Tricyclic sulfones as ROR gamma modulators
10435369 ยท 2019-10-08
Assignee
Inventors
- David Marcoux (Pennington, NJ, US)
- Myra Beaudoin Bertrand (Lambertville, NJ, US)
- T. G. Murali Dhar (Newtown, PA)
- Michael G. Yang (Narbeth, PA)
- Zili Xiao (East Windsor, NJ)
- Hai-Yun Xiao (Belle Mead, NJ)
- Yeheng Zhu (Stockton, NJ)
- Carolyn A. Weigelt (Langhorne, PA, US)
- Douglas G. Batt (Wilmington, DE)
Cpc classification
C07D231/08
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C07C2602/44
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C07C2603/16
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International classification
C07C317/12
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C07D401/04
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C07D233/90
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C07D233/76
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C07D233/64
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C07D231/06
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C07D307/22
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C07D295/195
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C07D241/08
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C07D231/08
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C07D213/75
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C07D207/277
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C07D207/16
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C07D207/10
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C07D205/08
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C07D205/04
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C07D211/48
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C07C317/44
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C07D305/08
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C07D211/78
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C07D285/06
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C07D207/28
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C07D207/09
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C07D261/18
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C07D401/12
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C07D405/04
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C07C317/20
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C07C317/24
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C07D405/12
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Abstract
There are described ROR modulators of the formula (I), ##STR00001##
or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein all substituents are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for modulating ROR activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of ROR activity, for example, autoimmune and/or inflammatory disorders.
Claims
1. A compound of the formula ##STR00415## R.sup.1 is, independently at each occurrence, selected from hydrogen, CD.sub.3, halo, OCF.sub.3, CN, S(O).sub.p(C.sub.1-C.sub.6)alkyl, S(O)(NR.sup.g)(C.sub.1-C.sub.6)alkyl, S(O).sub.p(C.sub.1-C.sub.6)alkyl-OH, S(O)(NR.sup.g)(C.sub.1-C.sub.6)alkyl-OH, -thioalkoxyalkoxy, NR.sup.11R.sup.11, C.sub.1-6 alkyl substituted with 0-3 R.sup.1a, OC.sub.1-6 alkyl substituted with 0-3 R.sup.1a, (CR.sup.1bR.sup.1c).sub.r-3-14 membered carbocycle substituted with 0-3 R.sup.1a and (CR.sup.1bR.sup.1c).sub.r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, S(O).sub.p and S(O)(NR.sup.g), substituted with 0-3 R.sup.1a; R.sup.1a is, independently at each occurrence, hydrogen, O, halo, CF.sub.3, OCF.sub.3, CN, NO.sub.2, (CR.sup.1bR.sup.1c).sub.rOR.sup.b, (CR.sup.1bR.sup.1c).sub.rS(O).sub.pR.sup.b, (CR.sup.1bR.sup.1c).sub.rS(O)(NR.sup.g)R.sup.b, (CR.sup.1bR.sup.1c).sub.rC(O)R.sup.b, (CR.sup.1bR.sup.1c).sub.rC(O)OR.sup.b, (CR.sup.1bR.sup.1c).sub.rOC(O)R.sup.b, (CR.sup.1bR.sup.1c).sub.rNR.sup.11R.sup.11, (CR.sup.1bR.sup.1c).sub.rC(O)NR.sup.11R.sup.11, (CR.sup.1bR.sup.1c).sub.rNR.sup.bC(O)R.sup.c, (CR.sup.1bR.sup.1c).sub.rNR.sup.bC(O)OR.sup.c, NR.sup.bC(O)NR.sup.11R.sup.11, S(O).sub.pNR.sup.11R.sup.11, NR.sup.bS(O).sub.pR.sup.c, C.sub.1-6 alkyl substituted with 0-3 R.sup.a, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl substituted with 0-3 R.sup.a, C.sub.2-6 alkynyl substituted with 0-3 R.sup.a, (CR.sup.1bR.sup.1c).sub.r-3-14 membered carbocycle substituted with 0-3 R.sup.a, or (CR.sup.1bR.sup.1c).sub.r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, S(O).sub.p and S(O)(NR.sup.g), substituted with 0-3 R.sup.a; R.sup.1b and R.sup.1c are, independently at each occurrence, hydrogen, halogen or C.sub.1-6 alkyl; R.sup.1d is, independently at each occurrence, hydrogen, CD.sub.3, halo, CF.sub.3, CN or C.sub.1-4 alkyl; R.sup.2 is, independently at each occurrence, hydrogen, C.sub.1-6 alkyl substituted with 0-3 R.sup.2a, CR.sup.2aR.sup.2a, C.sub.2-6 alkenyl substituted with 0-3 R.sup.2a, (CR.sup.2eR.sup.2f).sub.r
2. A compound according to claim 1 wherein R.sup.1 is halo, phenyl substituted with 0-3 R.sup.1a, C.sub.1-6 alkyl substituted with 0-3 R.sup.1a, or OC.sub.1-6 alkyl substituted with 0-3 R.sup.1a; R.sup.1a is, independently at each occurrence, hydrogen, CF.sub.3, halo, C.sub.1-6 alkyl substituted with 0-3 R.sup.a, (CR.sup.1bR.sup.1c).sub.rOR.sup.b, or (CR.sup.1bR.sup.1c).sub.r-phenyl substituted with 0-3 R.sup.a; R.sup.1b and R.sup.1c are, independently at each occurrence, hydrogen, halogen or C.sub.1-6 alkyl; R.sup.1d is, independently at each occurrence, hydrogen, CD.sub.3, halo, CF.sub.3, CN or C.sub.1-C.sub.4 alkyl; R.sup.2 is hydrogen, S(O).sub.2R.sup.2c, C.sub.1-6 alkyl substituted with 0-3 R.sup.2a, C(O)OR.sup.2b, C(O)R.sup.2b, C(O)NR.sup.11R.sup.11, NR.sup.2bC(O)NR.sup.11R.sup.11, NR.sup.2bC(O)R.sup.2c NR.sup.2bC(O)OR.sup.2c, NR.sup.11R.sup.11, NR.sup.2bS(O).sub.pR.sup.c, NR.sup.2bS(O).sub.pNR.sup.11R.sup.11, or a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(O), S(O).sub.p and S(O)(NR.sup.g), substituted with 0-4 R.sup.a; R.sup.2a is, independently at each occurrence, hydrogen or C.sub.1-6 alkyl substituted with 0-3 R.sup.a; R.sup.2b is hydrogen, C.sub.1-6 alkyl substituted with 0-2 R.sup.a, C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.a, (CR.sup.2eR.sup.2f).sub.r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, S(O).sub.p and S(O)(NR.sup.g), substituted with 0-4 R.sup.a, or (CR.sup.2eR.sup.2f).sub.r-phenyl substituted with 0-3 R.sup.a; R.sup.2c is C.sub.1-6 alkyl substituted with 0-3 R.sup.a, C.sub.2-6 alkenyl substituted with 0-3 R.sup.a, C.sub.3-10 cycloalkyl substituted with 0-3 R.sup.a, C.sub.6-10 aryl substituted with 0-3 R.sup.a, or (CR.sup.2eR.sup.2f).sub.r-5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, S(O).sub.p and S(O)(NR.sup.g), substituted with 0-4 R.sup.a; R.sup.3 is, independently at each occurrence, hydrogen, halo, N.sub.3, CN, OR.sup.3b, NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl substituted with 0-3 R.sup.3a, or C.sub.3-10 cycloalkyl substituted with 0-3 R.sup.3a; R.sup.3a is, independently at each occurrence, hydrogen, O, halo, OCF.sub.3, OCHF.sub.2, CF.sub.3, CHF.sub.2, CN, NO.sub.2, (CR.sup.1bR.sup.1c).sub.rOR.sup.b, (CR.sup.1bR.sup.1c).sub.rS(O).sub.pR.sup.b, (CR.sup.1bR.sup.1c).sub.rS(O)(NR.sup.g)R.sup.b, (CR.sup.1bR.sup.1c).sub.rC(O)R.sup.b, (CR.sup.1bR.sup.1c).sub.rC(O)OR.sup.b, (CR.sup.1bR.sup.1c).sub.rOC(O)R.sup.b, (CR.sup.1bR.sup.1c).sub.rNR.sup.11R.sup.11, (CR.sup.1bR.sup.1c).sub.rC(O)NR.sup.11R.sup.11, (CR.sup.1bR.sup.1c).sub.rNR.sup.bC(O)R.sup.c, (CR.sup.1bR.sup.1c).sub.rNR.sup.bC(O)OR.sup.c, NR.sup.bC(O)NR.sup.11R.sup.11, S(O).sub.pNR.sup.11R.sup.11, NR.sup.bS(O).sub.pR.sup.c, C.sub.1-6 alkyl substituted with 0-3 R.sup.a, C.sub.2-6 alkenyl substituted with 0-3 R.sup.a, C.sub.2-6 alkynyl substituted with 0-3 R.sup.a, C.sub.1-6 haloalkyl, (CR.sup.1bR.sup.1c).sub.r-3-14 membered carbocycle substituted with 0-3 R.sup.a, or (CR.sup.1bR.sup.1c).sub.r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, S(O).sub.p and S(O)(NR.sup.g), substituted with 0-3 R.sup.a; and R.sup.3b is, independently at each occurrence, hydrogen, C.sub.1-6 alkyl substituted with 0-3 R.sup.a or phenyl substituted with 0-3 R.sup.a; or a stereoisomer or pharmaceutically-acceptable salt thereof.
3. A compound according to claim 2 of the formula ##STR00416## wherein R.sup.1 is C.sub.1-6 alkyl substituted with 0-3 R.sup.1a or OC.sub.1-6 alkyl substituted with 0-3 R.sup.1a; R.sup.1a is, independently at each occurrence, hydrogen, CF.sub.3, halo or C.sub.1-6 alkyl substituted with 0-3 R.sup.a; R.sup.1d is, independently at each occurrence, hydrogen, halo, or CN; R.sup.2 is C.sub.1-6 alkyl substituted with 0-3 R.sup.2a, C(O)OR.sup.2b, C(O)R.sup.2b, C(O)NR.sup.11R.sup.11, NR.sup.2bC(O)NR.sup.11R.sup.11, R.sup.2bC(O)R.sup.2c NR.sup.2bC(O)OR.sup.2C NR.sup.11R.sup.11, NR.sup.2bS(O).sub.pR.sup.c, or NR.sup.2bS(O).sub.pNR.sup.11R.sup.11; R.sup.2a is, independently at each occurrence, hydrogen or C.sub.1-6 alkyl substituted with 0-3 R.sup.a; R.sup.2b is hydrogen, C.sub.1-6 alkyl substituted with 0-2 R.sup.a, C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.a, (CR.sup.2eR.sup.2f).sub.r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, S(O).sub.p and S(O)(NR.sup.g), substituted with 0-4 R.sup.a, or (CR.sup.2eR.sup.2f).sub.r-phenyl substituted with 0-3 R.sup.a; R.sup.2c is C.sub.1-6 alkyl substituted with 0-3 R.sup.a, C.sub.2-6 alkenyl substituted with 0-3 R.sup.a, C.sub.3-10 cycloalkyl substituted with 0-3 R.sup.a, C.sub.6-10 aryl substituted with 0-3 R.sup.a, or (CR.sup.2eR.sup.2f).sub.r-5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, S(O).sub.p and S(O)(NR.sup.g), substituted with 0-4 R.sup.a; R.sup.3 is, independently at each occurrence, hydrogen, halo, cyclopropyl or C.sub.1-6 alkyl; or a stereoisomer or pharmaceutically-acceptable salt thereof.
4. A compound according to claim 2 of the formula ##STR00417## wherein R.sup.1 is C.sub.1-6 alkyl substituted with 0-3 R.sup.1a or OC.sub.1-6 alkyl substituted with 0-3 R.sup.1a; R.sup.2 is C(O)NR.sup.11R.sup.11, (CH.sub.2).sub.0-1NHC(O)NR.sup.11R.sup.11 or (CH.sub.2).sub.0-1NHC(O)R.sup.2c; R.sup.2c is C.sub.1-4 alkyl substituted with 0-3 R.sup.a, C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.a or 5-10 membered heterocycle containing 1-2 heteroatoms selected from N, O and S(O).sub.2, substituted with 0-3 R.sup.a; R.sup.3 is, independently at each occurrence, hydrogen or halo; R.sup.11 is, independently at each occurrence, hydrogen, C.sub.1-6 alkyl substituted with 0-2 R.sup.f, C.sub.4-6 cycloalkyl substituted with 0-2 R.sup.f, -CH.sub.2-C.sub.4-6 cycloalkyl substituted with 0-2 R.sup.f, 5-6 membered heterocycle comprising carbon atoms and 1-2 heteroatoms selected from N, O and S(O).sub.2, substituted with 0-1 R.sup.d, -CH.sub.2-5-6 membered heterocycle comprising carbon atoms and 1-2 heteroatoms selected from N, O and S(O).sub.2, substituted with 0-2 R.sup.d; or one R.sup.11 and a second R.sup.11, both attached to the same nitrogen atom, combine to form a heterocycle comprising carbon atoms and 1-2 heteroatoms selected from N, O and S(O).sub.2, substituted with 0-2 R.sup.d; R.sup.a is, independently at each occurrence, hydrogen, O, halo, CF.sub.3, OH, CH.sub.2OH, S(O).sub.2CH.sub.3, C(O)CH.sub.3, NHC(O)CH.sub.3, OP(O)(OH).sub.2, C.sub.1-2 alkyl substituted with 0-1 R.sup.f or pyridyl; R.sup.d is, independently at each occurrence, hydrogen, OH, C(O)CH.sub.3, CO.sub.2H, CO.sub.2R.sup.c or SO.sub.2R.sup.c; R.sup.f is, independently at each occurrence, hydrogen, CO.sub.2H, CN or OH; or a stereoisomer or pharmaceutically-acceptable salt thereof.
