| (11) | EP 2 771 345 B1 |
(12) | EUROPEAN PATENT SPECIFICATION |
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(54) | FUSED BICYCLIC OXAZOLIDINONE CETP INHIBITOR KONDENSIERTE BICYCLISCHE OXAZOLIDINON-CETP-HEMMER INHIBITEUR DE CETP D'OXAZOLIDINONE BICYCLIQUE CONDENSÉE |
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Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). |
FIELD OF THE INVENTION
BACKGROUND OF THE INVENTION
SUMMARY OF THE INVENTION
R6 and R7 are each independently H or -C1-C5 alkyl;
R8 is H or -C1-5alkyl optionally substituted with 1-7 halogens;
HET(3) is a 3-6 membered heterocyclic ring having 1-3 heteroatom groups which are each independently N, NH, O, S, S(O), or S(O)2 and optionally having 1-3 double bonds;
x is 0 or 1;
The dashed lines in Formula I represent one optional double bond between 2 adjacent carbon atoms;
D1 is N or CR2;
D2 is N or CR3;
D3 is N or CR4;
R2, R3, and R4 are each independently H, -C1-C5 alkyl, -OC1-C5 alkyl, -C2-C5 alkenyl, -OC2-C5 alkenyl, -C2-C5 alkynyl, -OC2-C5 alkynyl, -OH, halogen, -CN, -NR6R7, -CO2R8, -C(O)NR6R7, or -SO2NR6R7, wherein -C1-C5 alkyl, -OC1-C5 alkyl, -C2-C5 alkenyl, -OC2-C5 alkenyl, -C2-C5 alkynyl, and -OC2-C5 alkynyl are optionally substituted with 1-7 halogens;
Each R5 is independently -C1-C5 alkyl, -OC1-C5 alkyl, -C2-C5 alkenyl, -OC2-C5 alkenyl, -C2-C5 alkynyl, -OC2-C5 alkynyl, -OH, halogen, -CN, -NR6R7, -CO2R8, -C(O)NR6R7, or -SO2NR6R7, wherein -C1-C5 alkyl, -OC1-C5 alkyl, -C2-C5 alkenyl, -OC2-C5 alkenyl, -C2-C5 alkynyl, and -OC2-C5 alkynyl are optionally substituted with 1-7 halogens;
A1 is phenyl, HET(1), or C3-C8 cycloalkyl optionally having 1-2 double bonds, wherein A1 is optionally substituted with one substituent group Z and is optionally substituted with 1-3 groups which are each independently -C1-C5 alkyl, -OC1-C5 alkyl, -C2-C5 alkenyl,-OC2-C5 alkenyl, -C2-C5 alkynyl, -OC2-C5 alkynyl, halogen, -OH, or -CN, wherein -C1-C5 alkyl,
-OC1-C5 alkyl, -C2-C5 alkenyl, -OC2-C5 alkenyl, -C2-C5 alkynyl, and -OC2-C5 alkynyl are optionally substituted with 1-7 halogens;
Each HET(1) is a 5- or 6-membered heterocyclic ring having 1-4 heteroatom groups which are each independently -N-, -NH-, -S-, -O-, -S(O)-, or -S(O)2-, optionally having one group -C(=O)-, and optionally having 1-3 double bonds;
Z is A3, -C1-C3alkylene-CO2R8, -C1-C3alkylene-C(O)NR6R7, -C1-C3alkylene-SO2NR6R7, -CO2R8, -C(O)NR6R7, -SO2NR6R7, or -C1-C3alkylene-HET(2), wherein
-C1-C3alkylene in all uses is optionally substituted with 1-7 halogens, and HET(2) is optionally substituted with 1-3 substituents which are independently -C1-3alkyl optionally substituted with 1-5 halogens, -OC1-3alkyl optionally substituted with 1-5 halogens, halogen or NR6R7.
A3 is phenyl, C3-C6 cycloalkyl optionally having 1-2 double bonds, or HET(1), wherein A3 is optionally substituted with 1-3 groups which are each independently -C1-C5 alkyl, -OC1-C5 alkyl, -C2-C5 alkenyl, -OC2-C5 alkenyl, -C2-C5 alkynyl, -OC2-C5 alkynyl, halogen, -OH, or -CN, wherein -C1-C5 alkyl, -OC1-C5 alkyl, -C2-C5 alkenyl, -OC2-C5 alkenyl, -C2-C5 alkynyl, and -OC2-C5 alkynyl are optionally substituted with 1-7 halogens; and A3 is optionally substituted with one group which is HET(2), -C1-4 alkylene-CO2R8, -C1-4alkylene-C(O)NR6R7, -C1-C4alkylene-SO2NR6R7, -CO2R8, -C(O)NR6R7, or -SO2NR6R7, wherein -C1-C4alkylene in all uses is optionally substituted with 1-7 halogens; and wherein HET(2) is optionally substituted with 1-3 groups which are each independently halogen, -C1-5alkyl optionally substituted with 1-7 halogens, -OC1-5alkyl optionally substituted with 1-7 halogens, or NR6R7;
HET(2) is a 5-6 membered heterocyclic ring having 1-3 heteroatom groups which are each independently N, NH, O, or S, optionally having one group -C(=O), and optionally having 1-3 double bonds;
A2 is phenyl or HET(1), wherein A2 is optionally substituted with 1-3 substituent groups which are each independently -C1-C5 alkyl, -OC1-C5 alkyl, -C2-C5 alkenyl, -OC2-C5 alkenyl, -C2-C5alkynyl, -OC2-C5alkynyl, halogen, -CN, -OH, or C3-6cycloalkyl, wherein -C1-C5 alkyl, -OC1-C5 alkyl, -C2-C5 alkenyl, -OC2-C5 alkenyl, -C2-C5alkynyl, and -OC2-C5 alkynyl are optionally substituted with 1-7 halogens, and C3-6cycloalkyl is optionally substituted with 1-3 substituents which are each independently halogen, -C1-C3 alkyl, or -OC1-C3 alkyl, wherein-C1-C3 alkyl and-OC1-C3 alkyl are each optionally substituted with 1-7 halogens; and
a is 0 or an integer from 1-3.
DETAILED DESCRIPTION OF THE INVENTION
Definitions and Abbreviations
Optical Isomers - Diastereomers - Geometric Isomers - Tautomers
Salts
Prodrugs
Isotopes
Utilities
Administration and Dose Ranges
Pharmaceutical Compositions
Combination Therapy
ASSAYS
Protocol: Scintillation Proximity Assay (SPA) for CETP activity
In vitro radioactive assays of CETP-catalyzed CE and TG transfer (RTA assay)
EXAMPLES
SYNTHETIC SCHEMES
Syntheses of Intermediates
(4S,SR)-5-[3,5-bis(trifluoromethyl)phenyl]-4-ethenyl-1,3-oxazolidin-2-one
Step 1: To a stirred solution of (4S)-4-phenyl-1,3-oxazolidin-2-one (12 g, 73.5 mmol) in THF (200 mL) was added n-BuLi (2.5 M, 29.4 mL, 73.5 mmol) dropwise via a syringe at -78 °C. The resulting reaction mixture was stirred at -78 °C for 5 minutes before (2E)-but-2-enoyl chloride (8.46 mL, 88.0 mmol) was added dropwise via a syringe. The reaction mixture was allowed to warm to ambient temperature and was quenched by addition of brine (100 mL) and water (100 mL). A mixture of ethyl acetate and hexanes (1:2, 100 mL) was added to partition the mixture and the organics were separated, dried over sodium sulfate, filtered and concentrated. The resultant oil was recrystallized in 5% ethyl acetate in hexanes (after seeding with crystals obtained from earlier batches) to yield (4S)-3-[(2E)-but-2-enoyl]-4-phenyl-1,3-oxazolidin-2-one (15.7 g, 67.9 mmol). 1H NMR (500 MHz, CDCl3) δ7.4 (m, 6H), 5.5 (m, 1H) 4.73 (t, J= 8.8 Hz, 1H), 4.30 (m, 1H), 1.97 (dd, J= 6.8, 1.5 Hz, 3H).
Step 2: To (4S)-3-[(2E)-but-2-enoyl]-4-phenyl-1,3-oxazolidin-2-one (13.8 g, 59.7 mmol) in DCM (100 mL) was added TiCl4 (1M in DCM, 59.7 mL, 59.7 mmol) at -10 °C. The resulting reaction solution was transferred by cannula to a flask containing DIPEA (11.26 mL, 64.5 mmol) and DCM (100 mL) at 10 °C. NMP (11.49 mL, 119 mmol) was added via a syringe and the reaction mixture was aged for 1 hour before cooling to -40 °C. 3,5-Bis(trifluoromethyl)benzaldehyde (17.3 g, 71.6 mmol) in DCM (25 mL) was added via a syringe and the reaction was allowed to warm to 0°C over 1.5 hr. The reaction was quenched by addition of acetic acid (15 mL), saturated Rochelle's salt (50 mL) and HCl (1.0 M, 200 mL). The organic was separated and the aqueous was back extracted with DCM (50 mL). The organics were combined, washed with HCl (1.0 M, 100 mL), dried over sodium sulfate, filtered and concentrated. The resultant oil was purified by column chromatography to give (4S)-3-{(2S)-2-[(S)-[3,5-bis(trifluoromethyl)phenyl](hydroxy)methyl]but-3-enoyl}-4-phenyl-1,3-oxazolidin-2-one (20 g, 42.3 mmol) as crystalline solid. 1H NMR (500 MHz, CDCl3) δ7.86 (s, 2H), 7.83 (s, 1H), 7.4 (m, 5H), 5.7 (m, 1H), 5.4 (m, 1H), 5.31 (d, J = 10.3 Hz, 1H), 5.28 (d, J= 3.9 Hz, 1H), 5.10 (d, J= 17.3 Hz, 1 H), 4.8 (m, 1H), 4.7 (t, J = 9.0 Hz, 1H), 4.3 (m, 1 H).
Step 3: (4S)-3-{(2S)-2-[(S)-[3,5-Bis(trifluoromethyl)phenyl](hydroxy)methyl]but-3-enoyl}-4-phenyl-1,3-oxazolidin-2-one (20 g, 42.5 mmol) and hydrazine (2.71 g, 85 mmol) in THF (100 mL) was stirred at room temperatire for 1 hour. The reaction was diluted with ethyl acetate: hexanes (2:1,200 mL) and was partitioned with water (100 mL). The organic was washed with brine (100 mL) and was dried over sodium sulfate, filtered, and concentrated. The crude product was triturated with IPA (30 mL) to remove the chiral auxiliary. The filtrate was concentrated to yield (2S)-2-[(S)-[3,5-bis(trifluoromethyl)phenyl](hydroxy)methyl]but-3-enehydrazide (14.5 g, 42.4 mmol), which was used without further purification. 1H NMR (500 MHz, CDCl3) δ7.81 (s, 3H), 7.83 (s, 1H), 7.0 (br s, 1H), 5.9 (m, 1H), 5.42 (d, J = 3.3 Hz, 1H), 5.29 (d, J = 10.3 Hz, 1H), 5.03 (d, J = 17.1 Hz, 1H), 3.1 (dd, J = 9.4, 3.5 Hz, 1 H).
Step 4: (2S)-2-[(S)-[3,5-Bis(trifluoromethyl)phenyl](hydroxy)methyl]but-3-enehydrazide (14.5 g, 42.4 mmol) was dissolved in IPA (100 mL) and HCl (4N in dioxane, 20 mL). tert-Butyl nitrite (5.24 g, 50.8 mmol) in IPA (20 mL) was added via a syringe pump at 50 °C over 1 hr. The reaction mixture was stirred at 50 °C and additional hour and the volatiles were removed. The crude mixture was dissolved in ethyl acetate (150 mL), washed with aqueous Na2CO3 (100 mL), dried over sodium sulfate, filtered and concentrated. The resultant oil was purified by column chromatography to yield (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-ethenyl-1,3-oxazolidin-2-one (7 g, 21.52 mmol) as light yellow crystalline solid. 1H NMR (500 MHz, CDCl3) δ7.90 (s, 1H), 7.82 (s, 2H), 5.91 (d, J = 8.3 Hz, 1H), 5.2 (m, 3H), 4.7 (m, 1H).
(4S,SR)-5-[3,5-bis(trifluoromethyl)phenyl]-4-ethenyl-1,3-oxazolidin-2-one
Step 1: To N-Boc-allylamine (50.0 g, 0.318mol) in anhydrous THF (800 mL) at -78 °C was added sec-butyllithium (1.30 M in cyclohexane, 538.0 mL, 0.7 mol) dropwise under a stream of N2 gas. The resulting yellow solution was stirred at -78 °C for an additional 2 hours, after which time ZnCl2 (1.1 M in Et2O, 349.8mL, 0.35mol) was added. The solution was stirred for 1 hour before 3,5-bis-trifluoromethylbenzaldehyde (169.3 g, 0.700 mol) was added to the clear solution. The mixture was stirred at -78 °C for 1 hour before quenching with acetic acid (227 mL). The reaction was poured into ice water (2 L) and the organic layer was washed with aqueous saturated NaHCO3 (2 L×2) and brine (1 L), was dried (MgSO4), and concentrated. The crude material was recrystallized from petroleum ether (300 mL) to yield tert-butyl {1-[3,5-bis(trifluoromethyl)phenyl]-1-hydroxybut-3-en-2-yl}carbamate (57 g) as a white powder. In total this process yielded 2.8 kg of material. MS ESI calc'd. for C17H20F6NO3 [M + H]+ 400.1, found 400.0.
Step 2: At 0 °C under N2, NaH (20 g, 0.500 mol) was added slowly to the mixture of tert-butyl {1-[3,5-bis(trifluoromethyl)phenyl]-1-hydroxybut-3-en-2-yl}carbamate (100 g, 0.250 mol) in anhydrous THF (1.5 L) while stirring. After the addition, the mixture was stirred at 0 °C for 1 hour, then at 80 °C for 2-6 hrs. (Caution: The mixture was stirred and heated at 80 °C for 0.5-1 hour of bubbling). The resulting mixture was cooled to 0 °C and MeOH (0.1 L) and ice water (0.2 L) was added carefully to quench the reaction. The mixture was concentrated and then diluted with ethyl acetate (2 L), washed with water (0.5 L x3), brine (0.5 L), dried and concentrated to give a black oil. Flash chromatography on silica gel yielded the crude product which was recrystallized from ethyl acetate, dichloromethane and petroleum ether to provide cis-5-[3,5-bis(trifluoromethyl)phenyl]-4-ethenyl-1,3-oxazolidin-2-one (25 g) as a white solid. The resultant solid was separated by chiral SFC (column- OJ 250 mm x50 mm, 10 um; mobile phase-A: supercritical CO2 , B: IPA, A:B =85:15 at 230 mL/min; column temp: 38 °C; nozzle pressure-100 bar; nozzle temp- 60 °C; evaporator temp- 20 °C; trimmer temp- 25 °C; wavelength-220nm). 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.10 (s, 1H), 7.93 (s, 2H), 6.05-6.03 (d, 1H), 5.27-5.11 (m, 2H), 4.99-4.97 (d, 1H), 4.76-4.73 (t, 1H).
(1R,5S,7aS)-1-(3,5-bis(trifluoromethyl)phenyl)-5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)tetrahydropyrrolo[1,2-c]oxazol-3(1H)-one
Intermediate B3
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[2-bromo-5-(trifluoromethyl)phenyl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one
Step 1a: To 2-bromo-5-trifluoromethylbenzaldehyde (20 g, 99 mmol) in THF (50 mL) was added vinyl magnesium bromide (1.0 M, 128 mL, 128 mmol) via a syringe addition at 0 °C. The reaction mixture was allowed to warm to room temperature and was stirred for 30 min. The reaction was quenched with the careful, dropwise addition of ethyl chloroformate (10.7 g, 99 mmol). After stirring for 30 minutes, the reaction was diluted with hexane (100 mL) and was partitioned with aqueous saturated NH4Cl. The organic was further washed with HCl (1.0 M in water, 50 mL), then brine (30 mL) before drying over sodium sulfate, filtering and concentrating to dryness. The crude material was purified by column chromatography to yield 1-(2-bromo-5-fluorophenyl)prop-2-en-1-yl ethyl carbonate (14.5 g, 47.8 mmol). 1H NMR (500 MHz, CDCl3) δ 7.56 (m, 1H), 7.24 (m, 1H), 6.97 (m, 1H), 6.43 (d, J = 5.5 Hz, 1H), 6.01 (m, 1H), 5.35-5.42 (m, 2H), 4.28 (m, 2H), 1.38 (m, 3H).
Step 2: To a 500 mL RBF was added 1-(2-bromo-5-fluorophenyl)prop-2-en-1-yl ethyl carbonate (10.4 g, 29.5 mmol), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-ethenyl-1,3-oxazolidin-2-one (4 g, 12.3 mmol), DCM (20 mL), and the Helmchen dibenzo[a,e]cyclooctatetraene (dbcot) iridium phosphoramidite catalyst complex (407 mg, 0.369 mmol) (Helmchen et al, Chem. Eur. J., 2010, 16, 6601-6615). The reaction was stirred at 33 °C for 2 days open to air. The reaction was filtered over Celite and purified by column chromatography to yield (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]prop-2-en-1-yl}-4-ethenyl-1,3-oxazolidin-2-one (4.5 g, 7.65 mmol). 1H NMR (500 MHz, CDCl3) δ 7.86 (m, 2H), 7.68 (s, 2H), 7.64 (s, 1H), 7.54 (d, J = 6.5 Hz, 1H), 6.22 (m, 1H), 5.75 (m, 2H), 5.43 (m, 2H), 5.20(m, 1H), 5.03 (d, J = 5.0 Hz, 1H), 4.8 (d, J = 8.5 Hz, 1H), 4.1 (m, 1H).
Step 3: To a 100 mL RBF equipped with a reflux condenser was added (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]prop-2-en-1-yl}-4-ethenyl-1,3-oxazolidin-2-one (4.5 g, 7.65 mmol) and toluene (20 mL). The system was flushed with nitrogen and 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene[2-(i-propoxy)-5-(N,N-dimethylaminosulfonyl)phenyl]methyleneruthenium(II) dichloride (274 mg, 0.374 mmol) (Zhan catalyst-1B) was added. The reaction mixture was heated at 60 °C for 2 hours. The solvent was removed under reduced pressure and the resultant oil was purified by column chromatography to yield (1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[2-bromo-5-(trifluoromethyl)phenyl]-5,7a-dihydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (Intermediate B1) 4.0 g, 7.14 mmol). 1H NMR (500 MHz, CDCl3) δ7.95 (s, 1H), 7.79 (s, 2H), 7.76 (d, J = 8.3 Hz, 1 H), 7.60 (s, 1 H), 7.47 (d, J = 8.2 Hz, 1H), 6.34 (d, J = 2.5 Hz, 1 H), 6.17 (s, H), 6.12 (d, J = 8.8 Hz, 1 H), 5.46(d, J = 8.7 Hz, 1H), 5.29 (d, J = 4.8 Hz, 1 H).
