1-ylmethyl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 58> (±)-1-{{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methyl}-1H-2-methylimidazole;
    <Example 59> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(1H-imidazole-2-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 60> (±)-2-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-5-methyl-1,3,4-oxadiazole;
    <Example 61> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-N-methylmethanesulfonamide;
    <Example 62> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-ol;
    <Example 63> (±)-(1S,2R,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-ol;
    <Example 64> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-methoxy-2-methyloctahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 65> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-ylcarbamate;
    <Example 66> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-indene-2-carboxylic acid;
    <Example 67> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-indene-2-carboxamide;
    <Example 68> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-indene-2-carbonitrile;
    <Example 69> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-methyl-2-(1H-tetrazol-5-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 70> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-methyl-2-(1-methyl-1H-tetrazol-5-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 71> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-methyl-2-(2-methyl-2H-tetrazol-5-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 72> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-indene-2-amine;
    <Example 73> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-yl}acetamide;
    <Example 74> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-yl}methanesulfonamide;
    <Example 75> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-isopropoxyoctahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 76> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro(indene-2,5'-oxazolidin)-2'-one;
    <Example 77> (±)-(1S,2R,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro(indene-2,5'-oxazolidin)-2'-one;
    <Example 78> (±)-2-{(E)-2-[(1'S,3a'R,7a'R)-1',3',3a',4',7',7a'-hexahydrospiro[(1,3)dioxolane-2,2'-indene]-1H-inden-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 79> (±)-(1S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-3a,4,7,7a-tetrahydro-1H-inden-2(3H)one;
    <Example 80> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,3,3a,4,7,7a-hexahydro-1H-inden-2-ol;
    <Example 81> (±)-2-{(E)-2-[(3a'R,4a'R,5'S,7a'R,8a'S)-2',2'-dimethyloctahydrospiro[(1,3)dioxolane-2,6'-indeno(5,6-d)(1,3)dioxol]-5'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 82> (±)-(3S,3aR,7aS)-3-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-octahydro-1H-isoindol-1-one;
    <Example 83> (±)-(3S,3aR,7aS)-3-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-isoindol-1-one;
    <Example 84> (±)-(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(N-(t)-butyloxycarbonyl)octahydro-1H-isoindole;
    <Example 85> (±)-(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-isoindole;
    <Example 86> (±)-(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(N-acetyl)octahydro-1H-isoindole;
    <Example 87> (±)-1-{(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(methylsulfonyl)octahydro-1H-isoindole;
    <Example 88> (±)-methyl-2-{(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-1H-isoindole-2-(3H,3aH,4H,5H,6H,7H,7aH)-yl}acetate;
    <Example 89> (±)-ethyl-2-{(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-1H-isoindole-2-(3H,3aH,4H,5H,6H,7H,7aH)-yl}acetate;
    <Example 90> (±)-2-{(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-1H-isoindole-2-(3H,3aH,4H,5H,6H,7H,7aH)-yl}acetic acid;
    <Example 91> (±)-1-{(1S,3aR,7aS)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-1H-isoindole-2-(3H,3aH,4H,5H,6H,7H,7aH)-yl}-2,2-dimethylpropan-1-one;