5. A compound selected from the following: 1-(4-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carbonyl)piperazin-1-yl)ethan-1-one, (3R, 3 aS,9bS)-N-((1,1-dioxidotetrahydrothiophen-3-yl)methyl)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide (diastereomeric mixture), methyl 4-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamido)tetrahydro-2H-thiopyran-4-carboxylate 1,1-dioxide, (3R,3 aS,9bS)-N-(2,3-dihydroxy-3-methylbutyl)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide, (3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-N-(2-hydroxy-2-methylpropyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide, (3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-N-((1r,4R)-4-hydroxycyclohexyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide, (1,1-dioxidothiomorpholino)((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)methanone, (3R,3 aS, 9bS)-9b-((4-fluorophenyl)sulfonyl)-N((R)-2-hydroxypropyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide, (3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-N-((1-hydroxycyclopentyl)methyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide, (3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-N-((1-hydroxycyclobutyl)methyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide, (3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-N-((1-hydroxycyclopropyl)methyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide, (3R,3 aS, 9bS)-9b-((4-fluorophenyl)sulfonyl)-N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-H-cyclopenta[a]naphthalene-3-carboxamide, (3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide, 3-(((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamido)methyl)cyclobutane-1-carboxylic acid (homochiral, from peak 1), 3-(((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamido)methyl)cyclobutane-1-carboxylic acid (homochiral, from peak 2), (1S,3R)-3-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamido)cyclopentane-1-carboxylic acid, 3-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamido)cyclohexane-1-carboxylic acid (homochiral, from peak 2), 1-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carbonyl)piperidine-4-carboxylic acid, (S)-1-(2-cyanoethyl)-N-((3R,3 aS, 9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-5-oxopyrrolidine-2-carboxamide, N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)acetamide-2,2,2-d3, N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-(pyridin-4-yl)acetamide, N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-4-hydroxytetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide, N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-4-hydroxy-1-(methylsulfonyl)piperidine-4-carboxamide, 1-acetyl-N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)piperidine-4-carboxamide, N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-4-hydroxytetrahydro-2H-pyran-4-carboxamide, (2S,4R)-4-fluoro-N-((3R,3 aS, 9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-1-(methyl-d.sub.3)-5-oxopyrrolidine-2-carboxamide, N-((3R, 3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (homochiral, from peak 1), N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (homochiral, from peak 3), N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-hydroxy-2-methylpropanamide, (R)-N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-hydroxypropanamide, N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide, N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3-methyloxetane-3-carboxamide, N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3-hydroxy-2,2-dimethylpropanamide, N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-1-hydroxycyclopropane-1-carboxamide, N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-methyl-5-oxopyrrolidine-2-carboxamide, N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-1-hydroxycyclohexane-1-carboxamide, N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide, (S)-3,3,3-trifluoro-N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-hydroxypropanamide, N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-hydroxy-3-(pyridin-4-yl)propanamide, N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3-hydroxy-3-methylbutanamide, (R)-4,4,4-trifluoro-N-((3R,3 aS, 9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3-hydroxybutanamide, 2-acetamido-N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3-hydroxypropanamide, N-((3R, 3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-methyl-2-morpholinopropanamide, (1s,3S)-N-((3R,3aS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3-hydroxy-3-methylcyclobutane-1-carboxamide, N-((3R, 3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-5-oxopyrrolidine-3-carboxamide, N-((3R, 3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-oxopiperidine-4-carboxamide (homochiral, from peak 2), N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-6-oxopiperidine-3-carboxamide (homochiral, from peak 1), N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-6-oxopiperidine-3-carboxamide (homochiral, from peak 2), N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide, N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-(3-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl)acetamide, 2-acetamido-N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)acetamide, 2-acetamido-N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-methylpropanamide, 1-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3-(2-hydroxy-2-methylpropyl)urea, 1-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3-(2-hydroxyethyl)urea, (3S,4R)-N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3,4-dihydroxypyrrolidine-1-carboxamide, N-(((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)methyl)-2-hydroxy-2-methylpropanamide trifluoroacetate, 1-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3-(2-hydroxyethyl-2,2-d2)urea, N-((3R, 3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-hydroxy-2-(4-hydroxytetrahydro-2H-pyran-4-yl)acetamide, (1r,3R,4S)-N-((3R,3aS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3,4-dihydroxycyclopentane-1-carboxamide, (1r,3R,4S)-N-((3R,3aS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3,4-dihydroxycyclopentane-1-carboxamide, (1s,3S)-N-((3R,3aS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3-hydroxy-3-(hydroxymethyl)cyclobutane-1-carboxamide, (1r,3R)-N-((3R,3 aS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3-hydroxy-3-(hydroxymethyl)cyclobutane-1-carboxamide, 1-(acetyl-d.sub.3)-N-((3R, 3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-4-hydroxypiperidine-4-carboxamide, N-((3R, 3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-4-hydroxy-1-(2-hydroxyacetyl)piperidine-4-carboxamide, (3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-N-((1-(methylsulfonyl)pyrrolidin-3-yl)methyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide (homochiral, from peak 1), (3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-N-((1-(methylsulfonyl)pyrrolidin-3-yl)methyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide (homochiral, from peak 2), 1-(((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)amino)-2-methyl-1-oxopropan-2-yl dihydrogen phosphate, (S)-N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-1-(methyl-d3)-5-oxopyrrolidine-3-carboxamide, N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4, 5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-4-hydroxy-1-(oxetan-3-yl)piperidine-4-carboxamide, (S)-1-(2-cyanoethyl)-N-((3R,3 aS, 9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-5-oxopyrrolidine-3-carboxamide, and 4-fluoro-N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide, or a stereoisomer or pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising one or more A compounds according to claim 1, and a pharmaceutically acceptable carrier or diluent.
Description
EXAMPLES
(1) The following examples illustrate the particular and preferred embodiments of the present invention and do not limit the scope of the present invention. Chemical abbreviations and symbols as well as scientific abbreviations and symbols have their usual and customary meanings unless otherwise specified. Additional abbreviations employed in the Examples and elsewhere in this application are defined below. Common Intermediates are generally useful for the preparation of more than one Example and are identified sequentially by the Intermediate number and step in which they were prepared (e.g., Intermediate 1, Step A), or by the Intermediate number only where the compound is the title compound. Compounds of the Examples are identified by the Example number and step in which they were prepared (e.g., Example 1, Step A) if the compound is an intermediate, or by the Example number only where the compound is the title compound of the Example. In some instances alternative preparations of Intermediates or Examples are described. Frequently chemists skilled in the art of synthesis may devise alternative preparations which may be desirable based on one or more considerations such as shorter reaction time, less expensive starting materials, ease of operation or isolation, improved yield, suitability to catalysis, avoidance of toxic reagents, accessibility of specialized instrumentation, decreased number of linear steps, etc. The intent of describing alternative preparations is to further enable the preparation of the Examples of this invention. In some instances some functional groups in the outlined Examples and claims may be replaced by well-known bioisosteric replacements known in the art, for example, replacement of a carboxylic acid group with a tetrazole or a phosphate moiety. Starting materials and intermediates for which no preparation is explicitly shown are available commercially, are known in the literature, or may be prepared by analogy to similar compounds which are known in the literature.
(2) Drying of organic solutions to remove residual water was done by allowing to stand over anhydrous sodium sulfate or anhydrous magnesium sulfate, followed by decantation or filtration. Solvent removal was performed by concentration under reduced pressure. Column chromatography was generally performed with pre-packed silica gel cartridges using a CombiFlash automated chromatography apparatus (Teledyne Isco), eluting with the solvent or solvent mixture indicated. Analytical and preparative high performance liquid chromatography (HPLC) was generally performed using a reverse phase column of a size appropriate to the quantity of material being separated, generally eluting with a gradient of increasing concentration of methanol or acetonitrile in water, also containing 0.05% or 0.1% trifluoroacetic acid or 10 mM ammonium acetate, at a rate of elution suitable to the column size and separation to be achieved. Chiral super-critical fluid chromatographic (SFC) separation of enantiomers or diastereomers was performed using conditions described for the individual cases. Mass spectral data were obtained by liquid chromatography mass spectroscopy (LCMS) using electrospray ionization.
(3) Many Intermediates and Examples are homochiral (entirely or mostly a single enantiomer). If the absolute configuration at an asymmetric center of an Intermediate or Example is known, or that asymmetric center is derived from a precursor whose absolute configuration is known, this is explicitly shown in the structure of the Intermediate or Example. In some cases an Intermediate or Example is homochiral but the absolute configuration has not been proven at all asymmetric centers. In those cases, the stereochemistry at the unknown asymmetric center is not explicitly shown, and a text notation below the structure will indicate that the compound is homochiral and that the compound was obtained from the specified peak eluting during chiral SFC separation. For example, the structure 94 shown below indicates that, while the material is homochiral, the absolute configuration at two asymmetric centers of the material, which was derived from the first-eluting peak during SFC separation, is not known, but the material has one of the absolute configurations shown in 94a, 94b, 94c, or 94d.
(4) ##STR00030##
(5) In some cases an Intermediate or Example is a mixture of diastereomers with one, some, or all of the asymmetric centers being either of undefined absolute configuration or a mixture of both absolute configurations. In those cases a text notation below the structure will indicate that the compound is a mixture of diastereomers.
(6) Chemical names were determined using ChemBioDraw Ultra, version 14.0.0.126 (PerkinElmer Inc.). The following abbreviations are used:
(7) TABLE-US-00001 ABBREVIATION NAME BINAP 2,2-bis(diphenylphosphino)-1,1- binaphthalene BOP benzotriazole-1-yl-oxy- tris(dimethylamino)-phosphonium hexafluorophosphate DAST (diethylamino)sulfur trifluoride DCM dichloromethane DIEA diisopropylethylamine (Hunig's base) DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EDC N-(3-dimethylaminopropyl)-N- ethylcarbodiimide EtOAc ethyl acetate h hours HATU O-(7-azabenzotriazol-1-yl)-1, 1,3,3-tetramethyluronium hexafluorophosphate HOBT 1-hydroxybenzotriazole HPLC high performance liquid chromatography IPA 2-propanol LCMS liquid chromatography - mass spectrometry LDA lithium diisopropylamide mCPBA m-chloroperoxybenzoic acid MeCN acetonitrile MeOH methanol min minutes MsCl methanesulfonyl chloride rt room temperature SFC super-critical fluid chromatography TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran t.sub.R chromatographic retention time
HPLC Methods
(8) Method A: (Analytical)
(9) Column: Acquity UPLC BEH C.sub.18 2.150 mm, 1.7 m (Waters Corp.); mobile phase A: water with 0.05% TFA; mobile phase B: MeCN with 0.05% TFA; temperature: 50 C.; flow rate 0.80 mL/min; gradient: 2-98% B over 1 min, then 0.5 min isocratic at 98% B.
(10) Method B: (Analytical)
(11) Column: Acquity UPLC BEH C.sub.18 2.150 mm, 1.7 m (Waters Corp.); mobile phase A: 5:95 MeCN-water with 10 mM ammonium acetate; mobile phase B: 95:5 MeCN-water with 10 mM ammonium acetate; temperature: 50 C.; flow rate 1.0 mL/min; gradient: 0-100% B over 3 min, then 0.75 min isocratic at 100% B.
(12) Method C: (Analytical)
(13) Column: Acquity UPLC BEH C.sub.18 2.150 mm, 1.7 m (Waters Corp.); mobile phase A: 5:95 MeCN-water with 0.1% TFA; mobile phase B: 95:5 MeCN-water with 0.1% TFA; temperature: 50 C.; flow rate 1.0 mL/min; gradient: 0-100% B over 3 min, then 0.75 min isocratic at 100% B.
(14) Method D: (Analytical)
(15) Column: Kinetex C.sub.18 2.150 mm, 2.6 m (Phenomenex Inc.); mobile phase A: 10:90 MeCN-water with 0.1% TFA; mobile phase B: 90:10 MeCN-water with 0.1% TFA; temperature: 40 C.; flow rate 1.0 mL/min; gradient: 0-100% B over 1.5 min, then isocratic at 100% B.
(16) Method E: (Preparative)
(17) Column: XBridge C.sub.18 19200 mm, 5 m (Waters Corp.); mobile phase A: 5:95 MeCN-water with 10 mM ammonium acetate; mobile phase B: 95:5 MeCN-water with 10 mM ammonium acetate; flow rate 20 mL/min; gradient: increasing B, then isocratic at 100% B.
(18) Method F: (Preparative)
(19) Column: XBridge C.sub.18 19200 mm, 5 m (Waters Corp.); mobile phase A: 5:95 MeCN-water with 0.1% TFA; mobile phase B: 95:5 MeCN-water with 0.1% TFA; flow rate 20 mL/min; gradient: increasing B, then isocratic at 100% B.
(20) Method G: (Preparative)
(21) Column: Sunfire C.sub.18 19200 mm, 5 m (Waters Corp.); mobile phase A: 10:90 MeCN-water with 0.1% TFA; mobile phase B: 90:10 MeCN-water with 0.1% TFA; flow rate 20 mL/min; gradient: increasing B, then isocratic at 100% B.
Intermediates 1-4
ethyl 9b-((4-fluorophenyl)sulfonyl)-7-iodo-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylate (four single enantiomers)
(22) ##STR00031##
Step A: 4-((4-fluorophenyl)sulfonyl)-7-iodo-1,2-dihydronaphthalene
(23) ##STR00032##
(24) A solution of 6-iodo-3,4-dihydronaphthalen-1(2H)-one (13.3 g, 48.9 mmol) and TiCl.sub.4 (1 M in DCM; 48.9 mL, 48.9 mmol) in THF (326 mL) in an ice-water bath was treated with a solution of 4-fluorobenzenethiol (6.3 mL, 58.7 mmol) and Et.sub.3N (13.6 mL, 98.0 mmol) in THF (25 mL) at a rate such that the temperature remained below 10 C. The solution was stirred at rt for 60 min, treated with water (200 mL) and concentrated to remove the bulk of the organic solvent. The aqueous residue was extracted with diethyl ether (2250 mL). The combined organic layers were dried and concentrated to provide crude (4-fluorophenyl)(6-iodo-3,4-dihydronaphthalen-1-yl)sulfane (20 g) as a mixture with (6-iodo-1,2,3,4-tetrahydronaphthalene-1,1-diyl)bis((4-fluorophenyl)sulfane), which was used directly. HPLC t.sub.R 1.36 min (method B).
(25) A solution of the mixture from the above reaction (18.7 g) in DCM (978 mL) was cooled on an ice-water bath and was treated portionwise with mCPBA (21.9 g, 98.0 mmol). The mixture was allowed to warm to rt and was stirred for 1 h, when LCMS showed consumption of the starting material and 4-((4-fluorophenyl)sulfinyl)-7-iodo-1,2-dihydronaphthalene as the major product. Additional mCPBA (11.0 g, 48.9 mmol) was added at rt. The mixture was stirred for 30 min, when LCMS showed very little sulfoxide (t.sub.R 1.00 min, method B). The mixture was washed twice with saturated aqueous NaHCO.sub.3, and the organic phase was dried and concentrated. The residue was purified by column chromatography, eluting with EtOAc-hexanes (gradient from 0-10%). The resulting material was dissolved in EtOAc and washed twice with saturated aqueous NaHCO.sub.3. The organic phase was dried and concentrated to provide 4-((4-fluorophenyl)sulfonyl)-7-iodo-1,2-dihydronaphthalene as a white amorphous solid (12.0 g, 59% yield over two steps). LCMS m/z 455.9 (M+H+MeCN).sup.+, HPLC t.sub.R 1.09 min (method A). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.97-7.89 (m, 2H), 7.64 (d, J=8.8 Hz, 1H), 7.57-7.47 (m, 3H), 7.22-7.13 (m, 2H), 2.79-2.68 (m, 2H), 2.61-2.50 (m, 2H). .sup.19F NMR (471 MHz, CDCl.sub.3) 102.7 (s, 1F).