Step 4: To (1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[2-bromo-5-(trifluoromethyl)phenyl]-5,7a-dihydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (3.0 g, 5.36 mmol) in ethanol (10 mL) was added Wilkinson's catalyst (Rh(PPh3)3Cl) (495 mg, 0.536 mmol). The mixture was placed on a Parr shaker under an atmosphere of hydrogen gas at 40 psi overnight. Upon completion, the solvent was removed under reduced pressure and the resultant oil was purified by column chromatography to yield (1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[2-bromo-5-(trifluoromethyl)phenyl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (Intermediate B2), (3.0 g, 5.34 mmol). 1H NMR (500 MHz, CDCl3) δ7.93 (s, 1H), 7.87 (s, 2H), 7.73 (m, 2H), 7.44 (d, J = 2 Hz, 1H), 6.14 (d, J = 7.9 Hz, 1H), 6.12 (d, J = 8.8 Hz, 1H), 5.35 (m, 1 H), 4.63 (m, 1H), 3.03 (m, 1H), 1.69 (m, 1H), 1.25 (m, 2H).
Step 5: To a 40 mL vial in glove box were added (1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[2-bromo-5-(trifluoromethyl)phenyl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (intermediate B2, 2.0 g, 3.56 mmol), bis(pinacolato)diboron (1.84 g, 7.11 mmol), potassium acetate (0.87 g, 8.9 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.122 g, 0.178 mmol) and 20 mL dimethylacetamide. The vial was sealed and heated at 80 °C for 20 hrs. Reaction mixture was diluted with methyl tButyl ether, washed with 15% NaCl aqueous solution. Organics were treated with metal scavenger resin and concentrated. Crude product was purified by column chromatography to yield (1R,5S,7aS)-1-(3,5-bis(trifluoromethyl)phenyl)-5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)tetrahydropyrrolo[1,2-c]oxazol-3(1H)-one (Intermediate B3, 1.65 g, 2.71 mmol). MS ESI calc'd. for C27H25BF9NO4 [M + H]+ 610.2, found 610.2.
2-bromo-3-methyl-5-(tritluoromethyl)benzaldehyde
5-bromo-2-(trifluoromethyl)pyridine-4-carbaldehyde
Int | Structure | IUPAC Name | Exact Mass [M+H]+ or 1H NMR |
B4 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-(5-bromo-2-chloropyridin-4-yl)tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 1H NMR (500 MHz, CDCl3) δ8.51 (s, 1H), 7.95 (s, 1H), 7.86 (s, 2H), 7.46 (s, 1H), 6.13 (d, J = 8.8 Hz, 1H), 5.25 (m, 1H), 4.59 (m, 1H), 3.0 (m, 1H), 1.69 (m, 1H), 1.25 (m, 2H). |
B5 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-(5-bromo-2-chloropyridin-4-yl)-5,7a-dihydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | Calc'd 529.0 and 527.0 found 528.9 and 526.9 |
B6 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-(2-bromo-5-fluorophenyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 1H NMR (500 MHz, CDCl3) δ7.95 (s, 1H), 7.86 (s, 2H), 7.54 (m, 1H), 7.23 (m, 1H), 6.92 (m, 1H), 6.09 (d, J = 8.0 Hz, 1H), 5.25 (m, 1H), |
4.59 (m, 1H), 2.98 (m, 1H), 1.67 (m, 1H), 1.25 (m, 2H). | |||
B7 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[5-bromo-2-(dimethylamino)pyrimidin-4-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | Calc'd 539.0 and 541.0 found 538.9 and 540.9 |
B8 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[5-bromo-2-(dimethylamino)pyrimidin-4-yl]-5,7a-dihydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | Calc'd 539.0 and 537.0 found 538.9 and 536.9 |
B9 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-(3-bromo-6-chloropyridin-2-yl)tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | Calc'd 529.0 and 531.0 found 529.0 and 531.0 |
B10 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-(3-bromo-6-chloropyridin-2-yl)-5,7a-dihydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | Calc'd 529.0 and 527.0 found 529.0 and 527.0 |
B11 |
|
(1R,5S,7aS)-1-(3,5-bis(trifluoromethyl)phenyl)-5-(2-bromo-3-methyl-5-(trifluoromethyl)phenyl)tetrahy dropyrrolo[1,2-c]oxazol-3(1H)-one | 1H NMR (500 MHz, CDCl3) δ 7.95 (s, 1H), 7.89 (s, 2H), 7.54 (s, 1H), 7.47 (s, 1H), 6.15 (d, J = 8.0 Hz, 1H), 5.41 (t, J = 8.0 Hz, 1H), 4.63 (m, 1H), 3.02 (m, 1H), 2.53 (s, 3H), 1.62 (m, 1H), 1.55 (m, 1H), 1.25 (m, 1H). |
B12 |
|
(1R,5S,7aS)-1-(3,5-bis(trifluoromethyl)phenyl)-5-(2-bromo-4-methyl-5-(trifluoromethyl)phenyl)tetrahy dropyrrolo[1,2-c]oxazol-3(1H)-one | Calc'd 575.3 and 577.3, found 575.9 and 577.9 |
B13 |
|
(1R,5S,7aS)-1-(3,5-bis(trifluoromethyl)phenyl)-5-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)tetrahydropyrrolo[1,2-c]oxazol-3(1H)-one | Calc'd 563.0 and 565.0 found 563.1 and 565.1 |
B14 |
|
(1R,5S,7aS)-1-(3,5-bis(trifluoromethyl)phenyl)-5-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)-1,7a-dihydropyrrolo[1,2-c]oxazol-3(5H)-one | Calc'd 517.0 found 516.8 |
B15 |
|
(1R,5S,7aS)-1-(3,5-bis(trifluoromethyl)phenyl)-5-(3-chloro-6-(trifluoromethyl)pyridin-2-yl)tetrahydropyrrolo[1,2-c]oxazol-3(1H)-one | Calc'd 519.0 found 519 |
Intermediate C
1-ethenyl-3-methyl-5-(trifluoromethyl)benzene
(1R,5S,7aS)-5-[2-bromo-5-(trifluoromethyl)phenyl]-1-[3-methyl-5-(trifluoromethyl)phenyl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one
Step 1: To a 250 mL RBF was added (R)-(+)-2-methyl-2-propanesulfinamide (3.16 g, 26.1 mmol), 2-bromo-5-trifluorobenzaldehyde (6.0 g, 23.7 mmol), and THF (20 mL). Titanium(IV) ethoxide (10.8 g, 47.4 mmol) was added dropwise via a syringe before heating the reaction at 40 °C for 1 hour. The reaction was cooled to room temperature and water (100 mL) and ethyl acetate (100 mL) were added. The organic was stirred with brine for 15 min and was filtered to remove solids. The organic was dried over sodium sulfate, filtered and concentrated before purifying by column chromatography to yield N-{(E)-[2-bromo-5-(trifluoromethyl)phenyl]methylidene}-2-methylpropane-2-sulfinamide (8.0 g, 22.5 mmol) as a colorless crystalline solid. 1H NMR (500 MHz, CDCl3) δ 7.72 (m, 2H), 7.44 (m, 3H), 6.06 (d, J = 8.1 Hz, 1H), 5.33 (t, J = 8 Hz, 1H), 4.57 (m, 1H), 2.99 (m, 1H), 2.48 (s, 3H), 1.68 (m, 1H), 1.59 (m, 1H), 1.38 (m, 1H).
Step 2: To a 100 mL three-neck RBF equipped with stir bar and condenser was added Mg (excess), catalytic iodine, THF (20 mL), followed by 4-bromobut-1-ene (4.55 g, 33.7 mmol) in small increments. The mixture was heated to 40 °C for 1 hour. The reaction was cooled to room temperature and the freshly made Grignard reagent was added via syringe into a 250 mL RBF with N-{(E)-[2-bromo-5-(trifluoromethyl)phenyl]methylidene}-2-methylpropane-2-sulfinamide (8.0 g, 22.5 mmol) in THF (100 mL). Upon completion, the reaction was quenched with saturated aqueous NH4Cl and partitioned with ethyl acetate. The organic was dried over sodium sulfate, filtered, concentrated and purified by column chromatography to yield N-{(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]pent-4-en-1-yl}-2-methylpropane-2-sulfinamide (6.0 g, 14.6 mmol). 1H NMR (500 MHz, CDCl3) δ 7.72 (m, 2H), 7.42 (d, J = 8.2 Hz, 1H), 5.87 (m, 1H), 5.13 (m, 2H), 5.02 (m, 1H), 2.24 (m, 1H), 2.18 (m, 1H), 2.08 (m, 1H), 1.98 (m, 1H), 1.27 (s, 9H).
Step 3: To N-{(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]pent-4-en-1-yl}-2-methylpropane-2-sulfinamide (6.0 g, 14.6 mmol) in methanol (80 mL) was added HCl (4 N in dioxanes, 25.5 mL, 102 mmol). The reaction was stirred overnight at room temperature and the solvent was removed in vacuo. The resulting oil was partitioned with ethyl acetate and was washed with 10% aqueous potassium hydroxide. The organic was dried over sodium sulfate and was concentrated. (1S)-1-[2-Bromo-5-(trifluoromethyl)phenyl]pent-4-en-1-amine (4.4 g, 14.3 mmol) was carried forward without futher purification. MS ESI calc'd. for C12H14BrF3N [M + H]+ 308.0 and 310.0, found 308.0 and 310.0.
Step 4: To DIPEA (7.48 mL, 42.8 mmol) and (1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]pent-4-en-1-amine (4.4 g, 14.3 mmol) in DCM (20 mL) was added benzyl chloroformate at 0 °C. The reaction was stirred at room temperature for 2 hours and was quenched with water. The organic was washed with 10% aqueous KOH and the aqueous was back-extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, concentrated and then purified by column chromatography to yield benzyl {(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]pent-4-en-1-yl}carbamate (5.8 g, 13.1 mmol). 1H NMR (500 MHz, CDCl3) δ 7.72 (m, 1H), 7.58 (s, 1H), 7.39 (b, 5H), 7.1 (m, 1H), 5.83 (m, 1H), 5.3 (b, 1H), 5.15 (m, 3H), 2.22 (m, 1H), 2.18 (m, 1H), 1.95 (m, 1H), 1.78 (m, 1H).
Step 5: To a 100 mL RBF equipped with a reflux condenser was added benzyl {(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]pent-4-en-1-yl}carbamate (0.5 g, 1.13 mmol), 1-ethenyl-3-methyl-5-(trifluoromethyl)benzene (421 mg, 2.26 mmol) and dichloromethane (10 mL). The system was flushed with nitrogen and 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene[2-(i-propoxy)-5-(N,N-dimethylaminosulfonyl)phenyl]methyleneruthenium(II) dichloride (41 mg, 0.57 mmol) (Zhan catalyst-1B) was added before heating at 60 °C for 20 min. The reaction was cooled to room temperature and was directly purified by column chromatography to yield benzyl {(1R,4E)-1-[2-bromo-5-(trifluoromethyl)phenyl]-5-[3-methyl-5-(trifluoromethyl)phenyl]pent-4-en-1-yl}carbamate (500 mg, 0.833 mmol). 1H NMR (500 MHz, CDCl3) δ 7.72 (m, 1H), 7.58 (s, 1H), 7.39 (b, 5H), 6.4 (d, J = 8.2 Hz, 1H), 6.25 (m, 1H), 5.35 (m, 1H), 5.20 (m, 1H), 5.10 (s, 2H), 2.40 (s, 3H), 2.19 (m, 1H), 2.05 (m, 1H), 1.95 (m, 1H), 1.78 (m, 1H).
Step 6: To a 250 mL RBF was added tetrabutylammonium hydrogen sulfate (28 mg, 0.083 mmol), D-Epoxone (215 mg, 0.833 mmol), benzyl {(1R,4E)-1-[2-bromo-5-(trifluoromethyl)phenyl]-5-[3-methyl-5-(trifluoromethyl)phenyl]pent-4-en-1-yl}carbamate (500 mg, 0.833 mmol) followed by MeCN (7 mL) and EtOAc (6 mL). Sodium tetraborate decahydrate (318 mg, 0.833 mmol) in an aqueous ethylenediaminetetraacetic acid disodium salt dihydrate solution (0.4 mM, 7 mL) was added to the reaction at 0 °C. A solution of potassium carbonate (1.51 g, 8.33 mmol) in water (7 mL) and a solution of OXONE® (1.54 g, 2.50 mmol) in an aqueous ethylenediaminetetraacetic acid disodium salt dihydrate (0.4 mM, 7 mL) were simultaneously added to the reaction at 0 °C over the course of two hours. An additional solution of D-Epoxone (107 mg, 0.417 mmol) in MeCN (3 mL) was added via syringe pump over 1.5 hours. The reaction was diluted with water (100 mL) and was extracted with ethyl acetate (2 x 100 mL). The organic was concentrated and purified by column chromatography to yield benzyl [(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]-3-{(2R,3R)-3-[3-methyl-5-(trifluoromethyl)phenyl]oxiran-2-yl}propyl]carbamate (300 mg, 0.487 mmol). 1H NMR (500 MHz, CDCl3) δ 7.73 (m, 1H), 7.56 (s, 1H), 7.38-7.42 (b, 5H), 5.47 (m, 1H), 5.21(m, 1H), 5.12 (s, 2H), 3.67 (s, 1H), 3.02(s, 1H), 2.42 (s, 3H), 2.10 (m, 1H), 1.99 (m, 2H), 1.76 (m, 1H).
Step 7: To benzyl [(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]-3-{(2R,3R)-3-[3-methyl-5-(trifluoromethyl)phenyl]oxiran-2-yl}propyl]carbamate (100 mg, 0.162 mmol) in DMF (2 mL) was added LiHMDS (1.0 M, 0.324 mL, 0.324 mmol) at 0 °C. The mixture was stirred at room temperature overnight and the solvent was removed under reduced pressure. The resultant residue was purified by preparative TLC to yield (1R,5S,7aS)-5-[2-bromo-5-(trifluoromethyl)phenyl]-1-[3-methyl-5-(trifluoromethyl)phenyl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (75 mg, 0.148 mmol). 1H NMR (500 MHz, CDCl3) δ 7.72 (m, 2H), 7.46 (s, 1H), 7.44 (d, J = 8.8 Hz, 3H), 6.06 (d, J = 8.1 Hz, 1H), 5.33 (t, J = 8.0 Hz, 1H), 4.57 (m, 1H), 2.99 (m, 1H), 2.48 (s, 3H), 1.68 (m, 1H), 1.57 (m, 1H), 1.38 (m, 1H).
Int | Structure | IUPAC Name | Exact Mass [M+H]+ or 1H NMR |
D2 |
|
(1R,5S,7aS)-5-[2-bromo-5-(trifluoromethyl)phenyl]-1-[3-fluoro-5-(trifluoromethyl)phenyl]tetrahy dro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 1H NMR (500 MHz, CDCl3) δ 7.75 (m, 2H), 7.46 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.42 (m, 2H), 6.07 (d, J = 8.1 Hz, 1H), 5.34 (t, J = 8.0 Hz, 1H), 4.59 (m, 1H), 3.02 (m, 1H), 1.68 (m, 1H), 1.60 (m, 1H), 1.33 (m, |
D3 |
|
(1R,5S,7aS)-5-[2-bromo-5-(trifluoromethyl)phenyl]-1-[3-(trifluoromethyl)phenyl]tetrahy dro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 1H). 1H NMR (500 MHz, CDCl3) δ 7.73 (m, 2H), 7.71 (s, 2H), 7.43 (d, J = 8.1 Hz, 1H), 6.09 (d, J = 8.1 Hz, 1H), 5.33 (t, J = 8.0 Hz, 1H), 4.57 (m, 1H), 2.99 (m, 1H), 1.53-1.66 (b, 2H), 1.38 (m, 1H). |
D4 |
|
(1R,5S,7aS)-5-[2-bromo-5-(trifluoromethyl)phenyl]-1-(3,5-dichlorophenyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 1H NMR (500 MHz, CDCl3) δ 8.04 (s, 1H), 7.72 (m, 2H), 7.44 (m, 3H), 5.98 (d, J = 8.1 Hz, 1H), 5.32 (t, J = 8.0 Hz, 1H), 4.59 (m, 1H), 3.02 (m, 1H), 1.68 (m, 1H), 1.60 (m, 1H), 1.33 (m, 1H). |
D5 |
|
(1R,5S,7aS)-5-[2-bromo-5-(trifluoromethyl)phenyl]-1-[3-chloro-5-(trifluoromethyl)phenyl]tetrahy dro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 1H NMR (500 MHz, CDCl3) δ 7.73 (m, 2H), 7.65 (s, 1H), 7.61 (s, 1H), 7.58 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 6.06 (d, J = 8.1 Hz, 1H), 5.34 (t, J = 8.0 Hz, 1H), 4.59 (m, 1H), 3.02 (m, 1H), 1.68 (m, 1H), 1.60 (m, 1H), 1.33 (m, 1H). |
Intermediate D6
(1R,5S,8aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[2-bromo-5-(trifluoromethyl)phenyl]hexahydro[1,3]oxazolo[3,4-a]pyridin-3-one
Step 1: To a 100 mL three-neck RBF equipped with stir bar and condenser was added Mg (excess), catalytic iodine, THF (20 mL), followed by 5-bromopent-1-ene (1.93 g, 12.9 mmol) added in small increments. The mixture was heated to 40 °C for 1 hour. The reaction was cooled to room temperature and the freshly made Grignard reagent was added via syringe into a 250 mL RBF with N-{(E)-[2-bromo-5-(trifluoromethyl)phenyl]methylidene}-2-methylpropane-2-sulfinamide (2.3 g, 6.5 mmol) in THF (20 mL). Upon completion, the reaction was quenched with saturated aqueous NH4Cl and partitioned with ethyl acetate. The organic was dried over sodium sulfate, filtered, concentrated and purified by column chromatography to yield N-{(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]hex-5-en-1-yl}-2-methylpropane-2-sulfinamide (1.5 g, 3.5 mmol). 1H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.41 (d, J = 6.4 Hz, 1H), 5.77 (m, 1H), 5.03 (m, 2H), 4.87 (m, 1H), 3.65 (m, 1H), 2.11 (m, 2H), 1.86 (m, 1H), 1.82 (m, 1H), 1.55 (m, 1H), 1.40(m, 1H), 1.22 (s, 9H).
Step 2: To N-{(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]hex-5-en-1-yl}-2-methylpropane-2-sulfinamide (1.5 g, 3.5 mmol) was added HCl (4 N in dioxanes, 6.16 mL, 24.6 mmol). The reaction was stirred overnight at room temperature and the solvent was removed in vacuo. The resultant oil was partitioned with ethyl acetate and was washed with 10% aqueous potassium hydroxide. The organic was dried over sodium sulfate and was concentrated. (1S)-1-[2-Bromo-5-(trifluoromethyl)phenyl]hex-5-en-1-amine (1.11 g, 3.45 mmol) was carried forward without futher purification. MS ESI calc'd. for C13H16BrF3N [M + H]+ 322.0 and 324.0, found 322.2 and 324.2.
Step 3: To DIPEA (1.81 mL, 10.3 mmol) and (1S)-1-[2-Bromo-5-(trifluoromethyl)phenyl]hex-5-en-1-amine (1.11 g, 3.45 mmol) in DCM (20 mL) was added benzyl chloroformate at 0 °C. The reaction was stirred at room temperature for 2 hours and was quenched with water. The organic was washed with 10% aqueous KOH and the aqueous layer was back-extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, concentrated and then purified by column chromatography to benzyl {(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]hex-5-en-1-yl}carbamate (1.5 g, 3.29 mmol). 1H NMR (500 MHz, CDCl3) δ 7.71 (m, 1H), 7.69 (s, 1H), 7.39-7.29 (b, 6H), 5.81 (m, 1H), 5.28 (m, 1H), 5.14 (s, 2H), 5.08 (m, 2H), 2.16 (m, 2H), 1.84 (m, 1H), 1.68 (m 1H), 1.59 (m, 1H), 1.51 (m, 1H).