    <Example 92> (±)-t-butyl (1S,2S)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,3-dihydro-1H-inden-2-ylcarbamate;
    <Example 93> (±)-(1S,2S)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,3-dihydro-1H-indene-2-amine;
    <Example 94> (±)-(1S,2S)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,3-dihydro-1H-indene-2-(N-acetyl)amine;
    <Example 95> (±)-(1S,2S)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,3-dihydro-1H-indene-2-(N-methylsulfonyl)amine;
    <Example 96> (±)-(1S,2S)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,3-dihydro-1H-indene-2-(N-methyl-N-methylsulfonyl)amine;
    <Example 97> (±)-2-{(E)-2-[(1'S,3a'S,5'S,7a'R)-5'-fluorooctahydrospiro[(1,3)dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 98> (±)-2-{(E)-2-[(1'S,3a'S,5'R,7a'R)-5'-fluorooctahydrospiro[(1,3)dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 99> (±)-2-{(E)-2-[(1S,2S,3aR,5R,7aR)-2-methoxy-5-(methoxymethoxy)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 100> (±)-2-{(E)-2-[(1S,2S,3aR,5R,7aR)-2-methoxy-5-hydroxyoctahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 101> (±)-(1S,2S,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5-ylcarbamate;
    <Example 102> (±)-2-{(E)-2-[(1'S,2'S,3a'S,7a'R)-2'-methoxyoctahydrospiro[(1,3)dioxolane-2,5'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 103> (±)-2-{(E)-2-[(1'S,2'S,3a'R,7a'R)-2'-methoxyoctahydrospiro[(1,3)dioxolane-2,5'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 104> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5(6H)-one;
    <Example 105> (±)-(1S,2S,3aR,7aR,E)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5(6H)-one oxime;
    <Example 106> (±)-(1S,2S,3aR,7aR,Z)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5(6H)-one oxime;
    <Example 107> (±)-t-butyl-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5-ylcarbamate;
    <Example 108> (±)-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-indene-5-amine;
    <Example 109> (±)-ethyl (1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5-ylcarbamate;
    <Example 110> (±)-N-(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-5-yl}methanesulfonamide;
    <Example 111> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-methoxy-5-(1H-pyrrol-1-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 112> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-methoxy-5-(pyrrolidin-2-one-1-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 113> (±)-t-butyl-(1S,2S,3aR,6S,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-6-ylcarbamate;
    <Example 114> (±)-t-butyl-(1S,2S,3aR,6R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methoxyoctahydro-1H-inden-6-ylcarbamate;
    <Example 115> (±)-t-butyl (1S,2S,3aR,5S,6S,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dimethoxyoctahydro-1H-inden-6-ylcarbamate;
    <Example 116> (±)-(1S,2S,3aR,5S,6S,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dimethoxyoctahydro-1H-indene-6-amine;
    <Example 117> (±)-(1S,2S,3aR,5S,6S,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dimethoxy-N,N-dimethyloctahydro-1H-indene-6-amine;
    <Example 118> (±)-t-butyl (1S,2S,3aR,5R,6S,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-fluoro-2-methoxyoctahydro-1H-inden-6-ylcarbamate;
    <Example 119> (±)-2-{(E)-2-[(1'S,3a'R,7a'R)-1',3',3a',4',7',7a'-hexahydrospiro[(1,3)dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 120> (±)-2-{(E)-2-[(1S,2S,3aR,7aR)-2-(1H-1,2,4-triazol-1-yl)-2,3,3a,4,7,7a-hexahydro-1H-inden]-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 121> (±)-2-{(E)-2-[(1S,2R,3aR,7aR)-2-(1H-1,2,4-triazol-1-yl)-2,3,3a,4,7,7a-hexahydro-1H-inden]-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 122> (±)-2-{(E)-2-[(1'S,3a'R,5'R,7a'R)-5'-methoxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 123> (±)-2-{(E)-2-[(1'S,3a'R,5'S,7a'R)-5'-methoxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 124> (±)-2-{(E)-2-[(1'S,3a'R,5'R,7a'R)-5'-hydroxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 125> (±)-4-(1'S,3a'R,5'S,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-yl}morpholine;