(26) Alternative Procedure:
(27) A solution of 6-iodo-3,4-dihydronaphthalen-1(2H)-one (5.0 g, 18.4 mmol), 4-fluorobenzenethiol (4.1 mL, 38.6 mmol) and absolute ethanol (20 mL) was cooled on an ice-water bath and bubbled with HCl gas until saturation was reached (observed by the formation of a white precipitate). The mixture was allowed to warm to rt and stirred overnight. The mixture was dissolved in diethyl ether (250 mL) and washed sequentially with water (2125 mL), 0.5 M aqueous Na.sub.2CO.sub.3 (3100 mL) and brine (100 mL). The organic layer was dried and concentrated to provide a solid (9.20 g) which was a mixture of (4-fluorophenyl)(6-iodo-3,4-dihydronaphthalen-1-yl)sulfane and (6-iodo-1,2,3,4-tetrahydronaphthalene-1,1-diyl)bis((4-fluorophenyl)sulfane). The solid was dissolved in chloroform (150 mL) and cooled in an ice-water bath. A solution of mCPBA (35.0 g, 156 mmol) in DCM (200 mL) was washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, and the filter cake was washed with DCM (50 mL). The combined filtrates were added dropwise in portions to the chloroform solution of the mixture of (4-fluorophenyl)(6-iodo-3,4-dihydronaphthalen-1-yl)sulfane and (6-iodo-1,2,3,4-tetrahydronaphthalene-1,1-diyl)bis((4-fluorophenyl)sulfane) until the reaction was completed as judged by LCMS (175 mL of the mCPBA solution was needed). The mixture was cooled in an ice bath, filtered to remove the insoluble material, and the filtrate was stirred with 10% aqueous Na.sub.2S.sub.2O.sub.3 (120 mL) for 5 min. The organic phase was separated, washed sequentially with 10% aqueous Na.sub.2S.sub.2O.sub.3 (2120 mL), 10% aqueous Na.sub.2CO.sub.3 (3200 mL) and brine (150 mL), dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (gradient from 0-20%) to give 4-((4-fluorophenyl)sulfonyl)-7-iodo-1,2-dihydronaphthalene (5.3 g, 70% yield) as a white amorphous solid.
Step B: ethyl 9b-((4-fluorophenyl)sulfonyl)-7-iodo-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylate (four single enantiomers)
(28) ##STR00033##
(29) A solution of ethyl 4-chlorobutanoate (4.9 mL, 35 mmol) and 4-((4-fluorophenyl)sulfonyl)-7-iodo-1,2-dihydronaphthalene (4.8 g, 12.0 mmol) in THF (120 mL) was cooled to 78 C. and treated dropwise with LDA (1.0 M in THF; 35 mL, 35 mmol). The mixture was stirred at 78 C. for 45 min, then was treated with saturated aqueous NH.sub.4Cl. The mixture was warmed to rt, diluted with EtOAc and washed with saturated aqueous NH.sub.4Cl. The organic layer was dried and concentrated. The residue was subjected to column chromatography on silica gel, eluting with EtOAc-hexanes, to provide a mixture of diastereomers of ethyl 9b-((4-fluorophenyl)sulfonyl)-7-iodo-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylate (4.4 g, 72% yield). The material was separated by preparative chiral SFC on a Lux Cell-4 column (46250 mm, 5 m) at 35 C., eluting with CO.sub.2-MeOH (80:20) at 100 bars, to provide 4 homochiral products:
(30) Peak 1: ethyl (3S,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-iodo-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylate (Intermediate 1, 789 mg). LCMS m/z 529.1 (M+H).sup.+; HPLC t.sub.R 1.16 min (Method B). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.66-7.58 (m, 1H), 7.37 (br d, J=8.5 Hz, 1H), 7.32-7.25 (m, 3H), 7.12-6.98 (m, 2H), 4.26-4.11 (m, 2H), 3.52 (dt, J=11.5, 7.3 Hz, 1H), 3.15-3.02 (m, 2H), 2.49-2.41 (m, 1H), 2.39-2.32 (m, 1H), 2.25-2.11 (m, 1H), 2.11-1.91 (m, 1H), 1.81-1.68 (m, 1H), 1.60-1.45 (m, 1H), 1.35-1.23 (m, 3H), 1.23-1.09 (m, 1H). .sup.19F NMR (471 MHz, CDCl.sub.3) 103.1 (s, 1F). The absolute configuration was determined by single crystal X-ray analysis of Example 21, from the anomalous dispersion signal using the Flack method (Acta Cryst. B, 2013, 69, 249.)
Peak 2: ethyl (3S,3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-iodo-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylate (Intermediate 2, 1.9 g). LCMS m/z 529.1 (M+H).sup.+; HPLC t.sub.R 1.16 min (Method A). .sup.1H NMR (499 MHz, CDCl.sub.3) 7.54 (dd, J=8.2, 1.4 Hz, 1H), 7.40-7.33 (m, 3H), 7.09-7.02 (m, 3H), 4.27-4.09 (m, 2H), 3.36 (ddd, J=10.0, 8.4, 6.5 Hz, 1H), 3.18 (ddd, J=13.9, 7.2, 2.5 Hz, 1H), 2.62 (dt, J=10.3, 8.0 Hz, 1H), 2.47-2.33 (m, 2H), 2.19-2.11 (m, 2H), 2.09-2.01 (m, 1H), 1.93 (ddd, J=15.6, 11.7, 3.9 Hz, 1H), 1.34-1.13 (m, 3H), 1.11-1.01 (m, 1H). .sup.19F NMR (471 MHz, CDCl.sub.3) 103.1 (s, 1F). The absolute configuration was determined by single crystal X-ray analysis of Example 2, from the anomalous dispersion signal using the Flack method.
Peak 3: ethyl (3R,3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-iodo-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylate (Intermediate 3, 286 mg). LCMS m/z 529.1 (M+H).sup.+; HPLC t.sub.R 1.16 min (Method B). .sup.1H NMR (499 MHz, CDCl.sub.3) 7.66-7.58 (m, 1H), 7.37 (br d, J=8.5 Hz, 1H), 7.32-7.25 (m, 3H), 7.12-6.98 (m, 2H), 4.26-4.11 (m, 2H), 3.52 (dt, J=11.5, 7.3 Hz, 1H), 3.15-3.02 (m, 2H), 2.49-2.41 (m, 1H), 2.39-2.32 (m, 1H), 2.25-2.11 (m, 1H), 2.11-1.91 (m, 1H), 1.81-1.68 (m, 1H), 1.60-1.45 (m, 1H), 1.35-1.23 (m, 3H), 1.23-1.09 (m, 1H). .sup.19F NMR (471 MHz, CDCl.sub.3) 103.1 (s, 1F). The absolute configuration was determined by single crystal X-ray analysis of Example 9, from the anomalous dispersion signal using the Flack method.
Peak 4: ethyl (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-iodo-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylate (Intermediate 4, 1.8 g). LCMS m/z 529.1 (M+H).sup.+; HPLC t.sub.R 1.16 min (Method B). .sup.1H NMR (499 MHz, CDCl.sub.3) 7.54 (dd, J=8.2, 1.4 Hz, 1H), 7.40-7.33 (m, 3H), 7.09-7.02 (m, 3H), 4.27-4.09 (m, 2H), 3.36 (ddd, J=10.0, 8.4, 6.5 Hz, 1H), 3.18 (ddd, J=13.9, 7.2, 2.5 Hz, 1H), 2.62 (dt, J=10.3, 8.0 Hz, 1H), 2.47-2.33 (m, 2H), 2.19-2.11 (m, 2H), 2.09-2.01 (m, 1H), 1.93 (ddd, J=15.6, 11.7, 3.9 Hz, 1H), 1.34-1.13 (m, 3H), 1.11-1.01 (m, 1H). .sup.19F NMR (471 MHz, CDCl.sub.3) 103.1 (s, 1F). The absolute configuration was determined by single crystal X-ray analysis of Example 14, from the anomalous dispersion signal using the Flack method.
Intermediate 5
5-(tert-butyl) 3-ethyl (3R,3aR,9bS)-7-bromo-9b-((4-fluorophenyl)sulfonyl)-1,2,3,3a,4,9b-hexahydro-5H-cyclopenta[c]quinoline-3,5-dicarboxylate
(31) ##STR00034##
Step A: tert-butyl 7-bromo-4-((4-fluorophenyl)sulfonyl)quinoline-1(2H)-carboxylate
(32) ##STR00035##
(33) A solution of 7-bromo-2,3-dihydroquinolin-4(1H)-one (8.0 g, 35 mmol) and 4-fluorobenzenethiol (7.9 mL, 74 mmol) in ethanol (44 mL) was cooled on an ice-water bath. HCl gas was bubbled through the mixture until saturation was reached (as indicated by the formation of a white precipitate). The mixture was stirred on the ice-water bath for 1 h and at rt for 1 h more. The mixture was concentrated and the resulting oil was dissolved in DCM (250 mL), washed with 1 M aqueous NaOH, dried and concentrated to give crude 7-bromo-4,4-bis((4-fluorophenyl)thio)-1,2,3,4-tetrahydroquinoline as a solid (16.4 g, quantitative yield). HPLC t.sub.R 1.27 min (method B).
(34) This material was dissolved in 1,4-dioxane (180 mL) and treated with 4-dimethylaminopyridine (13 g, 106 mmol) and di-tert-butyl dicarbonate (25 mL, 106 mmol). The mixture was stirred at rt for 16 h, then was diluted with EtOAc and washed twice with 1 M aqueous HCl. The organic phase was dried and concentrated to provide tert-butyl 7-bromo-4,4-bis((4-fluorophenyl)thio)-3,4-dihydroquinoline-1(2H)-carboxylate (20 g, quantitative yield). HPLC t.sub.R 1.37 min (method B).
(35) This material was dissolved in DCM (350 mL) and cooled on an ice-water bath. mCPBA (22 g, 172 mmol) was added and the mixture was stirred for 1 h. Additional mCPBA (22 g, 172 mmol) was added, and stirring was continued for 1 h more. The mixture was filtered, and the filtrate was treated with 10% aqueous Na.sub.2S.sub.2O.sub.3 (120 mL) and stirred for 5 min. The organic phase was separated, washed sequentially with 10% aqueous Na.sub.2S.sub.2O.sub.3 (2120 mL), 10% aqueous Na.sub.2CO.sub.3 (3200 mL) and brine (150 mL), dried over Na.sub.2SO.sub.4 and concentrated to give crude tert-butyl 7-bromo-4-((4-fluorophenyl)sulfonyl)quinoline-1(2H)-carboxylate (17 g, quantitative yield) which was used without further purification. LCMS m/z 468.0 (M+H+MeCN).sup.+; HPLC t.sub.R 1.16 min (method B).
Step B: 5-(tert-butyl) 3-ethyl (3R,3aR,9bS)-7-bromo-9b-((4-fluorophenyl)sulfonyl)-1,2,3,3a,4,9b-hexahydro-5H-cyclopenta[c]quinoline-3,5-dicarboxylate
(36) ##STR00036##
(37) A solution of ethyl 4-chlorobutanoate (6 mL, 43 mmol) and tert-butyl 7-bromo-4-((4-fluorophenyl)sulfonyl)quinoline-1(2H)-carboxylate (13 g, 28 mmol) in THF (240 mL) was cooled to 78 C. and treated dropwise with LDA (1 M in THF; 36 mL, 36 mmol). The mixture was stirred at 78 C. for 45 min, then was treated with saturated aqueous NH.sub.4Cl. The aqueous phase was extracted twice with EtOAc, and the combined organic phases were dried and concentrated. The residue was subjected to column chromatography on silica gel, eluting with EtOAc-hexanes, to provide a mixture of diastereomers of 5-(tert-butyl) 3-ethyl 7-bromo-9b-((4-fluorophenyl)sulfonyl)-1,2,3,3a,4,9b-hexahydro-5H-cyclopenta[c]quinoline-3,5-dicarboxylate (8 g, 48% yield). This material was separated by preparative chiral SFC on a Chiralcel IC column (46250 mm, 5 m; Chiral Technologies Inc.) at 35 C., eluting with CO.sub.2-MeOH (81:19) at 320 mL/min and 140 bars. The fourth peak to elute (t.sub.R 7.11 min) provided 5-(tert-butyl) 3-ethyl (3R,3aR,9bS)-7-bromo-9b-((4-fluorophenyl)sulfonyl)-1,2,3,3a,4,9b-hexahydro-5H-cyclopenta[c]quinoline-3,5-dicarboxylate (2.4 g). LCMS m/z 366.0 (M-(C.sub.6H.sub.4FSO.sub.2+tBu)+H).sup.+, HPLC t.sub.R 1.11 min (method B). The absolute configuration was determined by single crystal X-ray analysis of Example 216, Step A, from the anomalous dispersion signal using the Flack method.
Intermediate 6
ethyl (3S,3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylate
(38) ##STR00037##
(39) Activated copper was prepared by adding zinc dust (24.6 g, 376 mmol) portionwise with stirring to a solution of CuSO.sub.4 pentahydrate (45.1 g, 283 mmol) in water (250 mL) over 10 min. The mixture was stirred 10 min longer, then the supernatant was decanted from the red precipitate. This was washed twice with water by decantation, then was stirred with 1 M aqueous HCl (400 mL) for 2.5 h. The supernatant was decanted and the precipitate was washed repeatedly by decantation after stirring with fresh water until the pH of the supernatant was about 7. The solid was stored under water and an inert atmosphere (nitrogen or argon). For use the solid was washed twice by decantation from MeOH, then twice by decantation from diethyl ether, and dried under vacuum.
(40) Dried activated copper (240 mg, 3.8 mmol) under nitrogen in a vial was purged of air by evacuation and back-filling with nitrogen. A solution of ethyl (3S,3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-iodo-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylate (Intermediate 2; 200 mg, 0.38 mmol) in DMF (1.9 mL) was added, followed by 1,1,1,2,3,3,3-heptafluoro-2-iodopropane (270 L, 1.9 mmol). The vial was sealed under a nitrogen atmosphere and heated to 120 C. for 4 h. The mixture was cooled to rt, diluted with EtOAc and filtered through Celite. The solids were washed with EtOAc and the combined filtrates were washed 4 times with brine, dried and concentrated. The residue was subjected to column chromatography on silica gel, eluting with EtOAc-hexanes, to provide ethyl (3S,3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylate (150 mg, 70% yield). LCMS m/z 571.1 (M+H).sup.+; HPLC t.sub.R 1.20 min (Method B). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.47 (d, J=8.1 Hz, 1H), 7.43-7.33 (m, 2H), 7.25 (d, J=7.0 Hz, 4H), 4.14 (q, J=7.0 Hz, 2H), 3.28-3.20 (m, 1H), 3.04 (br dd, J=14.2, 5.6 Hz, 1H), 2.86-2.71 (m, 1H), 2.68-2.54 (m, 1H), 2.37-2.21 (m, 1H), 2.16 (br d, J=6.4 Hz, 1H), 2.13-2.04 (m, 1H), 2.01-1.94 (m, 2H), 1.28-1.18 (m, 4H). .sup.19F NMR (471 MHz, CDCl.sub.3) 103.1 (s, 1F), 75.1 (m, 6F), 75.0 (m, 1F).
(41) The Intermediates in Table 1 were prepared using the procedures used to prepare Intermediate 6, or similar procedures, from the appropriate precursors.