Step 4: To a 100 mL RBF equipped with a reflux condenser was added benzyl {(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]hex-5-en-1-yl}carbamate (1.5 g, 3.29 mmol), 1-ethenyl-3,5-bis(trifluoromethyl)benzene (1.58 g, 6.57 mmol) and dichloromethane (10 mL). The system was flushed with nitrogen and 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene[2-(i-propoxy)-5-(N,N-dimethylaminosulfonyl)phenyl]methyleneruthenium(II) dichloride (41 mg, 0.57 mmol) was added before heating at 60 °C for 20 min. The reaction was cooled to room temperature and was directly purified by column chromatography to yield benzyl {(1R,5E)-6-[3,5-bis(trifluoromethyl)phenyl]-1-[2-bromo-5-(trifluoromethyl)phenyl]hex-5-en-1-yl}carbamate (2.0 g, 2.99 mmol). 1H NMR (500 MHz, CDCl3) δ 7.81 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 5.82 (m, 1H), 5.05 (m, 2H), 4.41 (m, 1H), 3.82 (s, 1H), 2.13 (m, 2H), 1.76 (m, 1H), 1.42 (m, 1H).
Step 5: To a 250 mL RBF was added tetrabutylammoniuym hydrogen sulfate (97 mg, 0.284 mmol), D-Epoxone (370 mg, 1.43 mmol), benzyl {(1R,5E)-6-[3,5-bis(trifluoromethyl)phenyl]-1-[2-bromo-5-(trifluoromethyl)phenyl]hex-5-en-1-yl}carbamate (1.9 g, 2.84 mmol) followed by MeCN (15 mL) and EtOAc (20 mL). Sodium tetraborate decahydrate (1.08 g, 2.84 mmol) in an aqueous ethylenediaminetetraacetic acid disodium salt dihydrate solution (0.4 mM, 7 mL) was added to the reaction at 0 °C. A solution of potassium carbonate (3.93 g, 28.4 mmol) in water (25 mL) and a solution of OXONE® (5.24 g, 8.53 mmol) in an aqueous ethylenediaminetetraacetic acid disodium salt dihydrate (0.4 mM, 25 mL) were simultaneously added to the reaction at 0 °C over the course of two hours. An additional solution of D-Epoxone (370 mg, 1.43 mmol) in MeCN (3 mL) was added via syringe pump over 1.5 hours. The reaction was diluted with water (100 mL) and was extracted with ethyl acetate (2 x 100 mL). The organic was concentrated to yield a white solid that was resubjected to the reaction procedure. Benzyl {(1S)-4-{(2S,3S)-3-[3,5-bis(trifluoromethyl)phenyl]oxiran-2-yl}-1-[2-bromo-5-(trifluoromethyl)phenyl]butyl}carbamate (1.5 g, 2.19 mmol) was isolated by column chromatography. 1H NMR (500 MHz, CDCl3) δ 7.81 (s, 1H), 7.75 (s, 2H), 7.59 (s, 1H), 7.42 (m, 2H), 5.3 (m, 1H), 5.19 (m, 1H), 5.15 (s, 2H), 3.78 (m, 1H), 2.98 (m, 1H), 1.95 (m, 2H), 1.82-1,65 (br s, 2H).
Step 6: To benzyl {(1S)-4-{(2S,3S)-3-[3,5-bis(trifluoromethyl)phenyl]oxiran-2-yl}-1-[2-bromo-5-(trifluoromethyl)phenyl]butyl}carbamate (500 mg, 0.731 mmol) in DMF (2 mL) was added DBU (111 mg, 0.731 mmol). The system was heated to 125 °C for 6 hours. The solvent was removed in vacuo. The reaction was diluted with ethyl acetate and water. The organic was dried over sodium sulfate, filtered and concentrated. The resultant oil was purified by column chromatography to yield (R)-[3,5-bis(trifluoromethyl)phenyl]{(2S,6S)-6-[2-bromo-5-(trifluoromethyl)phenyl]piperidin-2-yl}methanol (280 mg, 0.509 mmol). 1H NMR (500 MHz, CDCl3) δ 7.9 (s, 2H), 7.81 (d, J = 5.4 Hz, 2H), 7.64 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 5.14 (d, J = 8.2 Hz, 1H), 4.51 (m, 1H), 3.16 (m, 1H), 2.06 (m, 1H), 1.95 (m, 1H), 1.80 (m, 2H), 1.62 (m, 1H), 1.29 (m, 1H).
Step 7: To (R)-[3,5-bis(trifluoromethyl)phenyl]{(2S,6S)-6-[2-bromo-5-(trifluoromethyl)phenyl]piperidin-2-yl}methanol (280 mg, 0.509 mmol) in DCM (5 mL) was added DIPEA (0.9 mL, 0.509 mmol) and phosgene (252 mg, 0.509 mmol). The reaction mixture was stirred at room temperature for 30 minutes before the solvent was removed and the reaction was diluted with ethyl acetate (15 mL) and aqueous KOH (15 mL). The organic was dried over sodium sulfate, filtered, and concentrated before purification by preparative TLC to yield (1R,5S,8aS)-5-[2-bromo-5-(trifluoromethyl)phenyl]-1-[3-methyl-5-(trifluoromethyl)phenyl]hexahydro[1,3]oxazolo[3,4-a]pyridin-3-one (200 mg, 0.347 mmol). MS ESI calc'd. for C22H16BrF9NO2 [M + H]+ 576.0 and 578.0, found 576.1 and 578.1.
Intermediate E1
(1R,4S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[5-bromo-2-(dimethylamino)pyridin-4-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one
Int | Structure | IUPAC Name | Exact Mass [M+H]+ |
E2 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[3-bromo-6-(dimethylamino)pyridin-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | Calc'd 538.1 and 540.1, found 538.0 and 540.0 |
E3 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[3-bromo-6-(dimethylamino)pyridin-2-yl]-5,7a-dihydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | Calc'd 536.0 and 538.0, 536.1 and 538.1 |
E4 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[5-bromo-2-(dimethylamino)pyridin-4-yl]-5,7a-dihydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | Calc'd 536.0 and 538.0, 536.2 and 538.2 |
Intermediate F
methyl 5-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-methylpyridine-2-carboxylate
Step 1: To a solution of 5-bromo-4-methylpyridine-2-carboxylic acid methyl ester (2.207 g, 9.59 mmol), 4-methoxylphenylboronic acid (1.604 g, 10.55 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.313 g, 0.480 mmol) in THF (30 mL) was added potassium carbonate (2.0 M in water, 10.1 mL, 20.15 mmol). The mixture was purged with nitrogen and heated at 50 °C for 1 hour and at 60 °C for 5 hours. The reaction was poured into ethyl acetate and was washed with brine, dried over sodium sulfate, filtered and concentrated. It was purified by column chromatography to yield methyl 5-(4-methoxyphenyl)-4-methylpyridine-2-carboxylate (2.47 g, 9.59 mmol) as a pink solid. MS ESI calc'd. for C15H16NO3 [M + H]+ 258.1, found 258.1.
Step 2: A suspension of iodine (2.45 g, 9.66 mmol), silver sulfate (3.01 g, 9.66 mmol) and methyl 5-(4-methoxyphenyl)-4-methylpyridine-2-carboxylate (2.47 g, 9.59 mmol) in MeOH (20 mL) was stirred at room temperature for 3.5 hours. It was then heated at 36 °C for 4 hours and then at room temperature for another 16 hours. Additional iodine (0.8 g, 3.15 mmol) and silver sulfate (1 g, 3.2 mmol) were added and the reaction was heated to 36 °C for 3 hours. The volatiles were removed and the reaction was diluted with ethyl acetate and aqueous sodium thiosulfate. The organic was washed with brine, dried over sodium sulfate, filtered and then concentrated. The resultant oil was purified by column chromatography to yield methyl 5-(3-iodo-4-methoxyphenyl)-4-methylpyridine-2-carboxylate (2.35 g, 6.12 mmol) as a white solid. MS ESI calc'd. for C15H15INO3 [M + H]+ 384.0, found 384.0.
Step 3: A solution of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.368 g, 0.451 mmol), potassium acetate (1.34 g, 13.6 mmol), bis(pinacolato)diboron (1.4 g, 5.50 mmol) and methyl 5-(3-iodo-4-methoxyphenyl)-4-methylpyridine-2-carboxylate (1.73 g, 4.51 mmol) in DMSO (20 mL) was heated at 80 °C for 80 minutes. The mixture was cooled to room temperature and was poured into ethyl acetate and water. The organic was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude oil was purified by column chromatography to yield methyl 5-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-methylpyridine-2-carboxylate (1.73 g, 4.51 mmol). MS ESI calc'd. for C21H26BNO5 [M + H]+ 384.2, found 384.2.
5-bromo-2-(dimethylamino)pyrimidine-4-carbaldehyde
Step 1: To [5-bromo-2-(methylsulfanyl)pyrimidin-4-yl]methanol (20 g, 85 mmol) in DCM (100 mL) was added m-CPBA (41.9 g, 187 mmol) portionwise at room temperature. The reaction was stirred for 1 hour before dimethylamine (2.0 M, 213 mL, 425 mmol) was added. After 2 hours, additional dimethylamine (2.0 M, 40 mL, 80 mmol) was added and the reaction was stirred overnight. The volatiles were removed and the crude oil was dissolved in ethyl acetate, washed with water and then brine, dried over magnesium sulfate, filtered and concentrated. [5-Bromo-2-(dimethylamino)pyrimidin-4-yl]methanol (19 g, 82 mmol) was carried forward as a crude oil. 1H NMR (500 MHz, CDCl3) δ 8.29 (s, 1H), 4.60 (s, 2H), 3.22 (s, 6H).
Step 2: To [5-bromo-2-(dimethylamino)pyrimidin-4-yl]methanol (19 g, 82 mmol) in DCM (10 mL) was added Dess-Martin periodinane (41.7 g, 98 mmol) at room temperature. The reaction was stirred overnight and the reaction was diluted with hexanes, filtered and was concentrated before purification by column chromatography to yield 5-bromo-2-(dimethylamino)pyrimidine-4-carbaldehyde (10 g, 43.5 mmol). 1H NMR (500 MHz, CDCl3) δ 9.95 (s, 1H), 8.52 (s, 1H), 3.24 (s, 6H).
methyl 3-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate
Step 1: A 3-neck 5 L RBF equipped with mechanical stirrer, thermometer, and a nitrogen bubbler, was charged with 3-(4-methoxyphenyl)propionic acid methyl ester (100 g, 515 mmol), silver sulfate (161 g, 515 mmol) and iodine (131 g, 515 mmol) in methanol (2 L). The reaction mixture was stirred vigorously at room temperature for 1 hour. The reaction was filtered through Solka-Floc® (ethyl acetate wash). The filtrate was concentrated and the residue was taken up in ethyl acetate (4 L). The organic was washed with water, saturated aq. NaHSO3 (50 mL), and brine (50 mL) before drying over Na2SO4, filtering, and concentrating to dryness. The crude reaction was purified by column chromatography to yield methyl 3-(3-iodo-4-methoxyphenyl)propanoate (155 g, 484 mmol) as a clear oil. MS ESI calc'd. for C11H14IO3 [M + H]+ 321.0, found 321.0.
Step 2: A 3-neck 12 L RBF equipped with mechanical stirrer, thermometer, nitrogen bubbler, condenser and addition funnel, was charged with methyl 3-(3-iodo-4-methoxyphenyl)propanoate (155 g, 484 mmol), bis(pinacolato)diboron (154 g, 605 mmol), and potassium acetate (95 g, 48.4 mmol) in DMSO (3 L) and dioxane (0.9 L). The system was degassed three times with nitrogen gas before the addition of dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (39.5 g, 48.4 mmol). The system was degassed three times and was then heated to 50 °C for 1 hour. The temperature was raised to 80 °C and the reaction was stirred overnight. The reaction was diluted with ethyl acetate (4 L) and was partitioned with water and then with brine. The organic was dried over MgSO4, filtered, and concentrated in vacuo. The crude reaction was purified by column chromatography to yield methyl 3-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (108.1 g, 338 mmol) as a tan solid. MS ESI calc'd. for C17H26BO5 [M + H]+ 321.2, found 321.2.
tert-butyl 4-[6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-3-methylbenzoate
Step 1: To a 250 mL RBF was added 4-bromo-3-methylbenzoic acid (10g, 46.5 mmol), DMAP (8.52 g, 69.8 mmol) and tert-butyl alcohol (100 mL). Di-tert-butyl dicarbonate (12.96 mL, 55.8 mmol) was added via a syringe to the solution, which caused vigorous bubbling, foaming and the loss of some material. The remaining reaction mixture was heated at 70 °C overnight. The reaction was cooled to room temperature and the volatiles were removed under reduced pressure. Crude material was diluted with ethyl acetate:hexanes (1:4, 200 mL) and was washed sequentially with 5% aqueous KOH (200 mL) and saturated aqueous ammonium chloride (2 x 100 mL). The organics were dried over sodium sulfate, filtered and concentrated before purification by column chromatography. tert-Butyl 4-bromo-3-methylbenzoate was isolated as a colorless oil (7.2 g, 26.6 mmol). 1H NMR (500 MHz, CDCl3) δ 7.87 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 2.47 (s, 3H), 1.62 (s, 9H).
Step 2: To a 250 mL RBF was added 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.317 g, 0.487 mmol), tert-butyl 4-bromo-3-methylbenzoate (6.6 g, 24.34 mmol), bis(pinacolato)diboron (7.42 g, 29.2 mmol), potassium acetate (5.97 g, 60.9 mmol) and dioxane (25 mL). The system was flushed with nitrogen and was heated at 125 °C overnight. The reaction was cooled to room temperature and was diluted with ethyl acetate:hexanes (1:9, 120 mL) and then was washed sequentially with water (150 mL) and then brine (50 mL). The organics were dried over sodium sulfate, filtered and concentrated before purification by column chromatography. tert-Butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate was isolated as a crystalline solid (6.6 g, 14.5 mmol). 1H NMR indicated it is about 70% pure. 1H NMR (500 MHz, CDCl3) δ 7.8 (m, 3H), 2.60 (s, 3H), 1.58 (s, 9H), 1.39 (s, 12H).
Step 3: To a 250 mL RBF was added 5-bromo-3-chloro-2-methoxypyridine (1.5 g), tribasic potassium phosphate (2.86 g, 13.5 mmol), bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.275 g, 6.74 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.27 g, 7.13 mmol), dioxane (50 mL) and water (3 mL). The flask was sealed and was stirred at 80 °C overnight. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water, filtered and concentrated. The resultant residue was purified by column chromatography to yield tert-butyl 4-(5-chloro-6-methoxypyridin-3-yl)-3-methylbenzoate (2.0 g, 5.99 mmol). MS ESI calc'd. for C18H21ClNO3 [M + H]+ 334.1, found 334.0.
Step 4: To a 250 mL RBF was added tert-butyl 4-(5-chloro-6-methoxypyridin-3-yl)-3-methylbenzoate (4.5 g, 13.5 mmol), bis(pinacolato)diboron (6.85 g, 27.0 mmol), potassium acetate (3.97g, 40.4 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.212 g, 0.27 mmol) followed by anhydrous dioxane (50 mL). The system was evacuted and backfilled with nitrogen (3x) and was heated to 120 °C for 2 hours. The mixture was cooled, filtered over Celite (ethyl acetate wash) and was concentrated. The residue was purified by column chromatography to afford tert-butyl 4-[6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-3-methylbenzoate as a solid (4.3 g, 10.11 mmol). MS ESI calc'd. for C24H33BNO5 [M + H]+ 426.2, found 426.0.
(2S,3S,4R)-tert-butyl 3-(3-chloro-4-methoxyphenyl)-2,4-dimethyl-5-oxopyrrolidine-1-carboxylate
Step 1: To a 100 mL RBF were added (3-chloro-4-methoxyphenyl)boronic acid (1.89 g, 10.14mmol), (S)-tert-butyl 2-methyl-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (1 g, 5.07mmol), hydroxy(cyclooctadiene)rhodiumRhodium(I) dimer (0.116 g, 0.254 mmol), potassium hydrogen fluoride (1.58 g, 20.28 mmol). The mixture was degased and filled back with N2. Dioxane (45 mL) and water (5 mL) were then added. The mixture was degased again and filled with N2. The reaction mixture was heated at 60°C overnight. It was diluted with EtOAc (200 mL), washed with water, brine. Organic layer was dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography, eluted with 30%EtOAc/Hexane to give (2S,3S)-tert-butyl 3-(3-chloro-4-methoxyphenyl)-2-methyl-5-oxopyrrolidine-1-carboxylate (intermediate J1,0.85 g) as white crystalline solid. 1H NMR (500 MHz, CDCl3): δ 7.20 (s,1H), 7.05 (d, 1H), 6.87 (d, 1H), 4.08 (m, 1H), 3.86 (s, 3H), 2.95 (m, 2H), 2.53 (m, 1H), 1.52 (s, 9H), 1.41 (d, 3H).
Step 2: To a solution of (2S,3S)-tert-butyl 3-(3-chloro-4-methoxyphenyl)-2-methyl-5-oxopyrrolidine-1-carboxylate (intermediate J1, 0.85g, 2.5 mmol) in THF (20 mL) was added LiHMDS (2.5 mL, 2.5 mmol) at -78 °C. After 30 mins, MeI (0.187 mL, 3.00 mmol) was added. The reaction mixture was stirred at -78 °C for 1.5 hr. It was warmed up to 0 °C for 30min and then warmed up to RT for 30min. The reaction mixture was quenched with 2 mL of AcOH and 100 mL of NH4Cl. The product was extracted with EtOAc (3x100 mL). The organic layer was washed with brine(100 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluted with 30%EtOAc/Hexane to give (2S,3S,4R)-tert-butyl 3-(3-chloro-4-methoxyphenyl)-2,4-dimethyl-5-oxopyrrolidine-1-carboxylate (intermediate J2, 0.55 g, yield of 62%) as off-white solid. 1H NMR (500 MHz, CDCl3): δ 7.29 (s,1H), 7.14 (d, 1H), 6.95 (d, 1H), 3.93 (s, 3H), 3.91 (m, 1H), 2.58 (m, 1H), 2.40 (m, 1H), 1.59 (s, 9H), 1.38 (d, 3H), 1.17 (d, 3H).
Intermediate K
(4S,5R)-5-(3-chloro-4-methoxyphenyl)-4-methyloxazolidin-2-one
Step 1. A solution of 4-bromo-2-chloroanisole (3 g, 13.55 mmol) and (S)-benzyl (1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (3.79 g, 14.22 mmol) in THF (33.9 mL) was cooled to -20 °C with dry ice/ acetone. To this solution was added isopropylmagnesium chloride lithium chloride complex (22.9 mL, 29.8 mmol) at -20 °C dropwise under N2. After addition, the reaction mixture was warmed up to rt and stirred overnight. The reaction mixture was cooled to -40 °C and slowly poured into a stirred mixture of crushed ice and 30 mL of 1N HCl. The resulting mixture was diluted with 30 mL of brine, extracted with EtOAc (3 x 50 mL). The organic layer was dried with Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluted with 0-100% EtOAc in hexane to give (S)-benzyl (1-(3-chloro-4-methoxyphenyl)-1-oxopropan-2-yl)carbamate (0.82 g) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.05 (s,1H), 7.92 (d, 1H), 6.98 (d, 1H), 5.93 (d,1H), 5.29 (m, 1H), 5.16 (s, 2H), 3.99 (s, 3H), 1.43 (d, 3H).