    <Example 126> (±)-2-{(E)-2-[(1'S,3a'R,5'S,7a'R)-5'-(1H-1,2,4-triazol-1-yl)octahydrospiro[(1,3)dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 127> (±)-4-{2-{(1'S,3a'R,5'R,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-yloxy}ethyl}morpholine;
    <Example 128> (±)-2-{(E)-2-[(1'S,3a'R,5'S,7a'R)-5'-hydroxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 129> (±)-(1'S,3a'R,5'S,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-indene]-5'-carbonitrile;
    <Example 130> (±)-(1'S,3a'R,5'R,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-indene]-5'-amine;
    <Example 131> (±)-2-{(E)-2-[(1'S,3a'R,5'R,7a'R)-5'-(1H-pyrrol-1-yl)octahydrospiro[(1,3)dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 132> (±)-ethyl (1'S,3a'R,5'R,7a'R)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate;
    <Example 133> (±)-(1S,2S,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-ol;
    <Example 134> (±)-(1S,2S,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-yl methanesulfonate;
    <Example 135> (±)-(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-indene-2-amine;
    <Example 136> (±)-N-{(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-yl}methanesulfonamide;
    <Example 137> (±)-N-{(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-hydroxyoctahydro-1H-inden-2-yl}methanesulfonamide;
    <Example 138> (±)-2-{(E)-2-[(1S,2R,3aS,5R,7aR)-5-(methoxymethoxy)-2-(1H-pyrrol-1-yl)octahydro-1H-inden-1-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 139> (±)-1-{(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-yl}pyrrolidin-2-one;
    <Example 140> (±)-{(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-yl}pivalamide;
    <Example 141> (±)-1-{(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-yl}sultam;
    <Example 142> (±)-(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-ol;
    <Example 143> (±)-(1S,2R,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-yl methanesulfonate;
    <Example 144> (±)-(1S,2S,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-indene-2-amine;
    <Example 145> (±)-N-{(1S,2S,3aR,5R,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-(methoxymethoxy)octahydro-1H-inden-2-yl}methanesulfonamide;
    <Example 146> (±)-t-butyl (1'S,3a'S,7a'R){1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro[(1,3)dioxolane-2,2'-inden]-6'-ylcarbamate;
    <Example 147> (±)-t-butyl (1'S,3a'S,7a'R){1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate;
    <Example 148> (±)-t-butyl (1S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-oxooctahydro-1H-inden]-6-ylcarbamate;
    <Example 149> (±)-t-butyl (1S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-oxooctahydro-1H-inden]-5-ylcarbamate;
    <Example 150> (±)-t-butyl (1S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxy-2-methyloctahydro-1H-inden]-6-ylcarbamate;
    <Example 151> (±)-t-butyl (1S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxy-2-methyloctahydro-1H-inden]-5-ylcarbamate;
    <Example 152> (±)-t-butyl (1'S,3a'R,7a'R){1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate;
    <Example 153> (±)-t-butyl (1S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-oxooctahydro-1H-inden]-5-ylcarbamate;
    <Example 154> (±)-t-butyl (1S,2S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxyoctahydro-1H-inden]-5-ylcarbamate;
    <Example 155> (±)-t-butyl (1S,2R,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxyoctahydro-1H-inden]-5-ylcarbamate;
    <Example 156> (±)-(1S,2S,3aS,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-2-yl methanesulfonate;
    <Example 157> (±)-(1S,2R,3aS,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-2-yl methanesulfonate;
    <Example 158> (±)-t-butyl (1S,2R,3aR,7aR)-2-amino-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-5-ylcarbamate;