(42) TABLE-US-00002 TABLE 1 HPLC Intermediate LCMS m/z t.sub.R HPLC number Structure observed (min) method 7
Intermediate 11
(3S,3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylic acid
(43) ##STR00042##
(44) A solution of ethyl (3S,3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-iodo-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylate (Intermediate 6; 140 mg, 0.25 mmol) in a mixture of THF (2.5 mL) and water (1.2 mL) was treated with LiOH hydrate (59 mg, 2.5 mmol). The reaction was heated to 65 C. and stirred for 1 h. The mixture was cooled to rt, diluted with EtOAc and washed with 1 M aqueous HCl. The organic layer was dried and concentrated to provide (3S,3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylic acid (133 mg, 99% yield), used without further purification. LCMS m/z 543.1 (M+H).sup.+; HPLC t.sub.R 1.08 min (Method B). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.47-7.37 (m, 2H), 7.37-7.25 (m, 5H), 3.04-2.91 (m, 2H), 2.64 (br d, J=16.2 Hz, 1H), 2.51-2.48 (m, 1H), 2.32-2.14 (m, 2H), 1.99-1.88 (m, 2H), 1.87-1.67 (m, 1H), 1.27-1.10 (m, 1H). .sup.19F NMR (471 MHz, DMSO-d.sub.6) 103.1 (s, 1F), 75.1 (m, 6F), 75.0 (m, 1F).
(45) The Intermediates in Table 2 were prepared using the procedures used to prepare Intermediate 11, or similar procedures, from the appropriate precursors.
(46) TABLE-US-00003 TABLE 2 LCMS HPLC Intermediate m/z t.sub.R HPLC number Structure observed (min) method 12
Intermediate 16
(3R,3aR,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[c]quinoline-3-carboxylic acid hydrochloride
(47) ##STR00047##
(48) (3R,3aR,9bS)-5-(tert-butoxycarbonyl)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[c]quinoline-3-carboxylic acid (Intermediate 15; 400 mg, 0.62 mmol) was dissolved in HCl (4 M in 1,4-dioxane; 10 mL). After 2 h, the solvent was removed under reduced pressure to provide (3R,3aR,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[c]quinoline-3-carboxylic acid hydrochloride (360 mg, 100% yield). LCMS m/z 544.0 (M+H).sup.+; HPLC t.sub.R 1.02 min (Method A).
Intermediate 17
1-(2-hydroxy-2-methylpropyl)-1H-tetrazole-5-carboxylic acid
(49) ##STR00048##
(50) A mixture of ethyl 1H-tetrazole-5-carboxylate (300 mg, 2.11 mmol), 2,2-dimethyloxirane (152 mg, 2.11 mmol) and K.sub.2CO.sub.3 (583 mg, 4.22 mmol) in tert-butanol (2 mL) was heated in a sealed vial at 100 C. overnight. The mixture was cooled to rt and concentrated, and the residue was suspended in THF (3 mL) and MeOH (1 mL). This mixture was treated with a solution of LiOH hydrate (266 mg, 6.33 mmol) in water (1 mL) and stirred at rt for 2 h. The mixture was concentrated and the residue was acidified to pH 1 with 1 M aqueous HCl. This mixture was frozen at 78 C. and lyophilized overnight to provide 1-(2-hydroxy-2-methylpropyl)-1H-tetrazole-5-carboxylic acid as a mixture with LiCl and KCl. The mixture was used without further purification. LCMS m/z 187.0 (M+H).sup.+, HPLC t.sub.R 0.39 min (method A).
Intermediate 18
(S)-1-(2-cyanoethyl)-5-oxopyrrolidine-2-carboxylic acid
(51) ##STR00049##
(52) A solution of NaOH (2.72 g, 68.0 mmol) in water (11.3 mL) was stirred at rt and treated with L-glutamic acid (5.00 g, 34.0 mmol), gradually forming a solution. Acrylonitrile (2.68 mL, 40.8 mmol) was added and the mixture was heated at 50 C. overnight. After 20 h, the mixture was cooled in an ice-water bath and treated slowly with concentrated aqueous HCl (5.2 mL, 64.6 mmol). The solution was concentrated and the residue was suspended in acetone (40 mL) and heated at reflux overnight. After 20 h the mixture was cooled to rt. A white precipitate was removed by filtration and the filtrate was concentrated to afford a colorless oil. This material was purified by preparative SFC on a Princeton Cyano column (30250 mm, 5 m) at 40 C., eluting with CO.sub.2-MeOH (80:20) at 160 mL/min and 100 bar. (S)-1-(2-cyanoethyl)-5-oxopyrrolidine-2-carboxylic acid was isolated as a white solid (3.72 g, 60% yield). LCMS m/z 183.1 (M+H).sup.+, HPLC t.sub.R 0.39 min (method A). .sup.1H NMR (499 MHz, DMSO-d.sub.6) 13.06 (br. s., 1H), 4.35-4.29 (m, 1H), 3.75 (dt, J=14.0, 7.0 Hz, 1H), 3.21-3.13 (m, 1H), 2.73 (t, J=6.8 Hz, 2H), 2.35-2.22 (m, 3H), 2.02-1.96 (m, 1H).
Intermediate 19
(2S,4R)-4-fluoro-1-(methyl-d3)-5-oxopyrrolidine-2-carboxylic acid
(53) ##STR00050##
Step A: 1-(tert-butyl) 2-methyl (2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate
(54) ##STR00051##
(55) A solution of (2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (10.0 g, 40.8 mmol) in DCM (204 mL) was cooled in an ice-water bath and treated slowly with DAST (6.5 mL, 48.9 mmol). The mixture was stirred at rt for 5.5 h, then was partitioned between water and additional DCM. The organic phase was washed with brine, dried and concentrated to afford 1-(tert-butyl) 2-methyl (2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate as a light yellow syrup (10.6 g, 94% yield, 90% estimated purity). LCMS m/z 270.2 (M+Na).sup.+; HPLC t.sub.R 0.80 min (method A).
Step B: 1-(tert-butyl) 2-methyl (2S,4R)-4-fluoro-5-oxopyrrolidine-1, 2-dicarboxylate
(56) ##STR00052##
(57) A solution of sodium periodate (44.6 g, 209 mmol) in water (435 mL) was treated with RuCl.sub.3 hydrate (7.84 g, 34.8 mmol), forming a dark red solution. This was treated slowly with a solution of crude (2S,4R)-1-tert-butyl 2-methyl 4-fluoropyrrolidine-1,2-dicarboxylate (9.55 g, 34.8 mmol) in EtOAc (145 mL). The mixture was stirred at rt for 17 h, then was treated with IPA (80 mL) and stirred at rt for 3 h. The mixture was filtered through Celite and the solids were washed with water and EtOAc. The combined filtrates were diluted with additional EtOAc and water. The organic phase was separated, washed with brine, dried and concentrated. The residue was purified by column chromatography on silica gel (120 g), eluting with EtOAc-hexanes (10-50%), to provide 1-(tert-butyl) 2-methyl (2S,4R)-4-fluoro-5-oxopyrrolidine-1,2-dicarboxylate as a light yellow oil (67% yield). LCMS m/z 284.0 (M+Na).sup.+; HPLC t.sub.R 0.76 min (method A). .sup.1H NMR (400 MHz, CDCl.sub.3) 5.30-5.11 (m, 1H), 4.68 (dd, J=9.5, 2.0 Hz, 1H), 3.81 (s, 3H), 2.61-2.40 (m, 2H), 1.53 (s, 9H).
Step C: methyl (2S,4R)-4-fluoro-5-oxopyrrolidine-2-carboxylate
(58) ##STR00053##
(59) A solution of (2S,4R)-1-tert-butyl 2-methyl 4-fluoro-5-oxopyrrolidine-1,2-dicarboxylate (7.75 g, 25.8 mmol) in DCM (32 mL) was cooled in an ice-water bath and treated with TFA (12 mL). The mixture was stirred at rt for 2 h, then was concentrated and the residue was partitioned between water and EtOAc. The organic phase was washed sequentially with 1.5 M aqueous K.sub.2HPO.sub.4 and brine, dried and concentrated. The aqueous phase was extracted with chloroform-IPA (3:1) to provide additional product. The two portions were combined to provide methyl (2S,4R)-4-fluoro-5-oxopyrrolidine-2-carboxylate as a dark yellow syrup (3.38 g, 81% yield), used without further purification. LCMS m/z 162.0 (M+H).sup.+; HPLC t.sub.R 0.41 min (method A). .sup.1H NMR (400 MHz, CDCl.sub.3) 6.86 (br. s., 1H), 5.23-5.03 (m, 1H), 4.47-4.34 (m, 1H), 3.82-3.78 (m, 3H), 2.69-2.58 (m, 2H).
Step D: methyl (2S,4R)-4-fluoro-1-(methyl-d3)-5-oxopyrrolidine-2-carboxylate
(60) ##STR00054##
(61) A mixture of (2S,4R)-methyl 4-fluoro-5-oxopyrrolidine-2-carboxylate (0.48 g, 2.98 mmol) and Cs.sub.2CO.sub.3 (2.43 g, 7.45 mmol) in MeCN (16.6 mL) was treated with iodomethane-d.sub.3 (927 L, 14.9 mmol) and heated in a sealed vial at 45 C. overnight. After 18 h, the mixture was cooled to rt, filtered and concentrated to provide methyl (2S,4R)-4-fluoro-1-(methyl-d.sub.3)-5-oxopyrrolidine-2-carboxylate as a light yellow solid (0.53 g, quantitative yield), used without further purification. LCMS m/z 179.1 (M+H).sup.+; HPLC t.sub.R 0.46 min (method A).
Step E: (2S,4R)-4-fluoro-1-(methyl-d3)-5-oxopyrrolidine-2-carboxylic acid
(62) ##STR00055##
(63) A mixture of methyl (2S,4R)-4-fluoro-1-(methyl-d.sub.3)-5-oxopyrrolidine-2-carboxylate (530 mg, 2.97 mmol) and LiOH monohydrate (221 mg, 9.22 mmol) in THF-MeOH-water (3:1:1) (29.7 mL) was stirred at rt for 18 h. The mixture was concentrated, the residue was treated with HCl (4 M in 1,4-dioxane; 2.4 mL, 9.6 mmol), and the mixture was concentrated again to dryness. The crude mixture containing (2S,4R)-4-fluoro-1-(methyl-d.sub.3)-5-oxopyrrolidine-2-carboxylic acid and LiCl was used without further purification. LCMS m/z 165.0 (M+H).sup.+; HPLC t.sub.R 0.35 min (method A).
Intermediate 20
(2S,4R)-4-fluoro-5-oxopyrrolidine-2-carboxylic acid
(64) ##STR00056##
(65) A solution of methyl (2S,4R)-4-fluoro-5-oxopyrrolidine-2-carboxylate (Intermediate 19, Step C; 1.01 g, 6.27 mmol) in THF (30 mL) and MeOH (10 mL) was treated with a solution of LiOH monohydrate (407 mg, 9.70 mmol) in water (10 mL). The mixture was stirred at rt for 2 h, then was acidified with 1 M aqueous HCl (9.8 mL) and concentrated under vacuum to remove the organic solvents. The aqueous residue was frozen at 78 C. and lyophilized to provide (2S,4R)-4-fluoro-5-oxopyrrolidine-2-carboxylic acid as a sticky yellow-tan amorphous solid (1.55 g) containing LiCl and residual water (estimated purity 60%) which was used without further purification. LCMS m/z 189.4 (M+H+MeCN).sup.+; HPLC t.sub.R 0.29 min (method A).
Intermediate 21
(2S,4R)-4-hydroxy-1-(methyl-d3)-5-oxopyrrolidine-2-carboxylic acid
(66) ##STR00057##
Step A: 1-(tert-butyl) 2-methyl (2S,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate
(67) ##STR00058##
(68) A solution of (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (2.00 g, 8.15 mmol) in THF (48 mL), cooled in an ice-water bath, was treated slowly with a solution of tert-butylchlorodimethylsilane (1.97 g, 13.1 mmol) in THF (6 mL), then with imidazole (1.22 g, 17.9 mmol). The mixture was stirred at rt overnight. After 18 h, the mixture was heated at 50 C. for 6 h, then stirred at rt for 3 days. The mixture was concentrated and the residue was partitioned between EtOAc and water. The organic phase was washed sequentially with 0.3 M aqueous HCl, saturated aqueous NaHCO.sub.3 and brine, dried and concentrated to provide 1-(tert-butyl) 2-methyl (2S,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate as a nearly colorless oil (3.22 g, quantitative yield). LCMS m/z 260.2 (M+HC.sub.4H.sub.8).sup.+, 741.3 (2M+Na).sup.+; HPLC t.sub.R 1.16 min (method B). .sup.1H NMR (400 MHz, CDCl.sub.3) 4.47-4.30 (m, 2H), 3.76-3.72 (m, 3H), 3.65-3.54 (m, 1H), 3.45-3.28 (m, 1H), 2.24-2.12 (m, 1H), 2.07-1.97 (m, 1H), 1.48-1.40 (m, 9H), 0.88 (s, 9H), 0.07 (s, 6H).
Step B: 1-(tert-butyl) 2-methyl (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-5-oxopyrrolidine-1,2-dicarboxylate
(69) ##STR00059##
(70) A solution of sodium periodate (4.39 g, 20.5 mmol) in water (78 mL) was treated with RuO.sub.2 hydrate (271 mg, 1.79 mmol) and stirred at rt for 5 min. This mixture was then treated with a solution of (2S,4R)-1-tert-butyl 2-methyl 4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (3.22 g, 8.15 mmol) in EtOAc (58 mL) and stirred at rt. After 5 h, the mixture was diluted with EtOAc, filtered through Celite, and the solids were washed with water and EtOAc. The combined filtrates were partitioned between water and EtOAc. The organic phase was washed sequentially with 10% aqueous Na.sub.2S.sub.2O.sub.3, saturated aqueous NaHCO.sub.3 and brine, dried and concentrated to provide 1-(tert-butyl) 2-methyl (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-5-oxopyrrolidine-1,2-dicarboxylate as a colorless oil (3.16 g, 86% yield, about 83% pure), used without further purification. LCMS m/z 274.2 (M+HC.sub.4H.sub.8).sup.+, 769.3 (2M+Na).sup.+.
Step C: methyl (2S,4R)-4-hydroxy-5-oxopyrrolidine-2-carboxylate
(71) ##STR00060##
(72) A solution of 1-tert-butyl 2-methyl (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-5-oxopyrrolidine-1,2-dicarboxylate (3.16 g, 7.02 mmol) in DCM (9 mL) was cooled in an ice-water bath and treated with TFA (1.9 mL). The mixture was warmed to rt and stirred overnight, then was concentrated to provide crude methyl (2S,4R)-4-hydroxy-5-oxopyrrolidine-2-carboxylate as a yellow syrup (2.08 g), used without further purification. LCMS m/z 160.1 (M+H).sup.+; HPLC t.sub.R 0.32 min (method B).