Step 2. To a solution of (S)-benzyl (1-(3-chloro-4-methoxyphenyl)-1-oxopropan-2-yl)carbamate (0.81 g, 2.456 mmol) in MeOH (10 mL) and THF (10 mL) was added NaBH4 (0.139 g, 3.68 mmol) at 0 °C. The solution was stirred at that temperature for 0.5 hr. The reaction was quenched with Saturated NH4Cl aq. solution (20 mL) and water (20 mL). The mixture was extracted 3 times with EtOAc (100 mL). The organic layer was washed with brine, dried with Na2SO4 and concentrated. The residue was purified by chromatography over silica gel and eluted with 40% EtOAc in hexane to give two isomers. The major isomer is benzyl ((1R,2S)-1-(3-chloro-4-methoxyphenyl)-1-hydroxypropan-2-yl)carbamate (0.41g).1H NMR (500 MHz, CDCl3): δ 7.28 (s,1H), 7.20 (d, 1H), 6.89 (d, 1H), 5.17 (s,2H), 5.02 (d, 1H), 4.81 (d, 1H), 4.03 (b, 1H), 3.93 (s, 3H), 1.01 (d, 3H).
Step 3. To a solution of benzyl ((1R,2S)-1-(3-chloro-4-methoxyphenyl)-1-hydroxypropan-2-yl)carbamate (0.24 g, 0.686 mmol) in THF (4.6 mL) was added NaH (0.036 g, 0.892 mmol) at 0 °C. The reaction micture was warmed to RT and stirred overnight. It was then quenched with 1N HCl (1.5 mL). This mixture was diluted with EtOAc and washed with sat. aqueous NaHCO3, water and brine. The organic phase was dried with Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluted with EtOAc to give (4S,5R)-5-(3-chloro-4-methoxyphenyl)-4-methyloxazolidin-2-one (intermediate K, 0.13 g).1H NMR (500 MHz, CDCl3): δ 7.37 (s,1H), 7.21 (d, 1H), 6.97 (d, 1H), 5.84 (b,1H), 5.65 (d, 1 H), 4.21 (m, 1 H), 3.96 (s, 3H), 0.87 (d, 3H).
Intermediate L
(3aR,5s,6aS)-5-(3-bromo-4-methoxyphenyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole
Step 1: To a 250 mL RBF was added methyl 3-bromo-4-methoxybenzoate (4.0 g, 16.3 mmol). The flask was flushed with N2. THF (60 mL) was added, followed by allylmagnesium bromide (39.2 mL, 39.2 mmol, 1.0 M in ether) at 0 °C via a syringe over 10 mins. The resulting reaction mixture was stirred at 0 °C for 2hrs. It was quenched by addition of 50 mL sat. NH4Cl at 0 °C and 100 mL of water. The product was extracted with EtOAc (3x100 mL). Organics were washed with 100 mL brine, dried over sodium sulfate, filtered, and concentrated to give 4-(3-bromo-4-methoxyphenyl)hepta-1,6-dien-4-ol (5.0 g) as a colorless oil. 1H NMR (500 MHz, CDCl3:) δ 7.61 (s,1H), 7.30 (d, 1H), 6.88 (d, 1H), 5.63 (m,2H), 5.12 (d, 4H), 3.93 (s, 3H), 2.65 (m, 2H), 2.53 (m, 2H).
Step 2: To a 250 mL RBF were added 4-(3-bromo-4-methoxyphenyl)hepta-1,6-dien-4-ol (4.85 g, 16.32 mmol), triethylsilane (5.21 mL, 32.6 mmol), and CH2Cl2 (50 mL). The flask was flushed with N2. BF3.Et2O (2.275 mL, 17.95 mmol) was added via syringe at -78°C. The resulting reaction mixture was stirred at -78 °C for 1 hr and was then allowed to warm to 0 °C briefly. 50 mL 10% KOH was added at 0 °C and the reaction mixture was extracted with 50 mL EtOAc/Hexane (1:1). The organics were washed with 30 mL brine, dried over sodium sulfate, filtered and concentrated. Crude product was purified by silica gel chromatography, eluted with 10% EtOAc/Hexane to give 2-bromo-4-(hepta-1,6-dien-4-yl)-1-methoxybenzene (3.6 g) as colorless oil. 1H NMR (500 MHz, CDCl3:) δ 7.38 (s,1H), 7.06 (d, 1H), 6.85 (d, 1H), 5.66 (m,2H), 4.99 (d, 4H), 3.91 (s, 3H), 2.66 (m, 1H), 2.42 (m, 2H), 2.33 (m, 2H).
Step 3: To a solution of 2-bromo-4-(hepta-1,6-dien-4-yl)-1-methoxybenzene (2.0 g, 7.11 mmol) in DCM (36 mL) was added Zhan catalyst (47 mg). The mixture was flushed with N2 and refluxed at 45 °C overnight. The reaction mixture was concentrated and the residue was purified by silica gel chromatography, eluting with 10% of EtOAc/isohexane to give 2-bromo-4-(cyclopent-3-en-1-yl)-1-methoxybenzene (1.9 g) as a colorless oil. 1H NMR (500 MHz, CDCl3:) δ 7.46 (s,1H), 7.18 (d, 1H), 6.83 (d, 1H), 5.80 (s,2H), 3.91 (s, 3H), 3.40 (m, 1H), 2.81 (m, 2H), 2.40 (m, 2H).
Step 4: To a 100 mL RBF were added 2-bromo-4-(cyclopent-3-en-1-yl)-1-methoxybenzene (1.9 g, 7.51 mmol), NMO (2.64 g, 22.5 mmol), osmium tetroxide (0.942 mL, 0.075 mmol, 2.5% in t-BuOH), t-butanol (13 mL) and water (13 mL). The resulting reaction mixture was stirred at rt over the weekend. Volatiles were removed. Crude material was dissolved in 100 mL EtOAc and washed with 50 mL water. Organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with 80% EtOAc in hexane to give 4-(3-bromo-4-methoxyphenyl)cyclopentane-1,2-diol (1.7 g) as white solid. 1H NMR (500 MHz, CDCl3): δ 7.39 (s,1H), 7.10 (d, 1H), 6.85 (d, 1H), 4.37 (m, 2H), 3.91 (s, 3H), 3.55 (m, 1H), 2.46 (b, 2H), 2.18 (m, 2H), 1.88 (m, 2H).
Step 5: To a solution of 4-(3-bromo-4-methoxyphenyl)cyclopentane-1,2-diol (2.0 g, 6.97 mmol) in acetone (50 mL) was added 2,2-dimethoxypropane (2.56 mL, 20.90 mmol) at 0 °C followed by adding methanesulfonic acid (0.167 g, 1.74 mmol) dropwise. The reaction mixture was stirred at RT overnight. Volatiles were removed under vacuum. To the residue was added aqueous NaHCO3, and the resulting mixture was extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. Crude product was purified by silica gel column chromatography, eluting with 15% EtOAc in hexane to give intermediate L (1.7 g) as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.43 (s,1H), 7.15 (d, 1H), 6.85 (d, 1H), 4.76 (d, 2H), 3.88 (s, 3H), 3.34 (m, 1H), 2.20 (dd, 2H), 1.59 (m, 2H), 1.55 (s, 3H), 1.35 (s, 3H).
Intermediate M
5-(3-bromo-4-methoxyphenyl)-6-methylpiperidin-2-one
Step 1: To a 100 mL RBF was added 2-bromo-4-iodo-1-methoxybenzene (0.59 g, 1.87 mmol), and 10 mL THF. iPrMgCl (0.94 mL, 1.89 mmol, 2M THF solution) was added at 0 °C via syringe. The reaction mixture was stirred at 0 °C for 1 hr. A solution of lithium 2-thenyl cyanocuprate (7.5 mL, 1.87 mmol) in THF was added, followed by 2-methylcyclopent-2-enone (150 mg, 1.56 mmol). The resulting reaction mixture was stirred at 0 °C for 1 hr and was allowed to warm up and stirred at rt for 1 hr. The reaction mixture was diluted with 30 mL EtOAc/hexane (1:1), washed with 30 mL 1N HCl, then 20 mL brine. Organics were dried over sodium sulfate, filtered and concentrated. Crude product was purified by silica gel chromatography to give 135 mg 3-(3-bromo-4-methoxyphenyl)-2-methylcyclopentanone as a mixture of two diastereomers at 1.6:1 ratio. 1H NMR for the major diastereomer (500 MHz, CDCl3): δ 7.35 (d, J= 2.2 Hz, 1H), 7.05 (dd, J= 2.2, 8.4 Hz, 1H), 6.89 (d, J= 8.4 Hz, 1H), 3.92 (s, 3H), 3.55 (m, 1H), 2.2-2.6 (m, 5H), 0.83 (d, J = 7.6 Hz, 3H). 1H NMR for the minor diastereomer (500 MHz, CDCl3): δ 7.48 (d, J = 2.1 Hz, 1H), 7.19 (dd, J = 2.2, 8.3 Hz, 1H), 6.93 (d, J= 8.3 Hz, 1H), 3.94 (s, 3H), 2.75 (m, 1H), 2.2-2.6 (m, 5H), 1.07 (d, J= 6.8 Hz, 3H).
Step 2: To a vial were added 3-(3-bromo-4-methoxyphenyl)-2-methylcyclopentanone (135 mg, 0.57 mmol), NH2OH (94 mg, 1.43 mmol), and 3 mL EtOH. The resulting reaction mixture was stirred at 75 °C for 2 hrs. Volatiles were removed and the resulting residue was diluted with 20 mL EtOAc, washed with 20 mL sat. Na2CO3 aqueous solution, and then 10 mL brine. The organics were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in 3 mL DCM and was transferred to a vial. To this vial were added tosyl-Cl (109 mg, 0.57 mmol), DMAP (catalytic) and TEA (0.13 mL, 0.95 mmol). The resulting reaction mixture was stirred at rt for 2 hrs. Volatiles were removed. To the remaining material was added acetic acid (3.0 mL). The resulting reaction mixture was stirred at rt overnight. Volatiles were removed. Crude material was diluted with 20 mL EtOAc, washed with 20 mL sat. Na2CO3 aqueous solution, then 10 mL brine. Organics were dried over sodium sulfate, filtered and concentrated. The crude product was purified on reverse phase HPLC eluted with acetonitrile/water (modified with 0.05% TFA) gradient solvents to give 72 mg 3-(3-bromo-4-methoxyphenyl)-2-methylcyclopentanone (intermediate M) as a mixture of cis and trans isomers. MS ESI calc'd. for C13H16BrNO2 [M + H]+ 298.0 and 300.20, found 298.1 and 300.1.
Intermediate N
(S)-5-(3-bromo-4-methoxyphenyl)-6,6-dimethyl-1,3-oxazinan-2-one
Step 1: To a stirred solution of 2-(3-bromo-4-methoxyphenyl)acetic acid (5 g, 20.40 mmol) in 60 mL THF was added TEA (3.13 mL, 22.44 mmol), and then pivaloyl chloride (2.64 mL, 21.42 mmol) at 0 °C. The resulting reaction mixture was stirred at 0 °C for 30 mins. Ice bath was replaced with dry ice acetone bath. To a separate round-bottom flask was added (S)-4-benzyl-2-oxazolidinone (3.62 g, 20.4 mmol) and 50 mL THF. To this solution was added n-BuLi (12.8 mL, 20.4 mmol, 1.6 M in hexane) dropwise via a syringe at -78 °C. The resulting reaction mixture was stirred -78 °C for 5 mins. This solution was transfered to the previous flask via channular transfering. After transfering, the reaction mixture was stirred at -78 °C for 30 mins and was allowed to warm up to rt. It was quenched by addition of 100 mL brine and 100 mL water. The reaction mixture was extracted with 200 mL 30% EtOAc in hexane. The organics were dried over sodium sulfate, filtered and concentrated. Crude product was purified on a Combiflash prepacked silica gel column eluted with 5% to 35% EtOAc in hexane to give 5.7 g desired product as colorless viscous material. 1H NMR (500 MHz, CDCl3): δ 7.57 (s, 1H), 7.3 (m, 4H), 7.18 (d, J= 7.3 Hz, 1H), 6.92 (d, J= 8.5 Hz, 1H), 4.71 (br, 1H), 4.1-4.3 (m, 4H), 3.93 (s, 3H), 3.31 (d, J = 12.9 Hz, 1H), 2.81 (dd, J = 9.8, 13.2 Hz, 1H).
Step 2. To a round bottom flask were added 10 mL DCM and (S)-4-benzyl-3-(2-(3-bromo-4-methoxyphenyl)acetyl)oxazolidin-2-one (1.0 g, 2.47 mmol). TiCl4 (2.6 mL, 2.60 mmol, 1M DCM solution) was added at 0 °C. After stirring at 0 °C for 5 mins, DIEA (0.45 mL, 2.6 mmol) was added via syringe. The reaction mixture was stirred at 0 °C for 30 mins. Acetone (0.27 mL, 3.71 mmol) was added followed by more of TiCl4 (2.6 mL, 2.6 mmol, 1 M DCM solution). The reaction mixture was stirred at 0 °C for 2 hrs. It was quenched by addition of 80 mL sat. NH4Cl aqueous solution. The resulting reaction mixture was extracted with 120 mL EtOAc/hexane (1:1). Organics wer dried over sodium sulfate, filtered and concentrated. Crude product was purfied on Combiflash prepacked silica gel column, eluted with 5% to 40% EtOAc in hexane to give 1.1 g desired product as viscous material. 1H NMR (500 MHz, CDCl3): δ 7.70 (s, 1H), 7.1-7.4 (m, 6H), 6.88 (d, J= 8.5 Hz, 1H), 4.68 (m, 1H), 4.1 (m, 2H), 3.93 (s, 3H), 3.83 (s, 1H), 3.43 (dd, J= 3.4,13.3 Hz, 1H), 2.82 (dd, J= 9.9, 13.3 Hz, 1H), 1.46 (s, 3H), 1.09 (s, 3H).
Step 3: To a solution of (S)-4-benzyl-3-((R)-2-(3-bromo-4-methoxyphenyl)-3-hydroxy-3-methylbutanoyl)oxazolidin-2-one (540 mg, 1.17 mmol) in 10 mL THF was added a solution of DIBAL-H (3.5 mL, 3.50 mmol, 1 M toluene solution) via a syringe at 0 °C. After stirring at 0 °C for 20 mins, more DIBAL-H (1.0 mL, 1.0 mmol) was added. After stirring at 0 °C for 10 mins, the reaction mixture was quenched by addition of 10 mL EtOAc and then 10 mL 3N HCl. After stirring at 0 °C for 15 mins, the reaction was diluted with 30 mL EtOAc/hexane (1:1) and 30 mL water. The layers were separated. The organics were washed with 20 mL 10% KOH aqueous solution, dried over sodium sulfate, filtered and concentrated. Crude product was purified on prepacked Combiflash column and eluted with 5% to 40% EtOAc in hexane to give 185 mg viscous material. NMR indicated it is a mixture of desired product and the chiral auxiliary. 1H NMR (500 MHz, CDCl3): δ 7.49 (d, J= 2.1 Hz, 1H), 7.23 (dd, J= 2.1, 8.3 Hz, 1H), 6.88 (d, J= 8.3 Hz, 1H), 4.05 (m, 2H), 3.92 (s, 3H), 2.85 (m, 1H), 1.27 (s, 3H), 1.24 (s, 3H).
Step 4: To a solution of (S)-2-(3-bromo-4-methoxyphenyl)-3-methylbutane-1,3-diol (115 mg, 0.40 mmol) in 2 mL DCM were added DMAP (catalytic), DIEA (0.21 mL, 1.29 mmol) and tosyl chloride (106 mg, 0.57 mmol). The resulting reaction mixture was stirred at 40 °C overnight. It was diluted with 20 mL EtOAc and washed with 20 mL water. The organics were dried over sodium sulfate, filtered and concentrated. Crude product was purified by chromatography to give 132 mg tosylate product. 1H NMR (500 MHz, CDCl3): δ 7.63 (d, J= 8.1 Hz, 2H), 7.31 (d, J= 8.1 Hz, 2H), 7.22 (d, J= 2.0 Hz, 1H), 7.07 (dd, J= 2.0, 8.6 Hz, 1H), 6.82 (d, J= 8.4 Hz, 1H), 4.65 (dd, J = 4.9, 10.0 Hz, 1H), 4.31 (t, J = 9.9 Hz, 1H), 3.92 (s, 3H), 2.9 (m, 1 H), 2.48 (s, 3H), 1.28 (s, 3H), 1.10 (s, 3H).
Step 5: To a solution of (S)-2-(3-bromo-4-methoxyphenyl)-3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (58 mg, 0.13 mmol) in 2 mL DMF was added NaN3 (34 mg, 0.52 mmol). The resulting reaction mixture was heated at 60 °C overnight and was then diluted with 10 mL EtOAc/hexane (1:1) and 10 mL water. The layers were separated. The organics were dried over sodium sulfate, filtered and concentrated. Crude product was purified on Combiflash prepacked silica gel column, eluted with hexane to 40% EtOAc in hexane to give 38 mg desired product. 1H NMR (500 MHz, CDCl3): δ 7.49 (d, J= 1.9 Hz, 1H), 7.22 (dd, J= 2.1, 8.5 Hz, 1H), 6.91 (d, J= 8.4 Hz, 1H), 3.93 (s, 3H), 3.9 (m, 1H), 3.71 (m, 1H), 2.82 (m, 1H), 1.28 (s, 3H), 1.17 (s, 3H).
Step 6: To a 25 mL round bottom flask containing (S)-4-azido-3-(3-bromo-4-methoxyphenyl)-2-methylbutan-2-ol (38 mg, 0.12 mmol) were added PPh3 (48 mg, 0.18 mmol), THF (2 mL) and water (0.2 mL). The resulting reaction mixture was heated to reflux for 2 hrs. Volatiles were removed under vacuum. To the residue was added 2 mL THF, DIEA (0.063 mL, 0.36 mmol) and CDI (39 mg, 0.24 mmol). The resulting reaction mixture was heated at 60 °C for 3 hrs. It was then diluted with 10 mL saturated NH4Cl and extracted with 15 mL EtOAc. The organics were dried over sodium sulfate, filtered and concentrated. Crude product was purified on a Combiflash prepacked silica gel column which was eluted with EtOAc to give 30 mg of the desired product (intermediate N). 1H NMR (500 MHz, CDCl3): δ 7.41 (s, 1H), 7.16 (d, J= 7.8 Hz, 1H), 6.88 (d, J= 8.5 Hz, 1H), 6.76 (s, 1H), 3.90 (s, 3H), 3.65 (t, J = 11.4 Hz, 1H), 3.46 (br, 1H), 3.0 (br, 1H), 1.34 (s, 3H), 1.32 (s, 3H).
Examples - General Synthetic Schemes
Examples
Example 1
methyl 3-[2'-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]propanoate (Scheme 1)
Example 2
3-[2'-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]propanoic acid (Scheme 1)
Example 3
4-{5-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4-(trifluoromethyl)phenyl]-6-methoxypyridin-3-yl}-3-methylbenzoic acid (Scheme 1)
Step 1: To a solution of Intermediate B2 (4.4 g, 7.83 mmol) in dioxane (50 mL) and water (5 mL) was added Intermediate I (3.66 g, 8.61 mmol), potassium phosphate (4.98 g, 23.5 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.255 g, 0.39 mmol). The mixture was purged with nitrogen and heated at 80 °C overnight. The reaction was poured into ethyl acetate and was washed with water, dried over sodium sulfate, filtered and concentrated. The resultant residue was purified by column chromatography to yield tert-butyl 4-{5-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4-(trifluoromethyl)phenyl]-6-methoxypyridin-3-yl}-3-methylbenzoate (4.5 g, 5.77 mmol). MS ESI calc'd. for C39H33F9N2O5 [M + H]+ 781.2, found 781.2.