    <Example 159> (±)-t-butyl (1S,2R,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(methanesulfonamido)octahydro-1H-inden-5-ylcarbamate;
    <Example 160> (±)-t-butyl (1S,2R,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(1H-1,2,3-triazol-1-yl)octahydro-1H-inden-5-ylcarbamate;
    <Example 161> (±)-t-butyl (1S,2R,3aR,7aR)-2-(N-cyclopropylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-5-ylcarbamate;
    <Example 162> (±)-t-butyl (1S,2R,3aS,7aR)-2-(N-cyclopropyl-N-methylsulfonamido)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-5-ylcarbamate;
    <Example 163> (±)-1-{(1S,2R,3aS,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-sultam;
    <Example 164> (±)-t-butyl (1S,2S,3aR,7aR)-2-amino-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-5-ylcarbamate;
    <Example 165> (±)-t-butyl 1-{(1S,2S,3aS,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-sultam;
    <Example 166> (±)-t-butyl (1S,2S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(2-oxooxazolidin-3-yl)-octahydro-1H-inden-5-ylcarbamate;
    <Example 167> (±)-(1S,2S,3aS,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl dimethylsulfamate;
    <Example 168> (±)-(1S,2S,3aS,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-ylsulfamate;
    <Example 169> (±)-t-butyl (1S,2S,3aS,7aR)-2-cyano-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxyoctahydro-1H-inden-5-ylcarbamate;
    <Example 170> (±)-t-butyl (1S,2R,3aS,7aR)-2-cyano-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxyoctahydro-1H-inden-5-ylcarbamate;
    <Example 171> (±)-5-{(E)-(4aR,5S,7aR)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-methyloctahydrocyclopenta[c]pyran-6-ol;
    <Example 172> (±)-2-{(E)-2-[(4aS,5S,7aR)-6-(methoxymethoxy)octahydrocyclopenta[c]pyran-7-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 173> (±)-t-butyl (1S,2R,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxyoctahydro-1H-inden-5-ylcarbamate;
    <Example 174> (±)-(1S,2R,3aR,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-2-yl methanesulfonate;
    <Example 175> (±)-(1S,2R,3aR,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-2-yl carbamate;
    <Example 176> (±)-t-butyl (1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(methanesulfonamido)octahydro-1H-inden-5-ylcarbamate;
    <Example 177> (±)-N-{(1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(methanesulfonamido)octahydro-1H-inden-5-yl}formamide;
    <Example 178> (±)-t-butyl (1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(formamido)octahydro-1H-inden-5-ylcarbamate;
    <Example 179> (±)-t-butyl (1S,2S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(2-oxazolidin-3-yl)octahydro-1H-inden-5-ylcarbamate;
    <Example 180> (±)-1-{(1S,2S,3aR,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}-sultam;
    <Example 181> (±)-(1S,2R,3aS,7aR)-5-(t-butoxycarbonylamino)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-ylsulfamate;
    <Example 182> (±)-t-butyl (1S,3aR,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(hydroxyimino)octahydro-1H-inden]-5-ylcarbamate;
    <Example 183> (±)-2-{(E)-2-[(1'S,3a'R,5'R,7a'R)-5'-hydroxyoctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 184> (±)-2-{(E)-2-[(1'S,3a'S,7a'R)-5'-oxooctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 185> (±)-methyl (1'S,3a'S,7a'R){1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate;
    <Example 186> (±)-ethyl (1'S,3a'S,7a'R){1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro[(1,3)dioxolane-2,2'-inden]-5'-ylcarbamate;
    <Example 187> (±)-2-{(E)-2-[(1'S,3a'R,7a'R)-5',5'-difluorooctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1’-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 188> (±)-2-{(E)-2-[(1'S,3a'R,5'S,7a'R)-5'-hydroxyoctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 189> (±)-2-{(E)-2-[(1'S,3a'R,5'S,7a'R)-5'-fluorooctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 190> (±)-2-{(E)-2-[(1'S,3a'R,5'R,7a'R)-5'-fluorooctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 191> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}hexahydro-1H-inden-2(3H)-one;