Step D: (2S,4R)-4-hydroxy-1-(methyl-d3)-5-oxopyrrolidine-2-carboxylic acid
(73) ##STR00061##
(74) Following the procedures used in Steps D and E of the preparation of Intermediate 19, methyl (2S,4R)-4-hydroxy-5-oxopyrrolidine-2-carboxylate was converted into (2S,4R)-4-hydroxy-1-(methyl-d.sub.3)-5-oxopyrrolidine-2-carboxylic acid. LCMS m/z 163.0 (M+H).sup.+; HPLC t.sub.R 0.26 min (method B).
Intermediate 22
(2RS,4RS)-2-methyltetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide
(75) ##STR00062##
Step A: 4-((benzyloxy)methyl)tetrahydro-2H-thiopyran
(76) ##STR00063##
(77) A suspension of NaH (60% in mineral oil; 1.234 g, 30.9 mmol) in DMF (50 mL) at 0 C. was treated portionwise with a solution of (tetrahydro-2H-thiopyran-4-yl)methanol (3.4 g, 25.7 mmol) in DMF (2 mL) and the mixture was stirred for 15 min. Benzyl bromide (3.4 mL, 28.3 mmol) was added dropwise over 2 min, and the mixture was allowed to warm to rt. After 1.5 h, the mixture was treated with saturated aqueous NH.sub.4Cl (20 mL), diluted with water (50 mL) and extracted with EtOAc (75 mL). The organic phase was washed sequentially with 10% aqueous LiCl (330 mL) and brine (30 mL), dried and concentrated. The residue was purified by column chromatography on silica gel (120 g), eluting with EtOAc-hexanes (gradient from 0-10%), to give 4-((benzyloxy)methyl)tetrahydro-2H-thiopyran as a colorless oil (3.4 g, 60% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.43-7.27 (m, 5H), 4.50 (s, 2H), 3.31 (d, J=6.4 Hz, 2H), 2.75-2.66 (m, 2H), 2.66-2.57 (m, 2H), 2.16-2.07 (m, 2H), 1.79-1.62 (m, 1H), 1.51-1.34 (m, 2H).
Step B: 4-((benzyloxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide
(78) ##STR00064##
(79) A solution of 4-((benzyloxy)methyl)tetrahydro-2H-thiopyran (4.7 g, 21.1 mmol) in DCM (125 mL) at 0 C. was treated portionwise with mCPBA (77%; 9.95 g, 44.4 mmol) and the ice bath was removed to allow the mixture to warm to rt. After 2 h, the mixture was cooled to 0 C. and filtered, and the filtrate was stirred at rt for 10 min with 10% aqueous Na.sub.2S.sub.2O.sub.3 (120 mL). The organic phase was separated and washed with 10% aqueous K.sub.2CO.sub.3 (2150 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography on silica gel (120 g), eluting with EtOAc-hexanes (gradient from 0-60%), to give 4-((benzyloxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide as a white solid (4.9 g, 91% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.42-7.28 (m, 5H), 4.51 (s, 2H), 3.43-3.30 (m, 2H), 3.14-2.87 (m, 4H), 2.20 (d, J=11.9 Hz, 2H), 2.00-1.76 (m, 3H).
Step C: (2RS,4RS)-4-((benzyloxy)methyl)-2-methyltetrahydro-2H-thiopyran 1,1-dioxide
(80) ##STR00065##
(81) A solution of diisopropylamine (579 L, 4.13 mmol) in THF (12 mL) under nitrogen was cooled to 78 C. and treated dropwise with n-butyllithium (2.4 M in hexanes; 1.556 mL, 3.74 mmol) and the mixture was stirred for 30 min, then at rt for 15 min. The mixture was cooled to 78 C., treated over 3 min with a solution of 4-((benzyloxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide (1.00 g, 3.93 mmol) in THF (5 mL) and stirred for 1 h. The mixture was then treated with a solution of iodomethane (257 L, 4.13 mmol) in THF (0.5 mL). After 45 min, the cooling bath was removed and the mixture was allowed to warm to rt, then was stirred for 1 h. The mixture was treated with saturated aqueous NH.sub.4Cl (50 mL) and extracted with EtOAc (250 mL). The combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (gradient from 0-35%), to give racemic cis-4-((benzyloxy)methyl)-2-methyltetrahydro-2H-thiopyran 1,1-dioxide as a white solid (450 mg, 43% yield). LCMS m/z 290.8 (M+Na).sup.+; HPLC t.sub.R 0.81 min (method B). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.41-7.28 (m, 5H), 4.51 (s, 2H), 3.33 (d, J=6.2 Hz, 2H), 3.12 (dt, J=14.3, 3.4 Hz, 1H), 3.04-2.87 (m, 2H), 2.23-2.12 (m, 1H), 2.11-2.03 (m, 1H), 2.00-1.76 (m, 2H), 1.69-1.59 (m, 1H), 1.35 (d, J=6.8 Hz, 3H). The dimethylated side product (2R,4r,6S)-4-((benzyloxy)methyl)-2,6-dimethyltetrahydro-2H-thiopyran 1,1-dioxide was also isolated in 75% purity (250 mg, 23% yield). LCMS m/z 283.1 (M+H).sup.+; HPLC t.sub.R 0.88 min (method B).
Step D: (2RS,4RS)-4-(hydroxymethyl)-2-methyltetrahydro-2H-thiopyran 1,1-dioxide
(82) ##STR00066##
(83) A solution of (2RS,4RS)-4-((benzyloxy)methyl)-2-methyltetrahydro-2H-thiopyran 1,1-dioxide (450 mg, 1.68 mmol) in MeOH (2 mL) and ethanol (10 mL) was treated with palladium on carbon (160 mg, 0.075 mmol) and stirred under a hydrogen atmosphere (balloon pressure) for 1.5 h. The mixture was filtered to remove the catalyst and the filtrate was concentrated to give (2RS,4RS)-4-(hydroxymethyl)-2-methyltetrahydro-2H-thiopyran 1,1-dioxide as a white solid (280 mg, 94% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) 3.53 (d, J=5.7 Hz, 1H), 3.20-3.09 (m, 1H), 3.06-2.85 (m, 2H), 2.24-2.12 (m, 1H), 2.10-2.00 (m, 2H), 1.92-1.73 (m, 2H), 1.67-1.52 (m, 1H), 1.36 (d, J=6.8 Hz, 3H).
Step E: (2RS,4RS)-2-methyltetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide
(84) ##STR00067##
(85) A solution of (2RS,4RS)-4-(hydroxymethyl)-2-methyltetrahydro-2H-thiopyran 1,1-dioxide (275 mg, 1.54 mmol) in MeCN (0.9 mL) and CCl.sub.4 (0.9 mL) was treated with a solution of sodium periodate (1.35 g, 6.33 mmol) in water (1.3 mL), then with RuCl.sub.3 hydrate (14 mg, 0.062 mmol), and the mixture was stirred at rt. After 30 min, the mixture was a yellow emulsion, and stirring was continued at rt for 30 min more with occasional sonication. An additional portion of RuCl.sub.3 hydrate (14 mg, 0.062 mmol) was added, and stirring was continued for 1 h with occasional sonication. The mixture was diluted with EtOAc (125 mL), the organic phase was separated and washed with water (25 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was treated with EtOAc (125 mL) and MeOH (10 mL), filtered and concentrated to give (2RS,4RS)-2-methyltetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide as a gray solid (165 mg, 56% yield), used without further purification. .sup.1H NMR (400 MHz, MeOH-d.sub.4) 3.28-3.04 (m, 3H), 2.69 (tt, J=12.4, 3.3 Hz, 1H), 2.37 (d quin, J=14.1, 3.5 Hz, 1H), 2.28 (dq, J=14.2, 3.2 Hz, 1H), 2.18-2.03 (m, 1H), 1.86 (dt, J=14.3, 12.5 Hz, 1H), 1.29 (d, J=6.8 Hz, 3H).
Intermediate 23
2-(3-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl)acetic acid (racemic)
(86) ##STR00068##
Step A: tert-butyl 2-(3-hydroxytetrahydrothiophen-3-yl)acetate (racemic)
(87) ##STR00069##
(88) A solution of tert-butyl acetate (3.1 mL, 23.4 mmol) in THF (50 mL) at 78 C. was treated slowly with lithium bis(trimethylsilyl)amide (1.0 M in THF; 22.2 mL, 22.2 mmol). The mixture was stirred for 45 min, then was treated slowly with a solution of tetrahydrothiophen-3-one (2.00 mL, 23.4 mmol) in THF (5 mL). The mixture was stirred at 78 C. for 20 min, then was treated slowly with 2 M aqueous HCl (12.3 mL). The cooling bath was removed and the mixture was warmed to rt, then was extracted twice with EtOAc. The combined organic phases were washed sequentially with 1.5 M aqueous K.sub.2HPO.sub.4 and brine, dried and concentrated to provide crude racemic tert-butyl 2-(3-hydroxytetrahydrothiophen-3-yl)acetate as a colorless oil, used without purification. LCMS m/z 163.0 (M+H-tBu).sup.+; HPLC t.sub.R 0.81 min (method A).
Step B: tert-butyl 2-(3-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl)acetate
(89) ##STR00070##
(90) A solution of crude racemic tert-butyl 2-(3-hydroxytetrahydrothiophen-3-yl)acetate (4.80 g, 22.0 mmol) in DCM (75 mL) at 0 C. was treated portionwise with mCPBA (70%, 17.3 g, 77.0 mmol). After 50 min, additional mCPBA (3.79 g) was added. After a total of 2 h, the mixture was filtered through Celite and the solids were washed with DCM. The combined filtrates were washed sequentially with saturated aqueous NaHCO.sub.3 and brine, dried and concentrated to provide racemic tert-butyl 2-(3-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl)acetate as a white solid (5.55 g, quantitative yield). .sup.1H NMR (499 MHz, DMSO-d.sub.6) 5.48 (s, 1H), 3.26-3.12 (m, 4H), 2.67-2.54 (m, 2H), 2.31-2.12 (m, 2H), 1.41 (s, 9H).
Step C: 2-(3-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl)acetic acid (racemic)
(91) ##STR00071##
(92) A solution of racemic tert-butyl 2-(3-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl)acetate (5.55 g, 22.2 mmol) in DCM (60 mL) at rt was treated with TFA (12 mL, 156 mmol). After 2 h the solution was concentrated and dried in vacuo to provide racemic 2-(3-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl)acetic acid as a white solid (4.21 g, 98% yield), used without further purification. .sup.1H NMR (499 MHz, DMSO-d.sub.6) 3.30-3.13 (m, 4H), 2.70-2.57 (m, 2H), 2.31-2.15 (m, 2H).
Intermediate 24
(1R,2S,4R)-4-(methoxycarbonyl)-2-methylcyclohexane-1-carboxylic acid
(93) ##STR00072##
Step A: tert-butyl 2-acetyl-5-oxohexanoate (racemic)
(94) ##STR00073##
(95) A mixture of methyl vinyl ketone (116 mL, 1.43 mol), tert-butyl acetoacetate (248 mL, 1.50 mol), and TEA (994 L, 7.13 mmol) was cooled to 12 C. in an acetone-dry ice bath. LiClO.sub.4 (15.2 g, 143 mmol) was added portionwise over 30 min, then the mixture was warmed to 25 C. and stirred for 22 h. Diethyl ether (5 L) and added and the resulting mixture was washed sequentially with water (75 mL) and brine (75 mL), dried and concentrated. The residue, a cloudy oil (331.8 g), was redissolved in ether, filtered, and the filtrate was concentrated to give racemic tert-butyl 2-acetyl-5-oxohexanoate as a colorless oil (330.5 g, quantitative yield). .sup.1H NMR (400 MHz, CDCl.sub.3) 3.40-3.40 (m, 1H), 2.54-2.45 (m, 2H), 2.25-2.21 (m, 3H), 2.15 (s, 3H), 2.12-2.01 (m, 2H), 1.48-1.45 (m, 9H).
Step B: tert-butyl (R)-2-methyl-4-oxocyclohex-2-ene-1-carboxylate
(96) ##STR00074##
(97) A mixture of tert-butyl 2-acetyl-5-oxohexanoate (57.5 g, 252 mmol), THF (331 mL), acetic acid (13.7 mL, 239 mmol) and piperidine (20.0 mL, 202 mmol) was heated to 60 C. and stirred for 44 h. EtOAc (670 mL) was added, followed by 1 N aqueous HCl (200 mL). The mixture was stirred for 10 minutes, then the layers were separated. The organic phase was washed sequentially with saturated aqueous NaHCO.sub.3 (2200 mL) and brine (200 mL), dried and concentrated. The residue was subjected to column chromatography, and the resulting racemic product was separated by preparative SFC to give tert-butyl (R)-2-methyl-4-oxocyclohex-2-ene-1-carboxylate (18.0 g, 34% yield). .sup.1H NMR (499 MHz, CDCl.sub.3) 6.09-5.75 (m, 1H), 3.36-3.05 (m, 1H), 2.68-2.47 (m, 1H), 2.41-2.27 (m, 2H), 2.26-2.13 (m, 1H), 2.09-2.00 (m, 3H), 1.50 (s, 9H).
Step C: tert-butyl (1R, 2S)-2-methyl-4-oxocyclohexane-1-carboxylate
(98) ##STR00075##
(99) A solution of tert-butyl (R)-2-methyl-4-oxocyclohex-2-enecarboxylate (20.5 g, 97 mmol) in THF (195 mL) was bubbled with N.sub.2 for several minutes. Wet 10% Pd on carbon (2 g, 1.88 mmol) was added and the mixture was stirred under a hydrogen atmosphere (balloon pressure) for 14 h. The mixture was filtered through Celite and the solids were rinsed with THF (500 mL). The combined filtrates were concentrated to give tert-butyl (1R, 2S)-2-methyl-4-oxocyclohexanecarboxylate (22.9 g, quantitative yield). .sup.1H NMR (400 MHz, CDCl3) 2.85-2.69 (m, 1H), 2.61-2.38 (m, 4H), 2.36-1.93 (m, 3H), 1.54-1.42 (m, 9H), 1.04-0.92 (m, 3H).
Step D: tert-butyl (1R, 6S)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate
(100) ##STR00076##
(101) A mixture of N,N-bis(trifluoromethylsulfonyl)aniline (50.1 g, 140 mmol) and tert-butyl (1R,2S)-2-methyl-4-oxocyclohexanecarboxylate (22.9 g, 108 mmol) in anhydrous THF (330 mL) was cooled to 70 C. on an acetone-dry ice bath. Potassium bis(trimethylsilyl)amide (1.0 M in THF; 140 mL, 140 mmol) was added dropwise with stirring over 1 h. After 1 h more, the mixture was treated with water (500 mL) and warmed to 0 C. The mixture was extracted with EtOAc (500 mL), and the organic phase was washed sequentially with water (500 mL) and brine (500 mL), and dried and concentrated. The residue (41 g) was subjected to column chromatography on silica gel to give tert-butyl (1R,2S)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate (30.2 g, 81% yield). .sup.1H NMR (499 MHz, CDCl.sub.3) 5.76 (td, J=5.4, 1.9 Hz, 1H), 2.99-2.09 (m, 5H), 2.02-1.86 (m, 1H), 1.48 (d, J=3.5 Hz, 9H), 1.05-0.99 (m, 3H).