Step 2: To tert-butyl4-{5-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4-(trifluoromethyl)phenyl]-6-methoxypyridin-3-yl}-3-methylbenzoate (1 g, 1.28 mmol) was added dichloromethane:TFA (9:1, 10mL). The reaction was stirred overnight at room temperature. Upon completion the solvent was removed under reduced pressure and the resultant residue was redissolved in acetonitrile for direct purification by reverse phase HPLC to yield 4-{5-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4-(trifluoromethyl)phenyl]-6-methoxypyridin-3-yl}-3-methylbenzoic acid (0.674 g, 0.931 mmol). 1H NMR indicated that this compound exists as a pair of rotamers at 1.2:1 ratio. 1H NMR (500 MHz, CDCl3) δ 8.27 (s, 1 H), 8.04 (m, 4H, peaks overlap for the two rotamers), 7.90 (s, 1H), 7.84 (s, 2H, minor rotamer), 7.83 (s, 2H, major rotamer), 7.75 (s, 1H, major rotamer), 7.67 (s, 1H, minor rotamer), 7.63 (d, J = 8Hz, 1 H, major rotamer), 7.42 (m, 2H), 7.38 (d, J = 7.9Hz, 1H, major rotamer), 7.36 (d, J = 7.9Hz, 1H, minor rotamer), 6.11(d, J = 7.9Hz, 1H, minor rotamer), 6.09 (d, J= 7.9 Hz, 1H, major rotamer), 5.27 (t, J = 7.9 Hz, 1H, major rotamer), 4.95 (t, J = 7.9 Hz, 1H, minor rotamer), 4.62 (m, 1H, minor rotamer), 4.51 (m, 1H, major rotamer), 4.12 (s, 3H, minor rotamer), 3.94(s, 3H, minor rotamer), 2.45 (s, 3H, minor rotamer), 2.45 (s, 3H, major rotamer), 2.37 (m, 1H), 2.2 (m, 1H), 2.05 (m, 1H), 1.85 (m, 1H), 1.55 (m, 1H), 1.4 (m, 1H), 1.1 (m, 2H). MS ESI calc'd. for C35H26F9N2O5 [M + H]+ 725.2, found 725.0. RTA (95% HS): 53.18 nM
Example 4
(1R,5S,7aS)-1-(3,5-bis(trifluoromethyl)phenyl)-5-(5'-((2S,3S,4R)-2,4-dimethyl-5-oxopyrrolidin-3-yl)-2'-methoxy-4-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)tetrahydropyrrolo[1,2-c]oxazol-3(1H)one (Scheme 1)
Ex | Structure | IUPAC Name | IC50(n M) | Exact Mass [M+H]+ |
5 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[4'-fluoro-2'-methoxy-5'-(1-methylethyl)-4-(trifluoromethyl)biphenyl-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 84.92 | Calc'd 650.2, found 650.3 |
6 |
|
methyl2"-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6'-fluoro-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylate | 641 | Calc'd 756.2, found 756.4 |
7 |
|
2"-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6'-fluoro-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"- | 53.7 | Calc'd 742.2, found 742.4 |
8 |
|
terphenyl-4-carboxylic acid trans-3-[2'-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]cyclobutanecarboxylic acid | 96.54 | Calc'd 688.2, found 688.3 |
9 |
|
2'-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-methoxy-4'-(trifluoromethyl)biphenyl-3-carbonitrile | 224.2 | Calc'd 615.1, found 615.4 |
10 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-{2-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-5-(trifluoromethyl)phenyl}tetrahyd ro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 371.4 | Calc'd 659.1, found 659.5 |
11 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[2-(5-chloro-2-methoxypyridin-3-yl)-5-(trifluoromethyl)phenyl]tetrahyd ro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 294.5 | Calc'd 625.1, found 625.3 |
12 |
|
4-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4-(trifluoromethyl)phenyl]thiophe ne-3-carbonitrile | 266 | Calc'd 591.1, found 591.4 |
13 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[2'-methoxy-5'-methyl-4-(trifluoromethyl)biphenyl-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 262.8 | Calc'd 604.2, found 604.5 |
14 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[5'-chloro-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 233.3 | Calc'd 624.1, found 624.5 |
15 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[2'-chloro-4-(trifluoromethyl)biphenyl-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 452.8 | Calc'd 594.1, found 594.3 |
16 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[2-(4-methylfuran-3-yl)-5-(trifluoromethyl)phenyl]tetrahyd ro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 343.4 | [M-H]- Calc'd 562.1, found 562.3 |
17 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[2-cyclohex-1-en-1-yl-5-(trifluoromethyl)phenyl]tetrahyd ro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 73.63 | Calc'd 564.2, found 564.5 |
18 |
|
(1R,5S,7aS)-1-[3,5-bIs(trifluoromethyl)phenyl]-5-[2-thiophen-3-yl-5-(trifluoromethyl)phenyl]tetrahyd ro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 102.8 | [M-H]- Calc'd 564.1, found 564.3 |
19 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[5'-fluoro-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 165.7 | Calc'd 608.1, found 608.4 |
20 |
|
2'-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4'-(trifluoromethyl)biphenyl-3-carbonitrile | 177.1 | [M-H]- Calc'd 583.4, found 583.4 |
21 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[2-(2-methoxypyridin-3-yl)-5-(trifluoromethyl)phenyl]tetrahyd ro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 316.3 | Calc'd 591.1, found 591.4 |
22 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[2-cyclopent-1-en-1-yl-5-(trifluoromethyl)phenyl]tetrahyd ro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 56.63 | Calc'd 550.1, found 550.4 |
23 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[5'-chloro-2'-fluoro-4-(trifluoromethyl)biphenyl-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 187.5 | Calc'd 612.1, found 612.5 |
24 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[2-(4-methylthiophen-3-yl)-5-(trifluoromethyl)phenyl]tetrahyd ro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 122.2 | [M-H]- Calc'd 578.1, found 578.4 |
25 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[2',5'-difluoro-4-(trifluoromethyl)biphenyl-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 104.1 | Calc'd 596.1, found 596.3 |
26 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[5'-chloro-2'-methyl-4-(trifluoromethyl)biphenyl-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 1223 | Calc'd 608.1, found 608.4 |
27 |
|
(1R,5S,7aS)-5-[4'-fluoro-2'-methoxy-5'-(1-methylethyl)-4-(trifluoromethyl)biphenyl-2-yl]-1-[3-methyl-5-(trifluoromethyl)phenyl]tetrahyd ro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 133.5 | Calc'd 596.2, found 596.3 |
28 |
|
(1R,5S,7aS)-5-[4'-fluoro-2'-methoxy-5'-(1-methylethyl)-4-(trifluoromethyl)biphenyl-2-yl]-1-[3-fluoro-5-(trifluoromethyl)phenyl]tetrahyd ro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 261.5 | Calc'd 600.2, found 600.3 |
29 |
|
6'-fluoro-4'-methoxy-2-methyl-2"-{(1R,5S,7aS)-1-[3-methyl-5-(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid | 44.65 | Calc'd 688.2, found 688.3 |
30 |
|
(1R,5S,7aS)-5-[4'-fluoro-2'-methoxy-5'-(1-methylethyl)-4-(trifluoromethyl)biphenyl-2-yl]-1-[3-(trifluoromethyl)phenyl]tetrahyd ro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 189.9 | Calc'd 582.2, found 582.2 |
31 |
|
(1R,5S,7aS)-1-(3,5-dichlorophenyl)-5-[4'-fluoro-2'-methoxy-5'-(1-methylethyl)-4-(trifluoromethyl)biphenyl-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 213.2 | Calc'd 582.1, found 582.1 |
32 |
|
(1R,5S,7aS)-1-[3-chloro-5-(trifluoromethyl)phenyl]-5-[4'-fluoro-2'-methoxy-5'-(1-methylethyl)-4-(trifluoromethyl)biphenyl-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 147.7 | Calc'd 616.1, found 616.1 |
33 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-{2-(dimethylamino)-5-[4-fluoro-2-methoxy-5-(1-methylethyl)phenyl]pyridin-4-yl}tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 108.2 | Calc'd 626.2, found 626.3 |
34 |
|
2"-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4"-fluoro-4'-methoxy-2-methyl-1,1':3',1"-terphenyl-4-carboxylic acid | 228.9 | Calc'd 674.2, found 674.4 |
35 |
|
3'-[4-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-2-(dimethylamino)pyrimidin-5-yl]-4'-methoxy-2-methylbiphenyl-4-carboxylic acid | 431.9 | Calc'd 701.2, found 701.2 |
36 |
|
3'-[4-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-(dimethylamino)pyridin-3-yl]-4'-methoxy-2-methylbiphenyl-4-carboxylic acid | 275.6 | Calc'd 700.2, found 700.2 |
37 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[4,4'-difluoro-2'-methoxy-5'-(1-methylethyl)biphenyl-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 474.5 | Calc'd 600.2, found 600.3 |
38 |
|
5-(2'-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4'-fluoro-6-methoxybiphenyl-3-yl)-4-methylpyridine-2-carboxylic acid | 1742 | Calc'd 675.2, found 675.4 |
39 |
|
3'-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-(dimethylamino)pyridin-3-yl]-4'-methoxy-2-methylbiphenyl-4-carboxylic acid | 714 | Calc'd 700.2, found 700.4 |
40 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-{6-(dimethylamino)-3-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]pyridin-2-yl}tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 889.9 | Calc'd 626.2, found 626.0 |
41 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-{2-(dimethylamino)-5-[4-fluoro-2-methoxy-5-(1-methylethyl)phenyl]pyrimidin-4-yl}tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 1138 | Calc'd 627.2, found 672.2 |
42 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-{2-(dimethylamino)-5-[4-fluoro-2-methoxy-5-(1-methylethyl)phenyl]pyridin-4-yl}tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 69.73 | Calc'd 626.2, found 626.5 |
43 |
|
(1R,5S,8aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[4'-fluoro-2'-methoxy-5'-(1-methylethyl)-4-(trifluoromethyl)biphenyl-2-yl]hexahydro[1,3]oxazolo[3,4-a]pyridin-3-one | 1208 | Calc'd 664.2, found 664.3 |
44 |
|
2"-{(1R,5S,8aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-5-yl}-6'-fluoro-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid | 717.5 | Calc'd 756.2, found 756.3 |
45 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-{2-[2-methoxy-5-(1-methylethyl)pyridin-3-yl]-5-(trifluoromethyl)phenyl}tetrahyd ro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 44.66 | Calc'd 633.2, found 633.4 |
46 |
|
3-[2'-{(1R,5S,8aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-5-yl}-4-fluoro-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]propanoic acid | 1629 | Calc'd 694.2, found 694.2 |
47 |
|
3'-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxo-5,7a-dihydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-(dimethylamino)pyridin-3-yl]-4'-methoxy-2-methylbiphenyl-4-carboxylic acid | 490.8 | Calc'd 698.2, found 698.3 |
48 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-{2-(dimethylamino)-5-[4-fluoro-2-methoxy-5-(1-methylethyl)phenyl]pyrimidin-4-yl}-5,7a-dihydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 694.7 | Calc'd 625.2, found 625.1 |
49 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-{2-(dimethylamino)-5-[4-fluoro-2-methoxy-5-(1-methylethyl)phenyl]pyridin-4-yl}-5,7a-dihydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 438.3 | Calc'd 624.2, found 624.5 |
50 |
|
2"-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxo-5,7a-dihydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6'-fluoro-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid | 47.94 | Calc'd 740.1, found 740.5 |
51 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[4'-fluoro-2'-methoxy-5'-(1-methylethyl)-4-(trifluoromethyl)biphenyl-2-yl]-5,7a-dihydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 122 | Calc'd 648.2, found 648.4 |
52 |
|
4-[6-methoxy-2'-{(1R,5S,7aS)-1-[3-methyl-5-(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4'-(trifluoromethyl)biphenyl-3-yl]cyclohexanecarboxylic acid | 260 | Calc'd 662.0, found 662.1 |
53 |
|
5'-[4-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-(trifluoromethyl)pyridin-3-yl]-2'-fluoro-4'-methoxy-2-methylbiphenyl-4-carboxylic acid | 191 | Calc'd 743.0, Found 743.5 |
54 |
|
4-[4'-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl)-2-methoxy-6'-(trifluoromethyl)-3,3'-bipyridin-5-yl]-3-methylbenzoic acid | 141 | Calc'd 726.0, Found 726.4 |
55 |
|
4-{6-methoxy-5-[2-{(1R,5S,7aS)-1-[3-methyl-5-(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4-(trifluoromethyl)phenyl]pyridin-3-yl}-3-methylbenzoic acid | 85 | Calc'd 671.0, Found 671.2 |
56 |
|
4-{5-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4-(trifluoromethyl)phenyl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoic acid | 47 | Calc'd 739.0, Found 739.4 |
57 |
|
trans-4-[2'-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]cyclohexanecarboxylic acid | 242 | Calc'd 716.0, Found 716.5 |
58 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-{5'-[(1s,3R,4S)-3,4-dihydroxycyclopentyl]-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl}tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 418 | Calc'd 690.0, Found 690.5 |
59 |
|
2"-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6'-fluoro-4'-methoxy-2,5"-dimethyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid | 120 | Calc'd 756.0, Found 756.1 |
60 |
|
4-{5-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-5-methyl-4-(trifluoromethyl)phenyl]-6-methoxypyridin-3-yl}-3-methylbenzoic acid | 106 | Calc'd 739.0, Found 739.1 |
61 |
|
2"-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4'-methoxy-2,6"-dimethyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid | 87 | Calc'd 738.0, Found 738.2 |
62 |
|
6'-fluoro-2"-{(1R,5S,7aS)-1-[3-fluoro-5-(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4'-methoxy-2-methyl-4"-(trifluoromethyl)-1,1':3',1"-terphenyl-4-carboxylic acid | 172 | Calc'd 692.0, Found 692.0 |
63 |
|
4-{5-[2-{(1R,5S,7aS)-1-[3-fluoro-5-(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4-(trifluoromethyl)phenyl]-6-methoxypyridin-3-yl}-3-methylbenzoic acid | 136 | Calc'd 675.0, Found 675.0 |
64 |
|
4-{5-[2-{(1R,5S,7aS)-1-[3-fluoro-5-(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4-(trifluoromethyl)phenyl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoic acid | 77 | Calc'd 689.0, Found 689.2 |
65 |
|
4-{5-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-methyl-4-(trifluoromethyl)phenyl]-6-methoxypyridin-3-yl}-3-methylbenzoic acid | 124 | Calc'd 739.0, Found 739.1 |
66 |
|
4-{5-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4-(trifluoromethyl)phenyl]-6-methylpyridin-3-yl}-3-methylbenzoic acid | 1292 | Calc'd 709.0, Found 709.1 |
67 |
|
4-(5-(2-((1R,5S,7aS)-1-(3,5-bis(trifluoromethyl)phenyl)-3-oxo-1,3,5,7a-tetrahydropyrrolo[1,2-c]oxazol-5-yl)-4-(trifluoromethyl)phenyl)-6-methoxypyridin-3-yl)-3-methylbenzoic acid | 199 | Calc'd 723.2, Found 723.1 |
68 |
|
3'-(3-((1R,5S,7aS)-1-(3,5-bis(trifluoromethyl)phenyl)-3-oxo-1,3,5,7a-tetrahydropyrrolo[1,2-c]oxazol-5-yl)-5-(trifluoromethyl)pyridin-2-yl)-4'-methoxy-2-methyl-[1,1'-biphenyl]-4-carboxylic acid | 424 | Calc'd 723.2, Found 723.1 |
69 |
|
4-(3-((1R,5S,7aS)-1-(3,5-bis(trifluoromethyl)phenyl)-3-oxo-1,3,5,7a-tetrahydropyrrolo[1,2-c]oxazol-5-yl)-2'-methoxy-5-(trifluoromethyl)-[2,3'-bipyridin]-5'-yl)-3-methylbenzoic acid | 456 | Calc'd 724.1, Found 724.1 |
70 |
|
4-[3-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-2'-methoxy-5-(trifluoromethyl)-2,3'-bipyridin-5'-yl]-3,5-dimethylbenzoic acid | 751 | Calc'd 740.0, Found 740.3 |
71 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[2'-methoxy-5'-(2-methyl-6-oxopiperidin-3-yl)-4-(trifluoromethyl)biphenyl-2-yl]tetrahydro-1H-pyrrolo1,2-c][1,3]oxazol-3-one | 198 | Calc'd 701.0, Found 701.1 |
72 |
|
3'-[3-{(1R,4S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-5-(trifluoromethyl)pyridin-2-yl]-4'-methoxy-2-methylbiphenyl-4-carboxylic acid | 427 | Calc'd 725.0, Found 725.2 |
73 |
|
4-[3-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-2'-methoxy-5-(trifluoromethyl)-2,3'-bipyridin-5'-yl]-3-methylbenzoic acid | 287 | Calc'd 726.0, Found 726.2 |
74 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-{5'-[(5S)-6,6-dimethyl-2-oxo-1,3-oxazinan-5-yl]-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl}tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 246 | Calc'd 717.0, Found 717.0 |
75 |
|
(1R,4S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-{2'-methoxy-5'-[(4S,5R)-4-methyl-2-oxo-1,3-oxazolidin-5-yl]-4-(trifluoromethyl)biphenyl-2-yl}tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 89 | Calc'd 689.0, Found 689.2 |
76 |
|
(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-{2'-methoxy-5'-[(2S,3S)-2-methyl-5-oxopyrrolidin-3-yl]-4-(trifluoromethyl)biphenyl-2-yl}tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 466 | Calc'd 687.0, Found 686.9 |
77 |
|
4-[2'-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-2-methoxy-6'-(trifluoromethyl)-3,3'-bipyridin-5-yl]-3,5-dimethylbenzoic acid | 561 | Calc'd 740.0, Found 740.2 |
78 |
|
4-{6-methoxy-5-[2-{(1R,5S,7aS)-3-oxo-1-[3-(trifluoromethyl)phenyl]tetrahyd ro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4-(trifluoromethyl)phenyl]pyridin-3-yl}-3-methylbenzoic acid | 864 | Calc'd 657.0, Found 657.1 |
Example 79
3'-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-(dimethylamino)-5-(propan-2-yl)pyridin-3-yl]-4'-methoxy-2-methylbiphenyl-4-carboxylic acid
(Scheme 2)
Step 1: To a slurry of (1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[3-bromo-6-(dimethylamino)pyridin-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (200 mg, 0.372 mmol) in MeOH (7.25 mL) under nitrogen at room temperature was added silver sulfate (116 mg, 0.372 mmol), followed by iodine (94 mg, 0.372 mmol). The resulting mixture was stirred for 1 hour. The reaction was partitioned with ethyl acetate and aqueous sodium hydroxide (1.0 M). The organic was then washed with aqueous saturated sodium thiosulfate and the combined aqueous layers were extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to yield (1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[3-bromo-6-(dimethylamino)-5-iodopyridin-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (180 mg, 0.271 mmol). MS ESI calc'd. for C21H18BrF6N3O2 [M +H]+666.0, found 666.1.