    <Example 192> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-ol;
    <Example 193> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-yl carbamate;
    <Example 194> (±)-(1S,2S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-ol;
    <Example 195> (±)-(1S,2S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl methanesulfonate;
    <Example 196> (±)-(1S,5R,3aR,7aR)-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-hydroxyoctahydro-1H-inden-2-one;
    <Example 197> (±)-(1S,2S,5R,3aR,7aR)-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dihydroxyoctahydro-1H-indene-2-carbonitrile;
    <Example 198> (±)-(1S,2R,5R,3aR,7aR)-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dihydroxyoctahydro-1H-indene-2-carbonitrile;
    <Example 199> (±)-(1S,2S,5R,3aR,7aR)-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dihydroxyoctahydro-1H-indene-2-carboxamide;
    <Example 200> (±)-(4aR,5S,7aS)-t-butyl-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-(methoxymethoxy)hexahydro-1H-cyclopenta[c]pyridine-2(3H)-carboxylate;
    <Example 201> (±)-(1S,3aS,7aR)-5-(t-butyloxycarbonylamino)-1-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden-2-yl methanesulfonate;
    <Example 202> (±)-2-{(E)-2-[(1'S,3a'S,7a'R)-5',5'-difluorooctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 203> (±)-2-{(E)-2-[(1'S,3a'S,7a'R)-6',6'-difluorooctahydrospiro[(1,3)-dioxolane-2,2'-inden]-1'-yl]vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 204> (±)-t-butyl(1S,3aS,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2'-oxooctahydrospiro[indene-2,5'-oxazolidin]-5-ylcarbamate;
    <Example 205> (±)-t-butyl (1'S,3a'S,7a'R)-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2,5-dioxooctahydrospiro[imidazolidine-4,2'-inden]-5'-ylcarbamate;
    <Example 206> (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one;
    <Example 207> (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-3'-methyloctahydrospiro[indene-2,5'-oxazolidin]-2'-one;
    <Example 208> (±)-(1'S,3'aS,7a'R)-5',5'-difluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[imidazolidine-4,2'-inden]-2,5-dione;
    <Example 209> (±)-(1'S,3'aS,7a'R)-5',5'-difluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[imidazolidine-4,2'-inden]-2-one;
    <Example 210> (±)-(1'S,3a'S,7a'R)-5',5'-difluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-1,3-dimethyloctahydrospiro[imidazolidine-4,2'-inden]-2-one;
    <Example 211> (±)-(1S,3aR,7aR)-6,6-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden]-2-ol;
    <Example 212> (±)-(1S,2R,3aR,7aR)-6,6-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden]-2-yl carbamate;
    <Example 213> (±)-(1S,2S,3aR,7aR)-6,6-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden]-2-yl carbamate;
    <Example 214> (±)-N-{(1S,3aR,7aR)-6,6-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden]-2-yl}acetamide;
    <Example 215> (±)-(1S,2R,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydrospiro-1H-inden]-2-ylcarbamate;
    <Example 216> (±)-(1S,2S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydrospiro-1H-inden]-2-ylcarbamate;
    <Example 217> (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one;
    <Example 218> (±)-(1S,3aR,7aR)-6,6-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one;
    <Example 219> (±)-N-{(1S,2R,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden]-2-yl}acetamide;
    <Example 220> (±)-N-{(1S,2S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyloctahydro-1H-inden]-2-yl}acetamide;
    <Example 221> (±)-3-{(1S,2R,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-2-yl}oxazolidin-2-one;
    <Example 222> (±)-N-{(1S,2R,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-2-yl}methanesulfonamide;
    <Example 223> (±)-N-{(1S,2R,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden]-2-yl}-N-methylmethanesulfonamide;