Step E: 4-(tert-butyl) 1-methyl (4R, 5S)-5-methylcyclohex-1-ene-1, 4-dicarboxylate
(102) ##STR00077##
(103) A solution of tert-butyl (1R, 6S)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-cyclohex-3-enecarboxylate (29.6 g, 86 mmol) in anhydrous DMF (215 mL) and MeOH (215 mL) was bubbled with nitrogen for 5 min. Palladium acetate (1.93 g, 8.59 mmol), 1,1-bis(diphenylphosphino)ferrocene (4.76 g, 8.59 mmol) and TEA (35.9 mL, 258 mmol) were added. The mixture was then bubbled with carbon monoxide for 10 min and stirred at rt under a carbon monoxide atmosphere (balloon pressure) for 18 h. The mixture was diluted with EtOAc (500 mL), washed sequentially with 10% aqueous LiCl (3500 mL) and brine (500 mL), dried and concentrated. The residue was subjected to column chromatography to give 4-tert-butyl 1-methyl (4R,5S)-5-methylcyclohex-1-ene-1,4-dicarboxylate (14.1 g, 65% yield). .sup.1H NMR (499 MHz, CDCl.sub.3) 6.97-6.89 (m, 1H), 3.74 (s, 3H), 2.88-1.75 (m, 6H), 1.47 (d, J=3.8 Hz, 9H), 1.01 (d, J=7.2 Hz, 2H), 0.92 (d, J=6.8 Hz, 1H).
Step F: 1-(tert-butyl) 4-methyl (1R, 2S, 4R)-2-methylcyclohexane-1,4-dicarboxylate
(104) ##STR00078##
(105) A solution of 4-tert-butyl 1-methyl (4R, 5S)-5-methylcyclohex-1-ene-1,4-dicarboxylate (14.09 g, 55.4 mmol) in DCM (554 mL) was bubbled with nitrogen for 10 min. (1,5-cyclooctadiene)-pyridine(tricyclohexylphosphine)iridium(1) hexafluorophosphate (Crabtree's catalyst; 1.12 g, 1.39 mmol) was added and the mixture was evacuated and purged 3 times with hydrogen. The mixture was stirred under a hydrogen atmosphere (balloon pressure) for 17 h. The solution was concentrated and the residue was subjected to column chromatography on silica gel to give 1-tert-butyl 4-methyl (1R,2S,4R)-2-methylcyclohexane-1,4-dicarboxylate as a colorless oil (14.1 g, 99% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) 3.66 (s, 3H), 2.54-2.34 (m, 3H), 2.00 (ddd, J=13.2, 3.7, 1.7 Hz, 1H), 1.89-1.80 (m, 1H), 1.78-1.56 (m, 3H), 1.46-1.38 (m, 10H), 0.92 (d, J=7.1 Hz, 3H).
Step G: (1R, 2S, 4R)-4-(methoxycarbonyl)-2-methylcyclohexane-1-carboxylic acid
(106) ##STR00079##
(107) A solution of 1-tert-butyl 4-methyl (1R,2S,4R)-2-methylcyclohexane-1,4-dicarboxylate (27.5 g, 107 mmol) in DCM (37.2 mL) was treated with TFA (37.2 mL, 483 mmol) and stirred at rt. After 9 h, the mixture was concentrated, and the residue was treated with heptane (100 mL) and concentrated again. The residue was treated with heptane twice more (220 mL) and concentrated under high vacuum. The residue was crystallized from 5% tert-butyl methyl ether-heptane to give (1R,2S,4R)-4-(methoxycarbonyl)-2-methylcyclohexanecarboxylic acid as a white solid (17.3 g, 80% yield). .sup.1H NMR (499 MHz, CDCl.sub.3) 3.68 (s, 3H), 2.57-2.46 (m, 3H), 2.04 (dqd, J=13.3, 3.8, 1.8 Hz, 1H), 1.93-1.87 (m, 1H), 1.83 (dq, J=14.0, 3.9 Hz, 1H), 1.78-1.63 (m, 2H), 1.52-1.39 (m, 1H), 0.98 (d, J=7.0 Hz, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) 179.7, 176.3, 51.7, 45.1, 37.0, 34.8, 29.5, 27.6, 21.1, 13.9.
Intermediate 25
(1s,4s)-4-(ethoxycarbonyl)-1-fluorocyclohexane-1-carboxylic acid
(108) ##STR00080##
Step A: mixture of ethyl (3r,6r)-1-oxaspiro[2.5]octane-6-carboxylate and ethyl (3s,6r)-1-oxaspiro[2.5]octane-6-carboxylate
(109) ##STR00081##
(110) A suspension of potassium tert-butoxide (5.03 g, 44.8 mmol) in dry THF (100 mL) was treated with trimethylsulfoxonium iodide (10.2 g, 46.4 mmol) and the mixture was stirred at reflux under nitrogen for 2 h. The mixture was cooled to rt, treated dropwise over 2 min with a solution of ethyl 4-oxocyclohexanecarboxylate (5.3 g, 31.1 mmol) in THF (30 mL), then heated at reflux for 2.5 h. The mixture was cooled to rt, partitioned between EtOAc (250 mL) and water (150 mL) and the aqueous phase was extracted with EtOAc (250 mL). The combined organic phases were dried and concentrated. The residue was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (gradient from 0-15%), to give a mixture of ethyl (3r,6r)-1-oxaspiro[2.5]octane-6-carboxylate and ethyl (3s,6r)-1-oxaspiro[2.5]octane-6-carboxylate (3.8 g, 66% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) 4.13 (q, J=7.2 Hz, 2.2H), 2.63 (s, 2H), 2.60 (s, 0.2H), 2.47-2.29 (m, 1.2H), 2.13-2.04 (m, 0.2H), 2.02-1.94 (m, 1.2H), 1.93-1.89 (m, 0.2H), 1.89-1.81 (m, 9.6H), 1.81-1.78 (m, 1.6H), 1.77-1.70 (m, 0.4H), 1.56-1.45 (m, 0.2H), 1.42-1.33 (m, 2H), 1.25 (t, J=7.2 Hz, 3.2H).
Step B: ethyl (1 s,4s)-4-fluoro-4-(hydroxymethyl)cyclohexane-1-carboxylate
(111) ##STR00082##
(112) Hydrogen fluoride (70% in pyridine; 5 mL, 5.43 mmol) was cooled to 78 C. in a polypropylene vial and treated with a solution of the mixture of ethyl (3r,6r)-1-oxaspiro[2.5]octane-6-carboxylate and ethyl (3s,6r)-1-oxaspiro[2.5]octane-6-carboxylate from Step A (1.0 g, 5.43 mmol) in DCM (5 mL). The mixture was stirred at 78 C. for 4.5 h, then was poured into ice-cold 2 M aqueous NH.sub.4OH (25 mL) and DCM (25 mL). The mixture was adjusted to pH 8 using concentrated aqueous NH.sub.4OH and extracted with DCM (250 mL). The combined organic phases were washed sequentially with 1 M aqueous HCl (50 mL) and brine (50 mL), dried and concentrated. The residue was purified by column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient from 0-30%), to give (1s,4s)-ethyl 4-fluoro-4-(hydroxymethyl)cyclohexanecarboxylate as a solid (390 mg, 35% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) 4.21-4.07 (m, 2H), 3.57 (dd, J=19.6, 5.7 Hz, 2H), 2.36-2.20 (m, 1H), 2.05 (dd, J=12.4, 9.4 Hz, 2H), 1.96-1.86 (m, 2H), 1.86-1.73 (m, 2H), 1.47-1.28 (m, 2H), 1.26 (t, J=7.2 Hz, 3H). (1s,4r)-ethyl 4-fluoro-4-(hydroxymethyl)cyclohexanecarboxylate was also isolated. .sup.1H NMR (400 MHz, CDCl.sub.3) 4.14 (q, J=7.1 Hz, 2H), 3.72-3.55 (m, 2H), 2.62-2.46 (m, 1H), 1.99-1.87 (m, 2H), 1.85-1.72 (m, 6H), 1.26 (t, J=7.2 Hz, 3H).
Step C: (1s,4s)-4-(ethoxycarbonyl)-1-fluorocyclohexane-1-carboxylic acid
(113) ##STR00083##
(114) A solution of (1s,4s)-ethyl 4-fluoro-4-(hydroxymethyl)cyclohexanecarboxylate (760 mg, 3.72 mmol) in MeCN (8 mL) and tetrachloromethane (8.00 mL) was treated with a solution of periodic acid (3.48 g, 15.26 mmol) in water (12.00 mL), then with RuCl.sub.3 hydrate (34 mg, 0.149 mmol). The mixture was stirred at rt for 1.5 h, then was diluted with diethyl ether (60 mL) and stirred at rt for 10 min. The mixture was filtered and the phases were separated, and the aqueous phase was extracted with diethyl ether (220 mL). The combined organic phases were washed with brine (230 mL), dried over Na.sub.2SO.sub.4 and concentrated to give crude (1s,4s)-4-(ethoxycarbonyl)-1-fluorocyclohexanecarboxylic acid as a solid (740 mg, 91% yield), used without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3) 4.16 (q, J=7.3 Hz, 2H), 2.45-2.31 (m, 1H), 2.23-2.11 (m, 2H), 2.04-1.94 (m, 3H), 1.94-1.72 (m, 3H), 1.27 (t, J=7.2 Hz, 3H).
Intermediates 26 and 27
8b-((4-fluorophenyl)sulfonyl)-6-iodo-2a,3,4,8b-tetrahydrocyclobuta[a]naphthalen-2(1H)-one (racemic) and 7b-((4-fluorophenyl)sulfonyl)-5-iodo-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carbaldehyde (mixture of diastereomers)
(115) ##STR00084##
Step A: 1-((4-fluorophenyl)sulfonyl)-6-iodo-2-vinyl-1,2,3,4-tetrahydronaphthalene (mixture of diastereomers)
(116) ##STR00085##
(117) A solution of 4-((4-fluorophenyl)sulfonyl)-7-iodo-1,2-dihydronaphthalene (Intermediate 1, Step A; 2.00 g, 4.83 mmol) in THF (40 mL) was stirred on a dry ice-acetone bath and treated dropwise over 10 min with vinylmagnesium bromide (1.0 M in THF; 7.0 mL, 7.00 mmol) over 10 min. The solution was stirred at 78 C. for 70 min, then was allowed to warm to rt. After 80 min more, the mixture was treated with saturated aqueous NH.sub.4Cl. The mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were washed with brine, dried and concentrated. The residue was subjected to column chromatography on silica gel (220 g), eluting with EtOAc-hexanes (gradient from 0-22%), to provide a mixture of diastereomers of 1-((4-fluorophenyl)sulfonyl)-6-iodo-2-vinyl-1,2,3,4-tetrahydronaphthalene as a white solid (1.55 g, 72%). LCMS m/z 906.9 (2M+Na).sup.+; HPLC t.sub.R 1.08 min (method A). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.70-7.60 (m, 2H), 7.58-7.48 (m, 1H), 7.47-7.25 (m, 2H), 7.24-7.12 (m, 2H), 6.77 (d, J=8.1 Hz, 0.6H), 6.41 (d, J=8.1 Hz, 0.4H), 6.38-6.25 (m, 0.4H), 5.76 (ddd, J=17.2, 10.4, 6.9 Hz, 0.6H), 5.17-4.99 (m, 2H), 4.33 (d, J=3.5 Hz, 0.4H), 4.20 (d, J=3.1 Hz, 0.6H), 3.13-2.17 (m, 4H).
Step B: 2-(1-((4-fluorophenyl)sulfonyl)-6-iodo-1,2,34-tetrahydronaphthalen-2-yl)oxirane (mixture of diastereomers)
(118) ##STR00086##
(119) A solution of 1-((4-fluorophenyl)sulfonyl)-6-iodo-2-vinyl-1,2,3,4-tetrahydronaphthalene (1.50 g, 3.39 mmol) in THF (40 mL) was stirred on an ice-water bath and treated with water until cloudy (about 22 mL). The mixture was treated in portions with N-bromosuccinimide (0.724 g, 4.07 mmol) over about 5 min, and the mixture was kept in the dark at 0 C. overnight. After 20 h, the mixture was warmed to rt while still protecting from light. After 2.5 h more, the mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were washed with brine, dried and concentrated. The residue was dissolved in MeOH (16 mL), stirred on an ice-water bath and treated with K.sub.2CO.sub.3 (0.656 g, 4.75 mmol). After 6.25 h, the mixture was concentrated and the residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with brine, dried and concentrated. The residue was subjected to column chromatography on silica gel (120 g), eluting with EtOAc-hexanes (gradient from 10-40%), to provide a mixture of diastereomers of 2-(1-((4-fluorophenyl)sulfonyl)-6-iodo-1,2,3,4-tetrahydronaphthalen-2-yl)oxirane (744 mg, 48% yield) as an off-white amorphous solid. LCMS m/z 459.3 (M+H).sup.+, 939.0 (2M+Na).sup.+; HPLC t.sub.R 1.06 min (method A). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.70-7.41 (m, 4H), 7.23-7.12 (m, 2H), 6.84-6.62 (2d, 1H), 4.32-4.18 (2d, 1H), 3.04-2.75 (4m, 3H), 2.74-2.52 (2m, 3H), 2.44-2.13 (2m, 2H).
(120) Also obtained was a mixture of diastereomers of the intermediate bromohydrin, 2-bromo-2-(1-((4-fluorophenyl)sulfonyl)-6-iodo-1,2,3,4-tetrahydronaphthalen-2-yl)ethan-1-ol, as an off-white amorphous solid (166 mg, 9% yield), which could be converted to additional 2-(1-((4-fluorophenyl)sulfonyl)-6-iodo-1,2,3,4-tetrahydronaphthalen-2-yl)oxirane, as a mixture of diastereomers, by treatment with K.sub.2CO.sub.3 in MeOH as described above. LCMS m/z 538.8, 540.8 (M+H).sup.+; HPLC t.sub.R 1.08 min (method A). .sup.1H NMR (499 MHz, CDCl.sub.3) ppm 7.42-7.51 (m, 4H), 7.09-7.17 (m, 2H), 6.83 (d, J=8.2 Hz, 1H), 4.51-4.61 (m, 1H), 4.38 (d, J=4.9 Hz, 1H), 3.99 (dd, J=12.1, 6.3 Hz, 1H), 3.87 (dd, J=12.1, 7.2 Hz, 1H), 3.06-3.18 (m, 1H), 2.50 (dt, J=15.1, 3.2 Hz, 1H), 2.02-2.16 (m, 2H), 1.45-1.57 (m, 1H).