Step 2: To (1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[3-bromo-6-(dimethylamino)-5-iodopyridin-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (50 mg, 0.075 mmol) in DMF (1 mL) was added isopropenylboronic acid pinacol ester (13.9 mg, 0.083 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (1.84 mg, 2.26 µmol) and potassium carbonate (0.5 M in water, 0.30 mL, 0.151 mmol). The system was stirred at 50 °C overnight before cooling and partitioning with water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated before purifying by column chromatography to yield (1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[3-bromo-6-(dimethylamino)-5-(prop-1-en-2-yl)pyridin-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (19 mg, 0.033 mmol). MS ESI calc'd. for C24H23BrF6N3O2 [M + H]+ 580.1, found 580.2.
Step 3: To (1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[3-bromo-6-(dimethylamino)-5-(prop-1-en-2-yl)pyridin-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (19 mg, 0.033 mmol) in THF (0.5 mL) was added methyl 4'-methoxy-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate (18.8 mg, 0.049 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (2.14 mg, 3.29 µmol) and potassium carbonate (2.0 M in water, 0.049 mL, 0.100 mmol). The system was stirred at room temperature overnight. The reaction was directly purified by column chromatography to yield (1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[3-bromo-6-(dimethylamino)-5-(prop-1-en-2-yl)pyridin-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (24 mg, 0.033 mmol). MS ESI calc'd. for C40H38F6N3O5 [M + H]+ 754.3, found 754.4.
Step 4: To (1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[3-bromo-6-(dimethylamino)-5-(prop-1-en-2-yl)pyridin-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (24 mg, 0.033 mmol) in ethanol (5 mL) was added palladium on carbon (0.54 mg, 5.04 µmol). The system was stirred at room temperature under a hydrogen atmosphere for 2 days. The reaction was filtered and the filtrate was concentrated. Crude methyl 3'-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-(dimethylamino)-5-(propan-2-yl)pyridin-3-yl]-4'-methoxy-2-methylbiphenyl-4-carboxylate (24 mg, 0.033 mmol) was carried forward without further purification. MS ESI calc'd. for C40H40F6N3O5 [M + H]+ 756.3, found 756.4.
Step 5: To methyl 3'-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-(dimethylamino)-5-(propan-2-yl)pyridin-3-yl]-4'-methoxy-2-methylbiphenyl-4-carboxylate (24 mg, 0.033 mmol) in THF (1 mL) was added lithium hydroxide (9.51 mg, 0.397 mmol). The reaction was stirred overnight at room temperature. Reaction was incomplete. More lithium hydroxide (4.76 mg, 1.99 mmol) was added, and the reaction was heated to 50 °C for 5 hours. The reaction was purified by HPLC to yield 3'[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-(dimethylamino)-5-(propan-2-yl)pyridin-3-yl]-4'-methoxy-2-methylbiphenyl-4-carboxylic acid (10 mg, 0.012 mmol). 1H NMR indicated that this compound exists as a pair of rotamers at 1.6:1 ratio. 1H NMR (500 MHz, CDCl3) δ 7.94-8.10 (m, 2H), 7.90 (s, 1H), 7.84 (s, 2H), 7.48 (m, 2H), 7.42 (dd, J = 8.5 Hz, J = 2.0 Hz, 1H), 7.37 (d, J = 7.5 Hz, 1H, minor rotamer), 7.30 (d, 1H, merged with solvent peak, major rotamer), 7.14 (d, J = 8.5 Hz, 1H, minor rotamer),7.07 (d, J = 8.5 Hz, 1H, major rotamer), 5.98 (d, J = 8.0 Hz, 1H, minor rotamer), 5.93 (d, J = 8.0 Hz, 1H, major rotamer), 5.09 (t, J = 7.5 Hz, 1H, minor rotamer), 5.01 (t, J = 7.5 Hz, 1H, major rotamer), 4.76 (m, 1H), 3.93 (s, 3H, minor rotamer), 3.83 (s, 3H, major rotamer), 3.40 (m, 1H), 3.07 (s, 6H), 2.47 (s, 3H, major rotamer), 2.40 (s, 3H, minor rotamer), 2.35 (m, 1H), 2.05 (m, 1H), 1.60 (m, 1H), 1.29 (t, J = 6.5 Hz, 6H), 1.08 (m, 1H). MS ESI calc'd. for C39H38F6N3O5 [M + H]+ 742.3, found 742.5. RTA (95% HS): 182 nM
Example 80
(1R,5S,8aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-{2'-methoxy-5'-[2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl]-4-(trifluoromethyl)biphenyl-2-yl}hexahydro[1,3]oxazolo[3,4-a]pyridin-3-one (Scheme 3)
Step 1: To methyl 3-[2'-{(1R,5S,8aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-5-yl}-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]propanoate (30 mg, 0.044 mmol) was added ethanol (2 mL) followed by hydrazine hydrate (21.8 mg, 0.435 mmol). The mixture was heated for 150 °C by microwave irradiation for an hour. The crude reaction was concentrated and 3-[2'-{(1R,5S,8aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-5-yl}-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]propanehydrazide (27 mg, 0.039 mmol) was carried forward without further purification. MS ESI calc'd. for C32H29F9N3O4 [M + H]+ 690.2, found 690.2.
Step 2: To 3-[2'-{(1R,5S,8aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxohexahydro [1,3]oxazolo[3,4-a]pyridin-5-yl}-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]propanehydrazide (10 mg, 0.015 mmol) in DCM (2 mL) was added DIPEA (5.6 mg, 0.044 mmol) and phosgene (4.30 mg, 0.44 mmol). The reaction was stirred at room temperature for 30 minutes before the reaction was directly purified by column chromatography to yield (1R,5S,8aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-{2'-methoxy-5'-[2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl]-4-(trifluoromethyl)biphenyl-2-yl}hexahydro[1,3]oxazolo[3,4-a]pyridin-3-one (5 mg, 6.99 µmol). 1H NMR indicated that this compound exists as a pair of rotamers at 3:1 ratio: 1H NMR (500 MHz, CDCl3) δ 9.23 (s, 1H), 7.88 (s, 1H), 7.80 (s, 2H), 7.79 (s, 1H, minor rotamer), 7.65 (s, 2H, major rotamer) 7.62 (m, 1H) 7.4 (d, J = 7.8 Hz, 1 H, major rotamer), 7.25 (d, J = 7.8 Hz, 1H, minor rotamer), 7.09 (s, 1H), 7.02 (m, 2H), 5.58 (m, 1H, minor rotamer) 5.42 (m, 1H, major rotamer), 4.19 (m, 1H), 3.85 (s, 3H, minor rotamer), 3.80 (s, 3H, major rotamer), 3.0-2.85 (m, 4H), 1.98 (m, 2H), 1.5-1.6 (m, 4H). MS ESI calc'd. for C33H27F9N3O5 [M + H]+ 716.2, found 716.3. RTA (95% HS): 942 nM
Ex | Structure | IUPAC Name | IC50(nM) | Exact Mass [M+H]+ |
81 |
|
(1R,5S,7aS)-5-[4'-fluoro-6'-methoxy-2"-methyl-4"-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)-1,1':3',"-terphenyl-2-yl]-1-[3-methyl-5-(trifluoromethyl)phenyl]tetrahy dro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 167.6 | Calc'd 728.2, found 728.3 |
Example 82
(1R,5S,8aS)-5-{5'-[2-(5-amino-1,3,4-oxadiazol-2-yl)ethyl]-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl}-1-[3,5-bis(trifluoromethyl)phenyl]hexahydro[1,3]oxazolo[3,4-a]pyridin-3-one (Scheme 3)
Ex | Structure | IUPAC Name | IC50(nM) | Exact Mass [M+H]+ |
83 |
|
(1R,5S,7aS)-5-[4"-(5-amino-1,3,4-oxadiazol-2-yl)-4'-fluoro-6'-methoxy-2"-methyl-4-(trifluoromethyl)-1,1':3',1"-terphenyl-2-yl]-1-[3-methyl-5-(trifluoromethyl)phenyl]tetrahy dro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | 95.01 | Calc'd 727.2, found 727.3 |
wherein R1 is H, -C1-C5 alkyl, -OC1-C5 alkyl, -C2-C5 alkenyl, -OC2-C5 alkenyl,-C2-C5 alkynyl, -OC2-C5 alkynyl, -OH, halogen, -CN, -NR6R7, -CO2R8, -C(O)NR6R7, -SO2NR6R7, HET(3), or C3-6 cycloalkyl optionally having 1-2 double bonds, wherein -C1-C5 alkyl, -OC1-C5 alkyl, -C2-C5 alkenyl, -OC2-C5 alkenyl, -C2-C5 alkynyl, and -OC2-C5 alkynyl are each optionally substituted with 1-7 halogens, and wherein HET(3) and C3-6 cycloalkyl optionally having 1-2 double bonds are optionally substituted with 1-3 substituent groups which are each independently halogen, -C1-C3 alkyl, -OC1-C3 alkyl, -C2-C3 alkenyl, -OC2-C3 alkenyl,-C2-C3 alkynyl, or -OC2-C3 alkynyl, wherein -C1-C3 alkyl, -OC1-C3 alkyl, -C2-C3 alkenyl, -OC2-C3 alkenyl, -C2-C3alkynyl, and -OC2-C3 alkynyl are each optionally substituted with 1-7 halogens;
R6 and R7 are each independently H or -C1-C5 alkyl;
R8 is H or -C1-5alkyl optionally substituted with 1-7 halogens;
HET(3) is a 3-6 membered heterocyclic ring having 1-3 heteroatom groups which are each independently N, NH, O, S, S(O), or S(O)2 and optionally having 1-3 double bonds;
x is 0 or 1;
The dashed lines in Formula I represent one optional double bond between 2 adjacent carbon atoms;
D1 is N or CR2;
D2 is N or CR3;
D3 is N or CR4;
R2, R3, and R4 are each independently H, -C1-C5 alkyl, -OC1-C5 alkyl, -C2-C5 alkenyl, -OC2-C5 alkenyl, -C2-C5 alkynyl, -OC2-C5 alkynyl, -OH, halogen, -CN, -NR6R7, -CO2R8, -C(O)NR6R7, or -SO2NR6R7, wherein -C1-C5 alkyl, -OC1-C5 alkyl, -C2-C5 alkenyl,-OC2-C5 alkenyl, -C2-C5 alkynyl, and -OC2-C5 alkynyl are optionally substituted with 1-7 halogens;
Each R5 is independently -C1-C5 alkyl, -OC1-C5 alkyl, -C2-C5 alkenyl, -OC2-C5 alkenyl, -C2-C5 alkynyl, -OC2-C5 alkynyl, -OH, halogen, -CN, -NR6R7, -CO2R8, -C(O)NR6R7, or -SO2NR6R7, wherein -C1-C5 alkyl, -OC1-C5 alkyl, -C2-C5 alkenyl, -OC2-C5 alkenyl, -C2-C5 alkynyl, and -OC2-C5 alkynyl are optionally substituted with 1-7 halogens;
A1 is phenyl, HET(1), or C3-C8 cycloalkyl optionally having 1-2 double bonds, wherein A1 is optionally substituted with one substituent group Z and is optionally substituted with 1-3 groups which are each independently -C1-C5 alkyl, -OC1-C5 alkyl, -C2-C5 alkenyl, -OC2-C5 alkenyl, -C2-C5 alkynyl, -OC2-C5 alkynyl, halogen, -OH, or -CN, wherein -C1-C5 alkyl, -OC1-C5 alkyl, -C2-C5 alkenyl, -OC2-C5 alkenyl, -C2-C5 alkynyl, and -OC2-C5 alkynyl are optionally substituted with 1-7 halogens;
Each HET(1) is a 5- or 6-membered heterocyclic ring having 1-4 heteroatom groups which are each independently -N-, -NH-, -S-, -O-, -S(O)-, or -S(O)2-, optionally having one group -C(=O)-, and optionally having 1-3 double bonds;
Z is A3, -C1-C3alkylene-CO2R8, -C1-C3alkylene-C(O)NR6R7, -C1-C3alkylene-SO2NR6R7, -CO2R8, -C(O)NR6R7, -SO2NR6R7, or -C1-C3alkylene-HET(2), wherein -C1-C3alkylene in all uses is optionally substituted with 1-7 halogens, and HET(2) is optionally substituted with 1-3 substituents which are independently -C1-3alkyl optionally substituted with 1-5 halogens, -OC1-3alkyl optionally substituted with 1-5 halogens, halogen or NR6R7;
A3 is phenyl, C3-C6 cycloalkyl optionally having 1-2 double bonds, or HET(1), wherein A3 is optionally substituted with 1-3 groups which are each independently -C1-C5 alkyl, - OC1-C5 alkyl, -C2-C5 alkenyl, -OC2-C5 alkenyl, -C2-C5 alkynyl, -OC2-C5 alkynyl, halogen, -OH, or -CN, wherein -C1-C5 alkyl, -OC1-C5 alkyl, -C2-C5 alkenyl, -OC2-C5 alkenyl, -C2-C5 alkynyl, and -OC2-C5 alkynyl are optionally substituted with 1-7 halogens; and A3 is optionally substituted with one group which is HET(2), -C1-4 alkylene-CO2R8, -C1-4alkylene-C(O)NR6R7, -C1-C4alkylene-SO2NR6R7, -CO2R8, -C(O)NR6R7, or -SO2NR6R7, wherein -C1-C4alkylene in all uses is optionally substituted with 1-7 halogens; and wherein HET(2) is optionally substituted with 1-3 groups which are each independently halogen, -C1-5alkyl optionally substituted with 1-7 halogens, -OC1-5alkyl optionally substituted with 1-7 halogens, or NR6R7;
HET(2) is a 5-6 membered heterocyclic ring having 1-3 heteroatom groups which are each independently N, NH, O, or S, optionally having one group -C(=O)-, and optionally having 1-3 double bonds;
A2 is phenyl or HET(1), wherein A2 is optionally substituted with 1-3 substituent groups which are each independently -C1-C5 alkyl, -OC1-C5 alkyl, -C2-C5 alkenyl, -OC2-C5 alkenyl, -C2-C5alkynyl, -OC2-C5alkynyl, halogen, -CN, -OH, or C3-6cycloalkyl, wherein -C1-C5 alkyl, -OC1-C5 alkyl, -C2-C5 alkenyl, -OC2-C5 alkenyl, -C2-C5alkynyl, and -OC2-C5alkynyl are optionally substituted with 1-7 halogens, and C3-6cycloalkyl is optionally substituted with 1-3 substituents which are each independently halogen, -C1-C3 alkyl, or -OC1-C3 alkyl, wherein-C1-C3 alkyl and-OC1-C3 alkyl are each optionally substituted with 1-7 halogens; and
a is 0 or an integer from 1-3.
wherein R1 is -C1-C5 alkyl, -OC1-C5 alkyl, halogen, -NR6R7, HET(3), or C3-6 cycloalkyl optionally having 1-2 double bonds, wherein -C1-C5 alkyl and -OC1-C5 alkyl are optionally substituted with 1-7 halogens, and wherein HET(3) and C3-6 cycloalkyl optionally having 1-2 double bonds are optionally substituted with 1-3 substituent groups which are each independently halogen, CH3, CF3, OCH3, or OCF3;
At least one of D1, D2, or D3 is CR2, CR3, or CR4;
R2, R3, and R4 are each independently H, -C1-C5 alkyl, -OC1-C5 alkyl, or halogen, wherein -C1-C5 alkyl and -OC1-C5 alkyl are optionally substituted with 1-7 halogens;
Each R5 is independently -C1-C5 alkyl, -OC1-C5 alkyl, or halogen, wherein -C1-C5 alkyl and -OC1-C5 alkyl are optionally substituted with 1-7 halogens;
A1 is phenyl, HET(1), or C3-C6 cycloalkyl optionally having 1-2 double bonds, wherein A1 is optionally substituted with one substituent group Z and is optionally substituted with 1-3 groups which are each independently halogen, -OH, -CN, -C1-5alkyl optionally substituted with 1-7 halogens, or -OC1-5alkyl optionally substituted with 1-7 halogens;
A3 is phenyl, C3-C6 cycloalkyl optionally having 1-2 double bonds, or HET(1), wherein A3 is optionally substituted with 1-3 groups which are each independently -C1-C5 alkyl optionally substituted with 1-7 halogens, -OC1-C5 alkyl optionally substituted with 1-7 halogens, -OH, or halogen, and is optionally substituted with one group which is HET(2), -C1-2 alkylene-CO2R8, -C1-2alkylene-C(O)NR6R7, -C1-C2alkylene-SO2NR6R7, -CO2R8, -C(O)NR6R7, or -SO2NR6R7, wherein -C1-C2alkylene is optionally substituted with 1-3 halogens; and wherein HET(2) is optionally substituted with 1-3 groups which are each independently halogen, -C1-5alkyl optionally substituted with 1-7 halogens, -OC1-5alkyl optionally substituted with 1-7 halogens, or NR6R7; and
A2 is phenyl or HET(1), wherein A2 is optionally substituted with 1-3 substituent groups which are each independently C1-5alkyl optionally subsituted with 1-7 halogens. -OC1-5alkyl optionally substituted with 1-7 halogens, halogen, -OH, -CN, or C3-6cycloalkyl optionally substituted with 1-3 substituents which are each independently halogen, CF3, CH3, -OCF3, or -OCH3.
wherein R1 is CH3, CF3, -OCH3, -OCF3, halogen, or -NR6R7;
R6 and R7 are each independently H or -C1-C3 alkyl;
R2, R3, and R4 are each independently H, C1-3alkyl, CF3, -OC1-3alkyl, -OCF3, or halogen;
Each R5 is independently CH3, CF3, -OCH3, -OCF3, or halogen;
A1 is phenyl, HET(1), or C3-C6 cycloalkyl optionally having 1-2 double bonds, wherein A1 is optionally substituted with one substituent group Z and is optionally substituted with 1-3 groups which are each independently -C1-3alkyl optionally substituted with 1-5 halogens, -OC1-3alkyl optionally substituted with 1-5 halogens, halogen, -OH, or -CN;
Each HET(1) is a 5- or 6-membered heterocyclic ring having 1-3 heteroatom groups which are each independently -N-, -NH-, -S-, or -O-, optionally having one group -C(=O)-, and optionally having 1-3 double bonds;
Z is A3, -(CH2)1-3-CO2R8, -(CH2)1-3-C(O)NR6R7, -(CH2)1-3-SO2NR6R7, -CO2R8, -C(O)NR6R7, -SO2NR6R7, or -(CH2)1-3-HET(2), wherein HET(2) is optionally substituted with 1-3 substituents which are independently -C1-3alkyl optionally substituted with 1-5 halogens, -OC1-3alkyl optionally substituted with 1-5 halogens, halogen or NR6R7;
R8 is H or -C1-3alkyl optionally substituted with 1-3 halogens;
A3 is phenyl, C3-C6 cycloalkyl optionally having 1-2 double bonds, or HET(1), wherein A3 is optionally substituted with 1-3 groups which are each independently CH3, CF3, -OCH3, -OCF3, -OH, or halogen, and is optionally substituted with one group which is HET(2), -(CH2)1-2-CO2R8, -(CH2)1-2-C(O)NR6R7, -(CH2)1-2-SO2NR6R7, -CO2R8, -C(O)NR6R7, or -SO2NR6R7, and HET(2) is optionally substituted with 1-3 groups which are each independently CH3, CF3, -OCH3, -OCF3, halogen, or NR6R7;
A2 is phenyl or HET(1), wherein A2 is substituted with 1-3 substituent groups which are each independently CH3, CF3, -OCH3, -OCF3, halogen, -CN, -OH, or C3-4cycloalkyl optionally substituted with 1-3 substituents which are each independently halogen, CF3, CH3, -OCF3, or -OCH3; and
a is 0, 1, or 2.