    <Example 224> (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiroindene-2,5'-oxathiazolidin-2',2'-dione;
    <Example 225> (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,2'-morpholine]-5'-one;
    <Example 226> (±)-(1S,3aR,7aR)-2-cyano-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl methanesulfonate;
    <Example 227> (±)-N-{(1S,3aR,7aR)-2-cyano-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-1H-inden-2-yl}methanesulfonamide;
    <Example 228> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro-[indene-2,4'-oxazolidin]-2'-one;
    <Example 229> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-3'-methyloctahydrospiro-[indene-2,4'-oxazolidin]-2'-one;
    <Example 230> (±)-(1'S,3a'R,7a'R)-5',5'-difluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-3H-spiro[furan-2,2'-inden]-5(4H)-one;
    <Example 231> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2',2'-dimethyl-3'-(methylsulfonyl)octahydrospiro[indene-2,4'-oxazolidine]
    <Example 232> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-3'-(methylsulfonyl)octahydrospiro[indene-2,4'-oxazolidine];
    <Example 233> (±)-{(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(hydroxymethyl)octahydro-1H-inden-2-yl}methanesulfonamide;
    <Example 234> (±)-{(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-(fluoromethyl)octahydro-1H-inden-2-yl}methanesulfonamide;
    <Example 235> (±)-(1S,3aS,5S,6S,7aR)-6-fluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-hydroxyoctahydrospiro[indene-2,5'-oxazolidin]-2'-one;
    <Example 236> (±)-(1S,3aS,5S,6S,7aR)-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5,6-dihydroxyoctahydrospiro[indene-2,5'-oxazolidin]-2'-one;
    <Example 237> (±)-(1aR,2aR,3S,5aS,6aS)-3-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indeno-[5,6-b]oxirane-4,5'-oxazolidin]-2'-one;
    <Example 238> (±)-(1aS,2aR,3S,5aS,6aR)-3-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indeno-[5,6-b]oxirane-4,5'-oxazolidin]-2'-one;
    <Example 239> (±)-(1S,3aR,5R,6R,7aR)-5,6-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one;
    <Example 240> (±)-(1'S,3a'S,5'S,6'S,7a'R)-6'-fluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-ol;
    <Example 241> (±)-2-{(E)-2-{(3'S,3a'R,5'S,6'S,7a'S)-5'-fluoro-6'-methoxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-3'-yl}vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 242> (±)-(1'S,2S,3a'S,7a'R)-5',5'-difluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-3H-spiro[furan-2,2'-inden]-5(4H)-one;
    <Example 243> (±)-(1'S,2R,3a'S,7a'R)-5',5'-difluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-3H-spiro[furan-2,2'-inden]-5(4H)-one;
    <Example 244> (±)-(1'S,3a'R,5'S,6'S,7a'R)-6'-fluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'-ol;
    <Example 245> (±)-2-{(E)-2-{(3'S,3a'R,5'S,6'S,7a'R)-5'-fluoro-6'-methoxyoctahydrospiro[(1,3)dioxolane-2,2'-inden]-3'-yl}vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 246> (±)-(1'S,3a'R,6'S,7a'R)-6'-fluoro-1'-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[(1,3)dioxolane-2,2'-inden]-5'(1'H)-one;
    <Example 247> (±)-2-{(E)-2-{(1'S,3a'S,5'R,6'S,7a'R)-5',6'-difluorooctahydrospiro[(1,3)dioxolane-2,2'-inden]-1'-yl}vinyl}-5-(3-fluorophenyl)pyridine;
    <Example 248> (-)-(1R,2S,3aS,7aS)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one.
    <Example 249> (-)-(1R,2R,3aS,7aS)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one;
    <Example 250> (±)-5-(3-fluorophenyl)-2-{(E)-2-[(3a'R,4a'R,5'S,7a'S,8a'S)- octahydrospiro[(1,3)dioxolane-2,6'-indeno(5,6-d)(1,3)dioxol]-5'-yl]vinyl}pyridine;
    <Example 251> (±)-5-(3-fluorophenyl)-2-{(E)-2-[(3a'S,4a'R,5'S,7a'S,8a'R)- octahydrospiro[(1,3)dioxolane-2,6'-indeno(5,6-d)(1,3)dioxol]-5'-yl]vinyl}pyridine;
    <Example 252> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,4'-oxazolidin]-2'-thione;
    <Example 253> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,4'-oxazolidin]-2'-imine;
    <Example 254> (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(2-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one;