Step C: mixture of (7b-((4-fluorophenyl)sulfonyl)-5-iodo-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-1-yl)methanol and 8b-((4-fluorophenyl)sulfonyl)-6-iodo-1,2,2a,3,4,8b-hexahydrocyclobuta[a]naphthalen-2-ol (mixtures of diastereomers)
(121) ##STR00087##
(122) A solution of a mixture of diastereomers of 2-(1-((4-fluorophenyl)sulfonyl)-6-iodo-1,2,3,4-tetrahydronaphthalen-2-yl)oxirane (277 mg, 0.574 mmol) in THF (12 mL) was stirred on a dry ice-acetone bath and treated with methylmagnesium bromide (3 M in diethyl ether; 574 L, 1.72 mmol) over about 1 min. The resulting solution was stirred at 78 C. for 30 min, then allowed to warm to rt over 50 min. The mixture was treated with saturated aqueous NH.sub.4Cl, extracted twice with EtOAc, and the combined organic phases were dried and concentrated. The residue was subjected to column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient from 0-60%), to provide a mixture of (7b-((4-fluorophenyl)sulfonyl)-5-iodo-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-1-yl)methanol and 8b-((4-fluorophenyl)sulfonyl)-6-iodo-1,2,2a,3,4,8b-hexahydrocyclobuta[a]naphthalen-2-ol (as mixtures of diastereomers) as a white amorphous solid (202 mg, 77% yield), used without further purification. LCMS m/z 440.9 (M+HH.sub.2O).sup.+, 521.9 (M+Na+MeCN).sup.+; HPLC t.sub.R 0.93, 0.94 min (method A).
Step D: 8b-((4-fluorophenyl)sulfonyl)-6-iodo-2a,3,4,8b-tetrahydrocyclobuta[a]naphthalen-2(1H)-one (racemic) and 7b-((4-fluorophenyl)sulfonyl)-5-iodo-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carbaldehyde (mixture of diastereomers)
(123) ##STR00088##
(124) A solution of a mixture of (7b-((4-fluorophenyl)sulfonyl)-5-iodo-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-1-yl)methanol and 8b-((4-fluorophenyl)sulfonyl)-6-iodo-1,2,2a,3,4,8b-hexahydrocyclobuta[a]naphthalen-2-ol (as mixtures of diastereomers; 199 mg, 0.434 mmol) in DCM (5 mL) was treated with Celite (500 mg, 0.434 mmol), then with pyridinium chlorochromate (206 mg, 0.955 mmol) and stirred at rt. After 3.5 h the mixture was diluted with ether, sonicated and stirred at rt for 45 min. The mixture was filtered through a pad of Florisil and the solids were washed thoroughly with ether. The filtrate was concentrated under vacuum, and the residue was subjected to column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient from 0-40%), to provide two products.
(125) The first product to elute was racemic 8b-((4-fluorophenyl)sulfonyl)-6-iodo-2a,3,4,8b-tetrahydrocyclobuta[a]naphthalen-2(1H)-one as an off-white amorphous solid (51 mg, 26% yield). LCMS m/z 519.8 (M+Na+MeCN).sup.+, 935.0 (2M+Na).sup.+; HPLC t.sub.R 0.97 min (method A). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.62 (dd, J=8.1, 1.1 Hz, 1H), 7.50-7.41 (m, 3H), 7.13 (t, J=8.6 Hz, 2H), 7.03 (d, J=8.1 Hz, 1H), 4.48-4.33 (m, 2H), 3.41-3.31 (m, 1H), 2.44 (dt, J=15.0, 3.4 Hz, 1H), 2.13 (ddt, J=13.1, 9.6, 3.6 Hz, 1H), 1.85-1.69 (m, 1H), 1.60 (m, 1H).
(126) The second product to elute was a mixture of diastereomers of 7b-((4-fluorophenyl)sulfonyl)-5-iodo-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carbaldehyde as a white amorphous solid (87 mg, 44% yield). LCMS m/z 478.9 (M+Na).sup.+, 519.9 (M+Na+MeCN).sup.+, 935.0 (2M+Na).sup.+; HPLC t.sub.R 0.96-1.01 min (method A). .sup.1H NMR (400 MHz, CDCl.sub.3) 9.88 (d, J=5.9 Hz, 0.4H), 9.14 (d, J=4.8 Hz, 0.6H), 7.69-7.33 (m, 5H), 7.11 (t, J=8.6 Hz, 2H), 3.28 (dd, J=9.8, 5.0 Hz, 0.6H), 3.17 (dt, J=8.8, 6.4 Hz, 0.4H), 2.69 (td, J=9.6, 7.0 Hz, 0.6H), 2.63-2.52 (m, 0.4H), 2.38-2.18 (m, 2H), 2.04-1.85 (m, 1H), 1.84-1.71 (m, 0.6H), 1.39-1.32 (m, 0.4H).
Intermediate 28
(7b-((4-fluorophenyl)sulfonyl)-5-iodo-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-1-yl)methanamine hydrochloride (mixture of diastereomers)
(127) ##STR00089##
Step A: tert-butyl ((7b-((4-fluorophenyl)sulfonyl)-5-iodo-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-1-yl)methyl)(4-methoxybenzyl)carbamate (mixture of diastereomers)
(128) ##STR00090##
(129) A mixture of 7b-((4-fluorophenyl)sulfonyl)-5-iodo-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carbaldehyde (Intermediate 27; 316 mg, 0.693 mmol) and powdered activated molecular sieves (1.3 g) in 1,2-dichloroethane (6 mL) was stirred at rt and treated with (4-methoxyphenyl)methanamine (109 L, 0.831 mmol) and acetic acid (59 L, 1.04 mmol). After 15.5 h, the solution was treated with sodium triacetoxyborohydride (323 mg, 1.52 mmol) and stirring was continued at rt. After 7 h, the mixture was filtered and the solids were washed with EtOAc. The combined filtrates were washed sequentially with 1.5 M aqueous Na.sub.2HPO.sub.4, water and brine, dried and concentrated to provide a mixture of diastereomers of crude 1-(7b-((4-fluorophenyl)sulfonyl)-5-iodo-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-1-yl)-N-(4-methoxybenzyl)methanamine as a brown gum, used without further purification. LCMS m/z 578.1 (M+H).sup.+; HPLC t.sub.R 0.86 and 0.88 min (method A). This material was dissolved in DCM (5 mL) and treated with TEA (338 L, 2.42 mmol) and di-tert-butyl dicarbonate (529 mg, 2.42 mmol). The mixture was stirred at rt for 4 days, then was diluted with additional DCM, washed with saturated aqueous NaHCO.sub.3, dried and concentrated. The residue was subjected to column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (5-50%), to provide a mixture of diastereomers of tert-butyl ((7b-((4-fluorophenyl)sulfonyl)-5-iodo-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-1-yl)methyl)(4-methoxybenzyl)carbamate as an off-white glassy solid (188 mg, 40% yield, purity about 85%), used without further purification. LCMS m/z 578.0 (M+H-Boc).sup.+, 1377.6 (2M+Na).sup.+; HPLC t.sub.R 1.24 min (method A).
Step B: tert-butyl ((7b-((4-fluorophenyl)sulfonyl)-5-iodo-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-1-yl)methyl)carbamate (mixture of diastereomers)
(130) ##STR00091##
(131) A solution of a mixture of diastereomers of tert-butyl ((7b-((4-fluorophenyl)sulfonyl)-5-iodo-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-1-yl)methyl)(4-methoxybenzyl)carbamate (about 85% pure; 50 mg, 0.074 mmol) in MeCN (0.6 mL) was stirred on an ice-water bath, treated with a solution of ceric ammonium nitrate (121 mg, 0.221 mmol) in water (0.3 mL) over about 3 min, and stirred at 0 C. After 1 h, the mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were dried and concentrated. The residue was subjected to column chromatography on silica gel (4 g), eluting with EtOAc-hexanes (gradient from 5-40%), to provide a mixture of diastereomers of tert-butyl ((7b-((4-fluorophenyl)sulfonyl)-5-iodo-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-1-yl)methyl)carbamate as an off-white amorphous solid (31.9 mg, 78% yield.) LCMS m/z 457.9 (M+H-Boc).sup.+; HPLC t.sub.R 1.12 min (method A). .sup.1H NMR (499 MHz, CDCl.sub.3) 7.62 (dd, J=8.5, 1.5 Hz, 1H), 7.54-7.48 (m, 2H), 7.45 (d, J=8.1 Hz, 1H), 7.35 (s, 1H), 7.08 (t, J=8.5 Hz, 2H), 4.55 (br s, 1H), 2.97-2.79 (m, 2H), 2.71-2.63 (m, 1H), 2.37-2.13 (m, 3H), 1.84-1.70 (m, 1H), 1.50-1.43 (2s, 9H), 1.40-1.31 (m, 1H).
Step C: (7b-((4-fluorophenyl)sulfonyl)-5-iodo-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-1-yl)methanamine hydrochloride (mixture of diastereomers)
(132) ##STR00092##
(133) A solution of tert-butyl ((7b-((4-fluorophenyl)sulfonyl)-5-iodo-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-1-yl)methyl)carbamate (29 mg, 0.052 mmol) in EtOAc (1 mL) was treated with HCl (4 M in 1,4-dioxane; 1 mL, 4.00 mmol) and allowed to stand at rt. After 75 min, the solution was concentrated to provide a crude mixture of diastereomers of (7b-((4-fluorophenyl)sulfonyl)-5-iodo-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-1-yl)methanamine hydrochloride as a pale yellow amorphous solid (31.8 mg), used without further purification. LCMS m/z 458.0 (M+H).sup.+, 498.9 (M+H+MeCN).sup.+, 915.0 (2M+H).sup.+, 937.0 (2M+Na).sup.+; HPLC t.sub.R 0.77, 0.79 min (method A). .sup.1H NMR (499 MHz, MeOH-d.sub.4) 7.72 (dd, J=8.1, 1.1 Hz, 1H), 7.64-7.59 (m, 2H), 7.54 (d, J=8.1 Hz, 1H), 7.48 (s, 1H), 7.24 (t, J=8.7 Hz, 2H), 3.79-3.73 (m, 1H), 2.98 (dd, J=13.7, 4.6 Hz, 1H), 2.74-2.65 (m, 1H), 2.54 (td, J=9.4, 7.3 Hz, 1H), 2.40 (dd, J=13.8, 9.5 Hz, 1H), 2.37-2.24 (m, 2H), 1.79 (td, J=14.2, 4.1 Hz, 1H).
Intermediate 29
8b-((4-fluorophenyl)sulfonyl)-6-iodo-1,2,2a,3,4,8b-hexahydrocyclobuta[a]naphthalen-2-amine hydrochloride (mixture of diastereomers)
(134) ##STR00093##
(135) Following the procedures used to prepare Intermediate 28, racemic 8b-((4-fluorophenyl)sulfonyl)-6-iodo-2a,3,4, 8b-tetrahydrocyclobuta[a]naphthalen-2(1H)-one (Intermediate 26; 178 mg, 0.390 mmol) was converted into a crude mixture of diastereomers of 8b-((4-fluorophenyl)sulfonyl)-6-iodo-1,2,2a,3,4,8b-hexahydrocyclobuta[a]naphthalen-2-amine hydrochloride (35 mg, 9% yield, about 50% purity), which was used without further purification. LCMS m/z 458.0 (M+H).sup.+, 498.9 (M+H+MeCN).sup.+, 915.7 (2M+H).sup.+; HPLC t.sub.R 0.76 min (method A).
Intermediate 30
2-(1-(aminomethyl)-7b-((4-fluorophenyl)sulfonyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol hydrochloride (mixture of diastereomers)
(136) ##STR00094##
Step A: tert-butyl ((7b-((4-fluorophenyl)sulfonyl)-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-1-yl)methyl)(4-methoxybenzyl)carbamate (mixture of diastereomers)
(137) ##STR00095##
(138) A solution of tert-butyl ((7b-((4-fluorophenyl)sulfonyl)-5-iodo-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-1-yl)methyl)(4-methoxybenzyl)carbamate (Intermediate 27; 106 mg, 0.156 mmol) in diethyl ether (2 mL) was stirred on a dry ice-acetone bath and treated dropwise with tert-butyllithium (1.7 M in pentane; 202 L, 0.344 mmol) over about 30 sec, forming a yellow-brown color. After 10 min, hexafluoroacetone was introduced via a needle above the surface of the solution for about 25 sec, causing rapid lightening of the color. (About 0.25-0.5 g of hexafluoroacetone was added.) The mixture was stirred at 78 C. for 1 h, then allowed to warm to rt and stirred for 25 min. The mixture was treated with saturated aqueous NH.sub.4Cl, diluted with EtOAc and water, and the layers mixed and separated. The organic phase was washed with brine, dried and concentrated. The residue was subjected to column chromatography on silica gel (12 g), eluting with EtOAc-hexanes (gradient from 0-50%), to provide a mixture of diastereomers of tert-butyl ((7b-((4-fluorophenyl)sulfonyl)-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-1-yl)methyl)(4-methoxybenzyl)carbamate as a white amorphous solid (37.5 mg, 33% yield), used without further purification. LCMS m/z 618.2 (M+H-Boc).sup.+, 662.3 (M+HC.sub.4H.sub.8).sup.+, 1457 (2M+Na).sup.+; HPLC t.sub.R 1.15 min (method A).
Step B: 2-(1-(aminomethyl)-7b-((4-fluorophenyl)sulfonyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol hydrochloride (mixture of diastereomers)
(139) ##STR00096##
(140) Following the procedure used to prepare Intermediate 28, a mixture of diastereomers of tert-butyl ((7b-((4-fluorophenyl)sulfonyl)-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-1a,2,3,7b-tetrahydro-H-cyclopropa[a]naphthalen-1-yl)methyl)(4-methoxybenzyl)carbamate (32.4 mg, 0.045 mmol) was converted into a mixture of diastereomers of 2-(1-(aminomethyl)-7b-((4-fluorophenyl)sulfonyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol hydrochloride as a colorless amorphous solid (15.6 mg, 48% yield), used without further purification. LCMS m/z 498.1 (M+H).sup.+, 539.3 (M+H+MeCN).sup.+, 995.2 (2M+H).sup.+; HPLC t.sub.R 0.77 min (method A).
Example 1
((3S,3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)(4-hydroxy-4-methylpiperidin-1-yl)methanone
(141) ##STR00097##
(142) A solution of (3S,3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylic acid (Intermediate 11; 20 mg, 0.037 mmol) in DMF (370 L) was treated with 4-methylpiperidin-4-ol (13 mg, 0.11 mmol), DIEA (32 L, 0.184 mmol) and HATU (21 mg, 0.055 mmol). The mixture was stirred at rt for 30 min, then was purified by preparative HPLC (Method E, gradient 45-90% B, 20 min) to provide ((3S,3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)(4-hydroxy-4-methylpiperidin-1-yl)methanone (11.5 mg, 49% yield). LCMS m/z 640.2 (M+H).sup.+; HPLC t.sub.R 1.03 min (Method A). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.46-7.36 (m, 2H), 7.36-7.24 (m, 5H), 4.51 (s, 1H), 3.94 (br s, 1H), 3.61-3.54 (m, 1H), 3.31 (br t, J=12.5 Hz, 1H), 3.17 (d, J=5.2 Hz, 1H), 3.14-3.04 (m, 1H), 3.03-2.90 (m, 2H), 2.73-2.54 (m, 1H), 2.41-2.22 (m, 1H), 2.18 (br d, J=10.7 Hz, 1H), 1.92 (br s, 2H), 1.86-1.66 (m, 1H), 1.44 (br s, 2H), 1.33 (br t, J=10.1 Hz, 2H), 1.18-1.06 (m, 4H). .sup.19F NMR (471 MHz, DMSO-d.sub.6) 103.1 (s, 1F), 75.1 (m, 6F), 75.0 (m, 1F).