wherein R1 is CH3, CF3, -OCH3, -OCF3, F, Cl, or -NR6R7;
D1 is N or CR2, wherein R2 is H, -C1-3alkyl, F, or Cl;
D2 is N or CR3, wherein R3 is H, -C1-3alkyl, F, or Cl;
D3 is N or CR4, wherein R4 is H, -C1-3alkyl, F, or Cl;
At least one of D1, D2, or D3 is CR2, CR3, or CR4;
R5 is H or CH3;
A1 is phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, oxazolyl, pyrrolyl, thienyl, furyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, cyclopentyl, or cyclopentenyl, wherein A1 is optionally substituted with 1-3 groups which are each independently F, Cl, -OCH3, -OCF3, -C1-3alkyl, -CN, or CF3, and optionally one substituent group Z;
Z is A3, -CH2CH2CO2R8, -CH2CH2C(O)NR6R7, -CH2CH2SO2NR6R7, or -CH2CH2-HET(2), wherein HET(2) is optionally substituted with 1-2 substituent groups which are each independently CH3, CF3, -OCH3,-OCF3, halogen, or NR6R7;
R8 is H or -CH3;
HET(2) is a 5-membered heterocyclic ring having 1-3 heteroatom groups which are each independently N, NH, O, or S, optionally having one group -C(=O), and optionally having 1-3 double bonds;
A3 is phenyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, or HET(1), wherein HET(1) is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, oxazolyl, pyrrolyl, thienyl, furyl, or a 5-6-membered heterocyclic ring having 1-2 heteroatom groups which are independently -N-, -NH- or -O-, and optionally one -C(=O)- group, wherein A3 is optionally substituted with 1-2 groups which are each independently CH3, CF3, -OCH3, -OCF3, -OH, or halogen, and is optionally substituted with 1 group which is -CO2R8, -C(O)NR6R7, -SO2NR6R7, or HET(2), wherein HET(2) is optionally substituted with 1-2 substituent groups which are each independently CH3, CF3, -OCH3; -OCF3, halogen, or NR6R7;
A2 is phenyl or HET(1) wherein A2 is substituted with 1-3 substituent groups which are each independently CF3, CH3, F, Cl, -CN, or cyclopropyl; and
a is 0 or 1.
wherein the dashed line in the ring in Formula Ia is an optional double bond when x is 0;
wherein R1 is CF3, F, or -N(CH3)2;
D1 is N or CR2, wherein R2 is H or C1-3alkyl;
D2 is N or CR3, wherein R3 is H or CH3;
D3 is N or CR4, wherein R4 is H or CH3;
A1 is phenyl, pyridyl, thienyl, furyl, cyclohexenyl, or cyclopentenyl, wherein A1 is optionally substituted with 1-3 groups which are each independently F, Cl, -OCH3, isopropyl, -CN, -CH3, or CF3, and optionally one substituent group Z;
Z is A3, -CH2CH2CO2R8, -CH2CH2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl), or -CH2CH2-(5-amino-1,3,4-oxadiazol-2-yl);
R8 is H or -CH3;
A3 is phenyl, cyclobutyl, cyclopentyl, cyclohexyl, or HET(1), wherein HET(1) is pyridinyl, 6-oxopiperidinyl, 2-oxo-1,3-oxazolidinyl, 2-oxo-1,3-oxazinanyl, or 5-oxopyrrolidinyl, wherein A3 is optionally substituted with 1-2 groups -CH3, -OCH3, or -OH, and is optionally substituted with 1 group -(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl), -(5-amino-1,3,4-oxadiazol-2-yl), or -CO2R8;
A2 is phenyl, which is substituted with 1-2 substituent groups which are each independently CF3, CH3, F, or Cl; and
a is 0.
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or Ex. 64 |
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or Ex. 64 |
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wobei R1 H, -C1-C5-Alkyl, -OC1-C5-Alkyl, -C2-C5-Alkenyl, -OC2-C5-Alkenyl, -C2-C5-Alkinyl, -OC2-C5-Alkinyl, -OH, Halogen, -CN, -NR6R7, -CO2R8, -C(O)NR6R7, -SO2NR6R7, HET(3) oder C3-6-Cycloalkyl, das gegebenenfalls 1-2 Doppelbindungen besitzt, ist, wobei -C1-C5-Alkyl, -OC1-C5-Alkyl, -C2-C5-Alkenyl, -OC2-C5-Alkinyl, -C2-C5-Alkinyl und -OC2-C5-Alkinyl jeweils gegebenenfalls mit 1-7 Halogenen substituiert sind, und wobei HET(3) und C3-6-Cycloalkyl, das gegebenenfalls 1-2 Doppelbindungen besitzt, gegebenenfalls substituiert sind mit 1-3 Substituentengruppen, die jeweils unabhängig Halogen, -C1-C3-Alkyl, -OC1-C3-Alkyl, -C2-C3-Alkenyl, -OC2-C3-Alkenyl, -C2-C3-Alkinyl oder -OC2-C3-Alkinyl sind, wobei -C1-C3-Alkyl, -OC1-C3-Alkyl, -C2-C3-Alkenyl, -OC2-C3-Alkenyl, -C2-C3-Alkinyl und -OC2-C3-Alkinyl jeweils gegebenenfalls substituiert sind mit 1-7 Halogenen,
R6 und R7 jeweils unabhängig H oder -C1-C5-Alkyl sind,
R8 H oder -C1-5-Alkyl, das gegebenenfalls mit 1-7 Halogenen substituiert ist, ist,
HET (3) ein 3-6-gliedriger heterocyclischer Ring mit 1-3 Heteroatomgruppen, die jeweils unabhängig N, NH, O, S, S(O) oder S(O)2 sind, und gegebenenfalls mit 1-3 Doppelbindungen ist,
x 0 oder 1 ist,
die gestrichelten Linien in Formel I eine optionale Doppelbindung zwischen 2 benachbarten Kohlenstoffatomen bedeuten,
D1 N oder CR2 ist,
D2 N oder CR3 ist,
D3 N oder CR4 ist,
R2, R3 und R4 jeweils unabhängig H, -C1-C5-Alkyl, -OC1-C5-Alkyl, -C2-C5-Alkenyl, -OC2-C5-Alkenyl, -C2-C5-Alkinyl, -OC2-C5-Alkinyl, -OH, Halogen, -CN, -NR6R7, -CO2R8, -C(O)NR6R7 oder -SO2NR6R7 sind, wobei -C1-C5-Alkyl, -OC1-C5-Alkyl, -C2-C5-Alkenyl, -OC2-C5-Alkenyl, -C2-C5-Alkinyl und -OC2-C5-Alkinyl gegebenenfalls mit 1-7 Halogenen substituiert sind,
jedes R5 unabhängig -C1-C5-Alkyl, -OC1-C5-Alkyl, -C2-C5-Alkenyl, -OC2-C5-Alkenyl, -C2-C5-Alkinyl, -OC2-C5-Alkinyl, -OH, Halogen, -CN, -NR6R7, -CO2R8, -C(O)NR6R7 oder -SO2NR6R7 ist, wobei -C1-C5-alkyl, -OC1-C5-Alkyl, -C2-C5-Alkenyl, -OC2-C5-Alkenyl, -C2-C5-Alkinyl und -OC2-C5-Alkinyl gegebenenfalls substituiert sind mit 1-7 Halogenen,
A1 Phenyl, HET(1) oder C3-C8-Cycloalkyl, das gegebenenfalls 1-2 Doppelbindungen besitzt, ist, wobei A1 gegebenenfalls substituiert ist mit einer Substituentengruppe Z und gegebenenfalls substituiert ist mit 1-3 Gruppen, die jeweils unabhängig -C1-C5-Alkyl, -OC1-C5-Alkyl, -C2-C5-Alkenyl, -OC2-C5-Alkenyl, -C2-C5-Alkinyl, -OC2-C5-Alkinyl, Halogen, -OH oder -CN sind, wobei -C1-C5-Alkyl, -OC1-C5-Alkyl, -C2-C5-Alkenyl, -OC2-C5-Alkenyl, -C2-C5-Alkinyl und -OC2-C5-Alkinyl gegebenenfalls mit 1-7 Halogenen substituiert sind,
jedes HET(1) ein 5- oder 6-gliedriger heterocyclischer Ring ist mit 1-4 Heteroatomgruppen, die unabhängig -N-, -NH-, -S-, -O-, -S(O)- oder -S(O)2- sind, gegebenenfalls mit einer Gruppe -C(=O)- und gegebenenfalls mit 1-3 Doppelbindungen,
Z A3, -C1-C3-Alkylen-CO2R8, -C1-C3-Alkylen-C(O)NR6R7, -C1-C3-Alkylen-SP2NR6R7, -CO2R8, -C(O)NR6R7, -SO2NR6R7 oder-C1-C3-Alkylen-HET(2) ist, wobei -C1-C3-Alkylen bei allen Verwendungen gegebenenfalls mit 1-7 Halogenen substituiert ist und HET(2) gegebenenfalls substituiert ist mit 1-3 Substituenten, die unabhängig -C1-3-Alkyl, gegebenenfalls substituiert mit 1-5 Halogenen, -OC1-3-Alkyl, gegebenenfalls substituiert mit 1-5 Halogenen, Halogen oder NR6R7 sind,
A3 Phenyl, C3-C6-Cycloalkyl, das gegebenenfalls 1-2 Doppelbindungen besitzt, oder HET(1) ist, wobei A3 gegebenenfalls substituiert ist mit 1-3 Gruppen, die jeweils unabhängig -C1-C5-Alkyl, -OC1-C5-Alkyl, -C2-C5-Alkenyl, -OC2-C5-Alkenyl, -C2-C5-Alkinyl, -OC2-C5-Alkinyl, Halogen, -OH oder -CN sind, wobei -C1-C5-Alkyl, -OC1-C5-Alkyl, -C2-C5-Alkenyl, -OC2-C5-Alkenyl, -C2-C5-Alkinyl und -OC2-C5-Alkinyl gegebenenfalls mit 1-7 Halogenen substituiert sind, und wobei A3 gegebenenfalls substituiert ist mit einer Gruppe, die HET(2), -C1-4-Alkylen-CO2R8, -C1-4-Alkylen-C(O)NR6R7, -C1-C4-Alkylen-SO2NR6R7, -CO2R8, -C(P)NR6R7 oder -SO2NR6R7 ist, wobei -C1-C4-Alkylen bei allen Verwendungen gegebenenfalls mit 1-7 Halogenen substituiert ist, und wobei HET(2) gegebenenfalls substituiert ist mit 1-3 Gruppen, die jeweils unabhängig Halogen, -C1-5-Alkyl, das gegebenenfalls mit 1-7 Halogenen substituiert ist, -OC1-5-Alkyl, das gegebenenfalls mit 1-7 Halogenen substituiert ist, oder NR6R7 ist,
HET(2) ein 5-6-gliedriger heterocyclischer Ring ist mit 1-3 Heteroatomgruppen, die unabhängig N, NH, O oder S sind, gegebenenfalls mit einer Gruppe -C(=O)- und gegebenenfalls mit 1-3 Doppelbindungen,
A2 Phenyl oder HET(1) ist, wobei A2 gegebenenfalls substituiert ist mit 1-3 Substituentengruppen, die jeweils unabhängig -C1-C5-Alkyl, -OC1-C5-Alkyl, -C2-C5-Alkenyl, -OC2-C5-Alkenyl, -C2-C5-Alkinyl, -OC2-C5-Alkinyl, Halogen, -CN, -OH oder C3-6-Cycloalkyl sind, wobei -C1-C5-Alkyl, -OC1-C5-Alkyl, -C2-C5-Alkenyl, -OC2-C5-Alkenyl, -C2-C5-Alkinyl und -OC2-C5-Alkinyl gegebenenfalls mit 1-7 Halogenen substituiert sind und C3-6-Cycloalkyl gegebenenfalls substituiert ist mit 1-3 Substituenten, die jeweils unabhängig Halogen, -C1-C3-Alkyl oder -OC1-C3-Alkyl sind, wobei -C1-C3-Alkyl und -OC1-C3-Alkyl jeweils gegebenenfalls mit 1-7 Halogenen substituiert sind, und
a 0 oder eine ganze Zahl von 1-3 ist.
wobei R1 CH3, CF3, -OCH3, -OCF3, Halogen oder -NR6R7 ist,
R6 und R7 jeweils unabhängig H oder -C1-C3-Alkyl sind, R2, R3 und R4 jeweils unabhängig H, C1-3-Alkyl, CF3, -OC1-3-Alkyl, -OCF3 oder Halogen sind,
jedes R5 unabhängig CH3, CF3, -OCH3, -OCF3 oder Halogen ist,
A1 Phenyl, HET(1) oder C3-C6-Cycloalkyl, das gegebenenfalls 1-2 Doppelbindungen besitzt, ist, wobei A1 gegebenenfalls substituiert ist mit einer Substituentengruppe Z und gegebenenfalls substituiert ist mit 1-3 Gruppen, die jeweils unabhängig -C1-3-Alkyl, das gegebenenfalls mit 1-5 Halogenen substituiert ist, -OC1-3-Alkyl, das gegebenenfalls mit 1-5 Halogenen substituiert ist, Halogen, -OH oder -CN sind,
jedes HET(1) ein 5- oder 6-gliedriger heterocyclischer Ring ist mit 1-3 Heteroatomgruppen, die jeweils unabhängig -N-, -NH-, -S- oder -O- sind, gegebenenfalls mit einer Gruppe -C(=O)- und gegebenenfalls mit 1-3 Doppelbindungen,
Z A3, -(CH2)1-3-CO2R8, -(CH2)1-3-C(O)NR6R7, -(CH2)1-3-SO2NR6R7, -CO2R8, -C(O)NR6R7, -SO2NR6R7 oder -(CH2)1-3-HET(2) ist, wobei HET(2) gegebenenfalls substituiert ist mit 1-3 Substituenten, die unabhängig -C1-3-Alkyl, das gegebenenfalls mit 1-5 Halogenen substituiert ist, -OC1-3-Alkyl, das gegebenenfalls mit 1-5 Halogenen substituiert ist, Halogen oder NR6R7 sind,
R8 H oder -C1-3-Alkyl, das gegebenenfalls mit 1-3 Halogenen substituiert ist, ist,
A3 Phenyl, C3-C6-Cycloalkyl, das gegebenenfalls 1-2 Doppelbindungen besitzt, oder HET(1) ist, wobei A3 gegebenenfalls substituiert ist mit 1-3 Gruppen, die jeweils unabhängig CH3, CF3, -OCH3, -OCF3, -OH oder Halogen sind, und gegebenenfalls substituiert ist mit einer Gruppe, die HET(2), -(CH2)1-2-CO2R8, -(CH2)1-2-C(O)NR6R7, -(CH2)1-2-SO2NR6R7, -CO2R8, -C(O)NR6R7 oder -SO2NR6R7 ist, und HET(2) gegebenenfalls substituiert ist mit 1-3 Gruppen, die jeweils unabhängig CH3, CF3, -OCH3, -OCF3, Halogen oder NR6R7 sind,
A2 Phenyl oder HET(1) ist, wobei A2 substituiert ist
mit 1-3 Substituentengruppen, die jeweils unabhängig CH3, CF3, -OCH3, -OCF3, Halogen, -CN, -OH oder C3-4-Cycloalkyl, das gegebenenfalls substituiert ist mit 1-3 Substituenten, die jeweils unabhängig Halogen, CF3, CH3, -OCF3 oder -OCH3 sind, sind, und
a 0, 1 oder 2 ist.
wobei R1 CH3, CF3, -OCH3, -OCF3, F, Cl oder-NR6R7 ist,
D1 N oder CR2 ist, wobei R2 H, -C1-3-Alkyl, F oder Cl ist,
D2 N oder CR3 ist, wobei R3 H, -C1-3-Alkyl, F oder Cl ist,
D3 N oder CR4 ist, wobei R4 H, -C1-3-Alkyl, F oder Cl ist,
wenigstens eines von D1, D2 oder D3 CR2, CR3 oder CR4 ist,
R5 H oder CH3 ist,
A1 Phenyl, Pyridyl, Pyrazinyl, Pyrimidinyl, Pyridazinyl, Pyrazolyl, Imidazolyl, Isoxazolyl, Thiazolyl, Oxadiazolyl, Thiadiazolyl, Oxazolyl, Pyrrolyl, Thienyl, Furyl, Cyclopropyl, Cyclobutyl, Cyclohexyl, Cyclohexenyl, Cyclopentyl oder Cyclopentenyl ist, wobei A1 gegebenenfalls substituiert ist mit 1-3 Gruppen, die jeweils unabhängig F, Cl, -OCH3, -OCF3, -C1-3-Alkyl, -CN oder CF3 sind, und gegebenenfalls einer Substituentengruppe Z,
Z A3, -CH2CH2CO2R8, -CH2CH2C(O)NR6R7, -CH2CH2SO2NR6R7 oder -CH2CH2-HET(2) ist, wobei HET(2) gegebenenfalls substituiert ist mit 1-2 Substituentengruppen, die jeweils unabhängig CH3, CF3, -OCH3, -OCF3, Halogen oder NR6R7 sind,
R8 H oder -CH3 ist,
HET(2) ein 5-gliedriger heterocyclischer Ring ist mit 1-3 Heteroatomgruppen, die jeweils unabhängig N, NH, O oder S sind, gegebenenfalls mit einer Gruppe -C(=O)- und gegebenenfalls mit 1-3 Doppelbindungen,
A3 Phenyl, Cyclopropyl, Cyclobutyl, Cyclohexyl, Cyclohexenyl, Cyclopentyl, Cyclopentenyl oder HET(1) ist, wobei HET(1) Pyridinyl, Pyrazinyl, Pyrimidinyl, Pyridazinyl, Pyrazolyl, Imidazolyl, Isoxazolyl, Thiazolyl, Oxadiazolyl, Thiadiazolyl, Oxazolyl, Pyrrolyl, Thienyl, Furyl oder ein 5-6-gliedriger heterocyclischer Ring mit 1-2 Heteroatomgruppen, die unabhängig -N-, -NH- oder -O- sind, und gegebenenfalls einer -(=O)-Gruppe, ist, wobei A3 gegebenenfalls substituiert ist mit 1-2 Gruppen, die unabhängig CH3, CF3, -OCH3, -OCF3, -OH oder Halogen sind, und gegebenenfalls substituiert ist mit 1 Gruppe, die -CO2R8, -C(O)NR6R7, -SO2NR6R7 oder HET(2) ist, wobei HET(2) gegebenenfalls substituiert ist mit 1-2 Substituentengruppen, die jeweils unabhängig CH3, CF3, -OCH3, -OCF3, Halogen oder NR6R7 sind,
A2 Phenyl oder HET(1) ist, wobei A2 substituiert ist mit 1-3 Substituentengruppen, die jeweils unabhängig CF3, CH3, F, Cl, -CN oder Cyclopropyl sind, und
a 0 oder 1 ist.
wobei die gestrichelte Linie im Ring der Formel la eine optionale Doppelbindung ist, wenn x 0 ist,
wobei R1 CF3, F oder -N(CH3)2 ist,
D1 N oder CR2 ist, wobei R2 H oder C1-3-Alkyl ist,
D2 N oder CR3 ist, wobei R3 H oder CH3 ist,
D3 N oder CR4 ist, wobei R4 H oder CH3 ist,
A1 Phenyl, Pyridyl, Thienyl, Furyl, Cyclohexenyl oder Cyclopentenyl ist, wobei A1 gegebenenfalls substituiert ist mit 1-3 Gruppen, die jeweils unabhängig F, Cl, -OCH3, Isopropyl, -CN, -CH3 oder CF3 sind, und gegebenenfalls einer Substituentengruppe Z,
Z A3, -CH2CH2CO2R8, -CH2CH2-(5-Oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) oder -CH2CH2-(5-Amino-1,3,4-oxadiazol-2-yl) ist,
R8 H oder -CH3 ist,
A3 Phenyl, Cyclobutyl, Cyclopentyl, Cyclohexyl oder HET(1) ist, wobei HET(1) Pyridinyl, 6-Oxopiperidinyl, 2-Oxo-1,3-oxazolidinyl, 2-Oxo-1,3-oxazinanyl oder 5-Oxopyrrolidinyl ist, wobei A3 gegebenenfalls substituiert ist mit 1-2 Gruppen -CH3, -OCH3 oder -OH, und gegebenenfalls substituiert ist mit 1 Gruppe -(5-Oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl), -(5-Amino-1,3,4-oxadiazol-2-yl) oder-CO2R8,
A2 Phenyl ist, das substituiert ist mit 1-2 Substituentengruppen, die jeweils unabhängig CF3, CH3, F oder Cl sind, und
a 0 ist.