    <Example 255> (±)-(1S,3aS,7aR)-5,5-difluoro-1-{(E)-2-[5-(2-methoxyphenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one;
    <Example 256> (±)-(1S,3aR,7aR)-5,5-difluoro-1-[(E)-2-(5-hydroxypyridin-2-yl)vinyl]octahydrospiro[indene-2,5'-oxazolidin]-2'-one;
    <Example 257> (±)-(1S,3aR,7aR)-1-{(E)-2-[5-(benzyloxy)pyridin-2-yl]vinyl} -5,5-difluorooctahydrospiro[indene-2,5'-oxazolidin]-2'-one;
    <Example 258> (±)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(2-morpholinoethoxy)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one;
    <Example 259> (+)-(1S,2R,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro[indene-2,5'-oxazolidin]-2'-one;
    <Example 260> (+)-ethyl {(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-hydroxyoctahydrospiro-1H-inden-2-yl}methylcarbamate;
    <Example 261> (+)-ethyl {(1S,3aR,7aR)-2,5,5-trifluoro-1-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydrospiro-1H-inden-2-yl}methylcarbamate;
    <Example 262> (±)-(4aR,5S,7aR)-t-butyl-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-hydroxy-6-methylhexahydro-1H-cyclopenta[c]pyridine-2(3H)-carboxylate;
    <Example 263> (±)-(4aR,5S,7aR)-t-butyl 6-(carbamoyloxy)-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-methylhexahydro-1H-cyclopenta[c]pyridine-2(3H)-carboxylate;
    <Example 264> (±)-(4aR,5S,7aR)-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-
    yl]vinyl}-6-methyloctahydro-1H-cyclopenta[c]pyridin-6-yl carbamate;
    <Example 265> (±)-(4aR,5S,7aR)-2-carbamoyl-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-methyloctahydro-1H-cyclopenta[c]pyridin-6-yl carbamate;
    <Example 266> (±)-(4aR,5S,7aR)-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-formyl-6-methyloctahydro-1H-cyclopenta[c]pyridin-6-yl carbamate;
    <Example 267> (±)-(4aR,5S,7aR)-t-butyl 5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5'-oxooctahydro-3'H-spiro(cyclopenta[c]pyridine-6,2'-furan)-2(1H)-carboxylate;
    <Example 268> (±)-(4aR,5S,7aR)-5-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-6-methyloctahydrocyclopenta[c]pyran-6-yl carbamate;
    <Example 269> (±)-t-butyl (1'S,3a'S,7a'R)-1'-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}-5-oxodecahydro-3H-spiro(furan-2,2'-inden)-5'-yl carbamate; and
    <Example 270> (±)-(1'S,3a'S,7a'R)-5'-amino-1'-{(E)-2-[(5-(3-fluorophenyl)pyridin-2-yl]vinyl}octahydro-3H-spiro(furan-2,2'-inden)-5(4H)-one.
  7. A process for preparing the compounds of formula (1) as defined in Claim 1 by reacting the compounds of formula (2) with the compounds of formula (3), or by reacting the compounds of formula (4) with the compounds of formula (5).
    Figure PCTKR2011004607-appb-I000211
    Figure PCTKR2011004607-appb-I000212
    Figure PCTKR2011004607-appb-I000213
    Figure PCTKR2011004607-appb-I000214
    in which
    A, E, G, Het, R1 to R8 are as defined in Claim 1, and
    X represents halogen.
  8. A pharmaceutical composition as an antagonist against PAR-1, which comprises the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof as defined in Claim 1 together with pharmaceutically acceptable carriers.
  9. The composition of Claim 8 which is useful for the treatment and prevention of thrombus, platelet aggregation, atherosclerosis, restenosis, blood coagulation, hypertension, arrhythmia, angina pectoris, heart failure, inflammation and cancer.
  10. The composition of Claim 8 or 9 which further comprises cardiovascular agents.
  11. A process for preparing a composition as an antagonist against PAR-1, characterized by mixing the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof as defined in Claim 1 with pharmaceutically acceptable carriers.
PCT/KR2011/004607 2010-06-25 2011-06-24 [6+5] fused bicycles as a thrombin antagonist, process for preparation thereof and pharmaceutical compositions containing the bicycles WO2011162562A2 (en)

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