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dans lequel R1 est H, -alkyle C1-C5, -Oalkyle C1-C5, -alcényle C2-C5, -Oalcényle C2-C5, -alcynyle C2-C5, -Oalcynyle C2-C5, -OH, halogène, -CN, -NR6R7, -CO2R8, - C(O)NR6R7, -SO2NR6R7, HET(3) ou cycloalkyle C3-6 ayant optionnellement 1-2 doubles liaisons, où l'-alkyle C1-C5, -Oalkyle C1-C5, -alcényle C2-C5, -Oalcényle C2-C5, -alcynyle C2-C5 et -Oalcynyle C2-C5 sont chacun optionnellement substitués par 1-7 halogènes, et où HET(3) et le cycloalkyle C3-6 ayant optionnellement 1-2 doubles liaisons sont optionnellement substitués par 1-3 groupes substituants qui sont chacun indépendamment un halogène, -alkyle C1-C3, -Oalkyle C1-C3, -alcényle C2-C3, -Oalcényle C2-C3, -alcynyle C2-C3 ou -Oalcynyle C2-C3, où l'-alkyle C1-C3, -Oalkyle C1-C3, -alcényle C2-C3, - Oalcényle C2-C3, -alcynyle C2-C3 et -Oalcynyle C2-C3 sont chacun optionnellement substitués par 1-7 halogènes;
R6 et R7 sont chacun indépendamment H ou bien -alkyle C1-C5;
R8 est H ou -alkyle C1-5 optionnellement substitué par 1-7 halogènes;
HET(3) est un cycle hétérocyclique à 3-6 chaînons ayant 1-3 groupes d'hétéroatomes qui sont chacun indépendamment N, NH, O, S, S(O), ou S(O)2 et ayant optionnellement 1-3 doubles liaisons;
x est 0 ou 1;
Les lignes en tirets dans la Formule I représentent une double liaison optionnelle entre 2 atomes de carbone adjacents;
D1 est N ou CR2;
D2 est N ou CR3,
D3 est N ou CR4,
R2, R3 et R4 sont chacun indépendamment H, -alkyle C1-C5, -Oalkyle C1-C5, - alcényle C2-C5, -Oalcényle C2-C5, -alcynyle C2-C5, -Oalcynyle C2-C5, -OH, halogène, - CN, -NR6R7, -CO2R8, -C(O)NR6R7 ou -SO2NR6R7, où l'-alkyle C1-C5, -Oalkyle C1-C5, - alcényle C2-C5, -Oalcényle C2-C5, -alcynyle C2-C5 et -Oalcynyle C2-C5 sont optionnellement substitués par 1-7 halogènes;
chaque R5 est indépendamment -alkyle C1-C5, -Oalkyle C1-C5, -alcényle C2-C5, - Oalcényle C2-C5, -alcynyle C2-C5, -Oalcynyle C2-C5, -OH, halogène, -CN, -NR6R7, - CO2R8, -C(O)NR6R7, ou -SO2NR6R7, où l'-alkyle C1-C5, -Oalkyle C1-C5, -alcényle C2-C5, -Oalcényle C2-C5, -alcynyle C2-C5 et -Oalcynyle C2-C5 sont optionnellement substitués par 1-7 halogènes;
A1 est un phényle, HET(1), ou un cycloalkyle C3-C8 ayant optionnellement 1-2 doubles liaisons, où A1 est optionnellement substitué par un groupe substituant Z et est optionnellement substitué par 1-3 groupes qui sont chacun indépendamment -alkyle C1-C5, -Oalkyle C1-C5, -alcényle C2-C5, -Oalcényle C2-C5, -alcynyle C2-C5, -Oalcynyle C2-C5, halogène, -OH ou -CN, où l'-alkyle C1-C5, -Oalkyle C1-C5, -alcényle C2-C5, - Oalcényle C2-C5, -alcynyle C2-C5 et -Oalcynyle C2-C5 sont chacun optionnellement substitués par 1-7 halogènes;
Chaque HET(1) est un cycle hétérocyclique à 5 ou 6 chaînons ayant 1-4 groupes d'hétéroatomes qui sont chacun indépendamment -N-, -NH-, -S-, -O-, -S(O)- ou -S(O)2-, ayant optionnellement un groupe -C(=O)-, et ayant optionnellement 1-3 doubles liaisons;
Z est A3, -alkylène C1-C3-CO2R8, -alkylène C1-C3-C(O)NR6R7, -alkylène C1-C3-SO2NR6R7, -CO2R8, -C(O)NR6R7, -SO2NR6R7, ou -alkylène C1-C3-HET(2), où l'-alkylène C1-C3 est, dans toutes les utilisations, optionnellement substitué par 1-7 halogènes, et HET(2) est optionnellement substitué par 1-3 substituants qui sont indépendamment un - alkyle C1-3 optionnellement substitué par 1-5 halogènes, -Oalkyle C1-3 optionnellement substitué par 1-5 halogènes, halogène, ou NR6R7;
A3 est un phényle, un cycloalkyle C3-C6 ayant optionnellement 1-2 doubles liaisons, ou HET(1), où A3 est optionnellement substitué par 1-3 groupes qui sont chacun indépendamment un -alkyle C1-C5, -Oalkyle C1-C5, -alcényle C2-C5, -Oalcényle C2-C5, - alcynyle C2-C5, -Oalcynyle C2-C5, halogène, OH, ou -CN, où l'-alkyle C1-C5, -Oalkyle C1-C5, -alcényle C2-C5, -Oalcényle C2-C5, -alcynyle C2-C5 et -Oalcynyle C2-C5 sont optionnellement substitués par 1-7 halogènes; et A3 est optionnellement substitué par un groupe qui est HET(2), -alkylène C1-4-CO2R8 -alkylène C1-4-C(O)NR6R7, -alkylène C1-4-SO2NR6R7, -CO2R8 -C(O)NR6R7, ou -SO2NR6R7, où l'-alkylène C1-4- est, dans toutes les utilisations, optionnellement substitué par 1-7 halogènes, et HET(2) est optionnellement substitué par 1-3 substituants qui sont chacun indépendamment un halogène, un -alkyle C1-5 optionnellement substitué par 1-7 halogènes, -Oalkyle C1-5 optionnellement substitué par 1-7 halogènes, ou NR6R7;
HET(2) est un cycle hétérocyclique à 5-6 chaînons ayant 1-3 groupes d'hétéroatomes qui sont chacun indépendamment N, NH, O ou S, ayant optionnellement un groupe -C(=O)-, et ayant optionnellement 1-3 doubles liaisons;
A2 est un phényle ou HET(1), où A2 est optionnellement substitué par 1-3 groupes substituants qui sont chacun indépendamment un -alkyle C1-C5, -Oalkyle C1-C5, -alcényle C2-C5, -Oalcényle C2-C5, -alcynyle C2-C5, -Oalcynyle C2-C5, halogène, -CN, OH, ou cycloalkyle C3-6, où l'-alkyle C1-C5, -Oalkyle C1-C5, -alcényle C2-C5, -Oalcényle C2-C5, - alcynyle C2-C5 et -Oalcynyle C2-C5 sont optionnellement substitués par 1-7 halogènes, et le cycloalkyle C3-6 est optionnellement substitué par 1-3 substituants qui sont chacun indépendamment halogène, -alkyle C1-C3, ou -Oalkyle C1-C3, où l'-alkyle C1-C3 et l'-Oalkyle C1-C3 sont chacun optionnellement substitués par 1-7 halogènes; et
a est 0 ou un nombre entier de 1-3.
dans lequel R1 est un -alkyle C1-C5, -Oalkyle C1-C5, halogène, NR6R7, HET(3), ou cycloalkyle C3-6 ayant optionnellement 1-2 doubles liaisons, où l'-alkyle C1-C5 et l'-Oalkyle C1-C5 sont optionnellement substitués par 1-7 halogènes, et où HET(3) et le cycloalkyle C3-6 ayant optionnellement 1-2 doubles liaisons sont optionnellement substitués par 1-3 groupes substituants qui sont chacun indépendamment halogène, CH3, CF3, OCH3 ou OCF3;
Au moins l'un d'entre D1, D2 ou D3 est CR2, CR3 ou CR4,
R2, R3 et R4 sont chacun indépendamment H, -alkyle C1-C5, -Oalkyle C1-C5, ou halogène, où l'-alkyle C1-C5 et l'-Oalkyle C1-C5 sont optionnellement substitués par 1-7 halogènes;
Chaque R5 est indépendamment un -alkyle C1-C5, -Oalkyle C1-C5, ou halogène, où l'-alkyle C1-C5 et l'-Oalkyle C1-C5 sont optionnellement substitués par 1-7 halogènes;
A1 est un phényle, HET(1) ou un cycloalkyle C3-C6 ayant optionnellement 1-2 doubles liaisons, où A1 est optionnellement substitué par un groupe substituant Z et est optionnellement substitué par 1-3 groupes qui sont chacun indépendamment halogène, - OH, -CN, -alkyle C1-5 optionnellement substitué par 1-7 halogènes, ou -Oalkyle C1-5 optionnellement substitué par 1-7 halogènes;
A3 est un phényle, cycloalkyle C3-C6 ayant optionnellement 1-2 doubles liaisons, ou bien HET(1), où A3 est optionnellement substitué par 1-3 groupes qui sont chacun indépendamment -alkyle C1-C5 optionnellement substitué par 1-7 halogènes, -Oalkyle C1-C5 optionnellement substitué par 1-7 halogènes, -OH ou halogène, et est optionnellement substitué par un groupe qui est HET(2), -alkylène C1-2-CO2R8 -alkylène C1-2-C(O)NR6R7, -alkylène C1-2-SO2NR6R7 -CO2R8, -C(O)NR6R7 ou -SO2NR6R7, où l'-alkylène C1-2 est optionnellement substitué par 1-3 halogènes; et où HET(2) est optionnellement substitué par 1-3 groupes qui sont chacun indépendamment halogène, -alkyle C1-5 optionnellement substitué par 1-7 halogènes, -Oalkyle C1-5 optionnellement substitué par 1-7 halogènes, ou NR6R7; et
A2 est un phényle ou HET(1), où A2 est optionnellement substitué par 1-3 groupes substituants qui sont chacun indépendamment alkyle C1-5 optionnellement substitué par 1-7 halogènes, -Oalkyle C1-5 optionnellement substitué par 1-7 halogènes, halogène, -OH, - CN, ou cycloalkyle C3-6 optionnellement substitué par 1-3 substituants qui sont chacun indépendamment halogène, CF3, CH3, -OCF3, ou OCH3.
dans lequel R1 est CH3, CF3, -OCH3, -OCF3, halogène, ou -NR6R7;
R6 et R7 sont chacun indépendamment H ou -alkyle C1-C3;
R2, R3 et R4 sont chacun indépendamment H, alkyle C1-3, CF3, -Oalkyle C1-3, - OCF3, ou halogène;
Chaque R5 est indépendamment CH3, CF3, -OCH3, -OCF3, ou halogène;
A1 est un phényle, HET(1), ou cycloalkyle C3-C6 ayant optionnellement 1-2 doubles liaisons, où A1 est optionnellement substitué par un groupe substituant Z et est optionnellement substitué par 1-3 groupes qui sont chacun indépendamment -alkyle C1-3 optionnellement substitué par 1-5 halogènes, -Oalkyle C1-3 optionnellement substitué par 1-5 halogènes, halogène, -OH ou -CN;
Chaque HET(1) est un cycle hétérocyclique à 5 ou 6 chaînons ayant 1-3 groupes d'hétéroatomes qui sont chacun indépendamment -N-, -NH-, -S- ou -O-, ayant optionnellement un groupe -C(=O)-, et ayant optionnellement 1-3 doubles liaisons;
Z est A3, -C(CH2)1-3-CO2R8, -(CH2)1-3-C(O)NR6R7, -(CH2)1-3;-SO2NR6R7, -CO2R8, -C(O)NR6R7, -SO2NR6R7, ou -C(CH2)1-3-HET(2), où HET(2) est optionnellement substitué par 1-3 substituants qui sont indépendamment -alkyle C1-3 optionnellement substitué par 1-5 halogènes, -Oalkyle C1-3 optionnellement substitué par 1-5 halogènes, halogène, ou NR6R7;
R8 est H ou -alkyle C1-3 optionnellement substitué par 1-3 halogènes;
A3 est un phényle, cycloalkyle C3-C6 ayant optionnellement 1-2 doubles liaisons, ou HET(1), où A3 est optionnellement substitué par 1-3 groupes qui sont chacun indépendamment CH3, CF3, -OCH3, -OCF3, -OH ou halogène, et est optionnellement substitué par un groupe qui est HET(2), -(CH2)1-2-CO2R8, -(CH2)1-2-C(O)NR6R7, - C(CH2)1-2-SO2NR6R7, -CO2R8, -C(O)NR6R7, ou -SO2NR6R7, et HET(2) est optionnellement substitué par 1-3 groupes qui sont chacun indépendamment CH3, CF3, - OCH3, -OCF3, halogène, ou NR6R7;
A2 est un phényle ou HET(1), où A2 est substitué par 1-3 groupes substituants qui sont chacun indépendamment CH3, CF3, -OCH3, -OCF3, halogène, -CN, -OH, ou cycloalkyle C3-4 optionnellement substitué par 1-3 substituants qui sont chacun indépendamment halogène, CF3, CH3, -OCF3, ou -OCH3; et
a est 0, 1 ou 2.
dans lequel R1 est CH3, CF3, -OCH3, -OCF3, F, Cl, ou -NR6R7;
D1 est N ou CR2, où R2 est H, -alkyle C1-3, F, ou Cl;
D2 est N ou CR3, où R3 est H, -alkyle C1-3, F, ou Cl;
D3 est N ou CR4, où R4 est H, -alkyle C1-3, F, ou Cl;
au moins l'un d'entre D1, D2, ou D3 est CR2, CR3, ou CR4,
R5 est H ou CH3;
A1 est un phényle, pyridyle, pyrazinyle, pyrimidinyle, pyridazinyle, pyrazolyle, imidazolyle, isoxazolyle, thiazolyle, oxadiazolyle, thiadiazolyle, oxazolyle, pyrrolyle, thiényle, furyle, cyclopropyle, cyclobutyle, cyclohexyle, cyclohexényle, cyclopentyle, ou cyclopentényle, où A1 est optionnellement substitué par 1-3 groupes qui sont chacun indépendamment F, Cl, -OCH3, -OCF3, -alkyle C1-3, -CN, ou CF3, et optionnellement un groupe substituant Z;
Z est A3, -CH2CH2CO2R8 -CH2CH2C(O)NR6R7, -CH2CH2SO2NR6R7, ou - CH2CH2-HET(2), où HET(2) est optionnellement substitué par 1-2 groupes substituants qui sont chacun indépendamment CH3, CF3, -OCH3, -OCF3, halogène, ou NR6R7;
R8 est H ou -CH3;
HET(2) est un cycle hétérocyclique à 5 chaînons ayant 1-3 groupes d'hétéroatomes qui sont chacun indépendamment N, NH, O, ou S, ayant optionnellement un groupe - C(=O), et ayant optionnellement 1-3 doubles liaisons;
A3 est un phényle, cyclopropyle, cyclobutyle, cyclohexyle, cyclohexényle, cyclopentyle, cyclopentényle, ou HET(1), où HET(1) est un pyridinyle, pyrazinyle, pyrimidinyle, pyridazinyle, pyrazolyle, imidazolyle, isoxazolyle, thiazolyle, oxadiazolyle, thiadiazolyle, oxazolyle, pyrrolyle, thiényle, furyle, ou un cycle hétérocyclique à 5-6 chaînons ayant 1-2 groupes d'hétéroatomes qui sont indépendamment -N-, -NH- ou -O-, et optionnellement un groupe -C(=O)-, où A3 est optionnellement substitué par 1-2 groupes qui sont chacun indépendamment CH3, CF3, -OCH3, -OCF3, -OH, ou halogène, et est optionnellement substitué par 1 groupe qui est -CO2R8, -C(O)NR6R7, -SO2NR6R7, ou HET(2), où HET(2) est optionnellement substitué par 1-2 groupes substituants qui sont chacun indépendamment CH3, CF3, -OCH3, -OCF3, halogène, ou NR6R7;
A2 est un phényle ou HET(1), où A2 est substitué par 1-3 groupes substituants qui sont chacun indépendamment CF3, CH3, F, Cl, -CN, ou cyclopropyle; et
a est 0 ou 1.
dans lequel la ligne en tirets dans le cycle de la Formule Ia est une double liaison optionnelle lorsque x est 0;
dans lequel R1 est CF3, F, ou -N(CH3)2;
D1 est N ou CR2, où R2 est H ou -alkyle C1-3;
D2 est N ou CR3, où R3 est H ou CH3;
D3 est N ou CR4, où R4 est H ou CH3,
A1 est un phényle, pyridyle, thiényle, furyle, cyclohexényle, ou cyclopentényle, où A1 est optionnellement substitué par 1-3 groupes qui sont chacun indépendamment F, Cl, -OCH3, isopropyle, -CN, -CH3, ou CF3, et optionnellement un groupe substituant Z;
Z est A3, -CH2CH2CO2R8, -CH2CH2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yle), ou -CH2CH2-(5-amino-1,3,4-oxadiazol-2-yle),
R8 est H ou -CH3;
A3 est un phényle, cyclobutyle, cyclopentyle, cyclohexyle ou HET(1), où HET(1) est un pyridinyle, 6-oxopipéridinyle, 2-oxo-1,3-oxazolidinyle, 2-oxo-1,3-oxazinalyle, ou 5-oxopyrrolidinyle, où A3 est optionnellement substitué par 1-2 groupes -CH3, -OCH3, ou -OH, et est optionnellement substitué par 1 groupe -(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yle), -(5-amino-1,3,4-oxadiazol-2-yle), ou -CO2R8;
A2 est un phényle, qui est substitué par 1-2 groupes substituants qui sont chacun indépendamment CF3, CH3, F, ou Cl; et
a est 0.
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ou Ex. 64 |
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REFERENCES CITED IN THE DESCRIPTION
Patent documents cited in the description
Non-patent literature cited in the description