(143) The Examples in Table 3 were prepared using the procedures used to prepare Example 1, or similar procedures, from the appropriate carboxylic acid and amine starting materials.
(144) TABLE-US-00004 TABLE 3 LCMS HPLC Ex. m/z t.sub.R HPLC number Structure observed (min) method 2
Examples 86 and 87
3-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamido)methyl)cyclobutane-1-carboxylic acid (two single geometric isomers)
(145) ##STR00182##
(146) A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylic acid (Intermediate 60 mg, 0.11 mmol) in DMF (1.1 mL) was treated with methyl 3-(aminomethyl)cyclobutane-carboxylate (32 mg, 0.22 mmol), DIEA (77 L, 0.44 mmol) and HATU (63 mg, 0.17 mmol). The mixture was stirred at rt for 30 min, then was diluted with EtOAc and washed sequentially with 1 M aqueous HCl, 1 M aqueous NaOH and brine. The organic layer was dried and concentrated to provide methyl 3-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamido)methyl)cyclobutanecarboxylate (74 mg, 100%) as a mixture of cis and trans isomers. LCMS m/z 668.2 (M+1).sup.+; HPLC t.sub.R 1.10 min (Method A).
(147) This material was separated by preparative chiral SFC on a Chiralcel OD-H column (50250 mm, 5 m; Chiral Technologies Inc.) at 35 C., eluting with CO.sub.2-MeOH (90:10) at 300 mL/min and 100 bars. The separated geometric isomers were isolated from two peaks: Peak 1 eluted with t.sub.R 2.45 min, and Peak 2 eluted with t.sub.R 3.55 min
(148) A solution of the material from Peak 1 (30 mg, 0.045 mmol) in THF (450 L) was treated with LiOH hydrate (22 mg, 0.90 mmol) and water (0.5 mL). The mixture was stirred at rt for 2 h, then was purified via preparative HPLC (Method E, gradient 45-90% B, 20 min) to provide a single geometric isomer of 3-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamido)methyl)cyclobutanecarboxylic acid (Example 86; 13 mg, 43% yield). LCMS m/z 654.2 (M+1).sup.+; HPLC t.sub.R 1.02 min (Method A). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.96-7.78 (m, 1H), 7.53-7.24 (m, 6H), 3.66-3.49 (m, 1H), 3.26-3.08 (m, 2H), 3.07-2.85 (m, 3H), 2.81-2.59 (m, 1H), 2.43-2.27 (m, 2H), 2.27-2.06 (m, 3H), 2.03-1.74 (m, 4H), 1.35-1.14 (m, 2H), 1.04-0.94 (m, 2H).
(149) Using the same procedure, the material from Peak 2 (30 mg, 0.045 mmol) was converted to the other geometric isomer of 3-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamido)methyl)cyclobutanecarboxylic acid (Example 87; 18.6 mg, 63% yield). LCMS m/z 654.2 (M+1).sup.+; HPLC t.sub.R 1.02 min (Method A).
(150) The absolute configurations (cis or trans) on the cyclobutane ring were not assigned.
(151) The Examples in Table 4 were prepared using the procedures used to prepare Examples 86 and 87, or similar procedures, from the appropriate carboxylic acid and amine starting materials.
(152) TABLE-US-00005 TABLE 4 Ex. LCMS m/z HPLC t.sub.R HPLC number Structure observed (min) method 88
Example 106
((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfon)-7-(perfluoropropan-2-yl)-2)-23a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carbonyl)glycine
(153) ##STR00201##
(154) A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylic acid (Intermediate 14; 25 mg, 0.046 mmol) in DMF (460 L) was treated with tert-butyl 2-aminoacetate (12 mg, 0.092 mmol), DIEA (32 L, 0.18 mmol) and HATU (26 mg, 0.069 mmol) and the mixture was stirred at rt for 30 min. The mixture was diluted with EtOAc and washed sequentially with 1 M aqueous HCl, 1 M aqueous NaOH and brine, and dried and concentrated. The residue was dissolved in TFA (1 mL) and the mixture was stirred at rt for 1 h, then was concentrated and the residue was purified by preparative HPLC (Method E, gradient 45-90% B, 20 min) to provide ((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carbonyl)glycine (14 mg, 49% yield). LCMS m/z 600.1 (M+1).sup.+; HPLC t.sub.R 1.01 min (Method A). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.26-8.11 (m, 1H), 7.52-7.44 (m, 1H), 7.44-7.38 (m, 2H), 7.38-7.24 (m, 4H), 3.87-3.65 (m, 2H), 3.28-3.12 (m, 1H), 3.07-2.92 (m, 1H), 2.81-2.69 (m, 1H), 2.61-2.54 (m, 1H), 2.33-2.16 (m, 2H), 2.09-1.78 (m, 3H), 1.38-1.22 (m, 1H).
(155) The Examples in Table 5 were prepared using the procedures used to prepare Example 106, or similar procedures, from the appropriate carboxylic acid and amine starting materials.
(156) TABLE-US-00006 TABLE 5 Ex. LCMS m/z HPLC t.sub.R HPLC number Structure observed (min) method 107
Example 110
(perfluoropropan-2-yl)-2,3,3a,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide hydrochloride
(157) ##STR00205##
(158) A solution of (3R,3aS,9b S)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-1-yl)-2,3,3a,4,5,9b-hexahydro-H-cyclopenta[a]naphthalene-3-carboxylic acid (Intermediate 14; 100 mg, 0.18 mmol) in DMF (1.8 mL) was treated with tert-butyl ((1s,3s)-3-aminocyclobutyl)carbamate (69 mg, 0.37 mmol), DIEA (130 L, 0.74 mmol) and HATU (105 mg, 0.28 mmol). The mixture was stirred at rt for 30 min, then was diluted with EtOAc and washed sequentially with 1 M aqueous HCl, 1 M aqueous NaOH and brine. The organic layer was dried and concentrated to provide tert-butyl ((1S,3s)-3-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamido)cyclobutyl)carbamate (130 mg, 100%), used without further purification. LCMS m/z 711.2 (M+1).sup.+; HPLC t.sub.R 1.12 min (Method A). This material was dissolved in HCl (4 M in 1,4-dioxane; 1.8 mL, 7.4 mmol) and the mixture was stirred at rt. After 30 min, the mixture was concentrated to provide (3R,3aS,9bS)N-((1s,3S)-3-aminocyclobutyl)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide (110 mg, 95% yield). LCMS m/z 611.1 (M+1).sup.+; HPLC t.sub.R 0.85 min (Method B). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.25-8.05 (m, 1H), 7.52-7.41 (m, 1H), 7.41-7.31 (m, 2H), 7.31-7.14 (m, 3H), 3.91-3.61 (m, 3H), 3.26-3.11 (m, 2H), 3.05-2.89 (m, 1H), 2.75-2.59 (m, 1H), 2.46-2.33 (m, 1H), 2.29-2.08 (m, 2H), 2.02-1.90 (m, 1H), 1.90-1.76 (m, 2H), 1.76-1.54 (m, 2H), 1.32-1.12 (m, 2H).
(159) The Examples in Table 6 were prepared using the procedures used to prepare Example 110, or similar procedures, from the appropriate carboxylic acid and amine starting materials.
(160) TABLE-US-00007 TABLE 6 Ex. LCMS m/z HPLC t.sub.R HPLC number Structure observed (min) method 111
Example 114
(3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine
(161) ##STR00209##
(162) A suspension of (3R,3aS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylic acid (Intermediate 14; 200 mg, 0.369 mmol) in toluene (6 mL) was cooled on an ice/water bath and treated with TEA (154 L, 1.11 mmol). The resulting solution was stirred at 0 C. for 5 min, then was treated with diphenyl phosphorazidate (254 L, 1.11 mmol) and warmed to rt. After being stirred for 1 h, the mixture was treated with water and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was suspended in 2-(trimethylsilyl)ethanol (3 mL, 20.9 mmol) and the mixture was warmed to 80 C. After 1.5 h, the mixture was concentrated under reduced pressure. Water and EtOAc were added, and the organic layer was separated, washed with brine, dried and concentrated. The resulting oil was subjected to column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient from 0-50%). The resulting colorless oil (680 mg) was dissolved in DCM (5 mL) and treated with TFA (1 mL). After 1 h, the mixture was concentrated and the residue was dissolved in EtOAc, washed with brine, dried and concentrated to provide crude (3S,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine (trifluoroacetate) as a yellow oil (373 mg). A portion of this (23.2 mg) was purified by preparative HPLC (Method E, gradient 30-70% B, 20 min) to provide (3S,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine (5.3 mg, 28% yield). LCMS m/z 514.3 (M+H).sup.+; HPLC t.sub.R 1.78 min (Method C). .sup.1H NMR (499 MHz, DMSO-d.sub.6) 8.37-8.05 (m, 1H), 7.49 (br d, J=9.0 Hz, 1H), 7.43-7.35 (m, 2H), 7.34-7.19 (m, 3H), 5.30-4.31 (m, 2H), 3.51-3.35 (m, 1H), 3.19-2.98 (m, 2H), 2.77-2.61 (m, 1H), 2.40-2.28 (m, 1H), 2.28-2.18 (m, 1H), 2.17-2.02 (m, 2H), 1.99-1.86 (m, 1H), 1.41 (br d, J=2.6 Hz, 1H). .sup.19F NMR (470 MHz, DMSO-d.sub.6) 181.78 (br d, J=8.5 Hz, 3F), 103.20 (br s, 1F), 75.06 (m, 6F), 74.33 (s, 1F).
(163) The Examples in Table 7 were prepared using the procedures used to prepare Example 114, or similar procedures, from the appropriate carboxylic acid starting material.
(164) TABLE-US-00008 TABLE 7 Ex. LCMS m/z HPLC t.sub.R HPLC number Structure observed (min) method 115
Example 118
(165) (S)-1-(2-cyanoethyl)-N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-5-oxopyrrolidine-2-carboxamide
(166) ##STR00213##
(167) A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine trifluoroacetate (Example 114; 23 mg, 0.037 mmol) in DMF (1 mL) was treated with (S)-1-(2-cyanoethyl)-5-oxopyrrolidine-2-carboxylic acid (Intermediate 18; 20 mg, 0.111 mmol), DIEA (97 L, 0.554 mmol) and HATU (42 mg, 0.111 mmol). The mixture was stirred at rt for 30 min, then was purified by preparative HPLC (Method E, gradient 45-90% B over 20 min) to provide (S)-1-(2-cyanoethyl)-N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-5-oxopyrrolidine-2-carboxamide (13.1 mg, 52% yield). LCMS m/z 678.2 (M+H).sup.+; HPLC t.sub.R 1.01 min (Method A). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.55 (d, J=7.6 Hz, 1H), 7.50-7.39 (m, 2H), 7.34 (s, 1H), 7.25 (d, J=7.0 Hz, 4H), 4.32-4.18 (m, 1H), 4.01-3.91 (m, 1H), 3.75 (dt, J=13.8, 7.0 Hz, 1H), 3.50 (br d, J=8.5 Hz, 1H), 3.03 (br dd, J=13.6, 6.6 Hz, 2H), 2.94-2.84 (m, 1H), 2.81-2.61 (m, 3H), 2.41-2.20 (m, 3H), 2.12-1.94 (m, 3H), 1.94-1.80 (m, 2H), 1.25 (br d, J=10.1 Hz, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) 103.3 (s, 1F), 75.1 (m, 6F), 75.0 (m, 1F).
Example 119
N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)acetamide-2,2,2-d3
(168) ##STR00214##
(169) A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine trifluoroacetate (Example 114; 25 mg, 0.040 mmol) in DMF (1 mL) was treated with acetic anhydride-d.sub.6 (20 L, 0.199 mmol) and DIEA (84 L, 0.478 mmol). The mixture was stirred at rt for 2 h, then was purified by preparative HPLC (Method E, gradient 45-90% B, 20 min) to provide N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)acetamide-2,2,2-d.sub.3 (12.4 mg, 56% yield). LCMS m/z 558.9 (M+H).sup.+; HPLC t.sub.R 2.16 min (Method B). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.11 (br d, J=7.9 Hz, 1H), 7.52-7.44 (m, 2H), 7.35 (s, 1H), 7.32-7.24 (m, 4H), 3.98-3.87 (m, 1H), 3.07-2.97 (m, 1H), 2.84-2.74 (m, 1H), 2.65 (br d, J=14.6 Hz, 1H), 2.27-2.15 (m, 1H), 2.08-1.89 (m, 3H), 1.86-1.73 (m, 1H), 1.34-1.18 (m, 1H).
Example 120
N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)acetamide
(170) ##STR00215##
(171) A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine (Example 114; 40 mg, 0.078 mmol) in DCM (2 mL) was treated with acetyl chloride (8 mg, 0.101 mmol) and triethylamine (11 L, 0.078 mmol) and stirred at rt. After 2 h the mixture was diluted with water and saturated aqueous NaHCO.sub.3 and extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative HPLC (Method E, gradient 40-80% B, 20 min) to provide N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)acetamide (11.2 mg, 26% yield). LCMS m/z 556.1 (M+H).sup.+; HPLC t.sub.R 1.08 min (Analytical HPLC Method A); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.14-8.09 (m, 1H), 7.53-7.46 (m, 2H), 7.39-7.25 (m, 6H), 3.97-3.90 (m, 1H), 3.07-2.98 (m, 1H), 2.83-2.76 (m, 1H), 2.70-2.62 (m, 1H), 2.26-2.18 (m, 1H), 2.05-1.93 (m, 3H), 1.88-1.85 (m, 3H), 1.85-1.78 (m, 1H), 1.33-1.24 (m, 2H).
(172) The Examples in Table 8 were prepared using the procedures used to prepare Examples 118 through 120, or similar procedures, from the appropriate amine and carboxylic acid, carboxylic acid chloride, or carboxylic acid anhydride starting materials.
(173) TABLE-US-00009 TABLE 8 Ex. LCMS m/z HPLC t.sub.R HPLC number Structure observed (min) method 121
Example 191
(1s,4s)-4-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)carbamoyl)-4-hydroxycyclohexane-1-carboxylic acid
(174) ##STR00286##
(175) A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine trifluoroacetate (Example 114; 25 mg, 0.040 mmol) and (1s,4s)-4-(ethoxycarbonyl)-1-hydroxycyclohexanecarboxylic acid (22 mg, 0.100 mmol) in DMF (1 mL) was treated with DIEA (84 L, 0.478 mmol) and HATU (38 mg, 0.100 mmol) and the mixture was stirred at rt. After 3 h, the mixture was diluted with EtOAc, washed sequentially with 10% aqueous LiCl (once) and brine (twice), dried and concentrated. The residue was dissolved in THF (3 mL) and 1 M aqueous NaOH (2.1 mL, 2.1 mmol) was added. MeOH was added until the mixture was homogenous. After stirring overnight at rt, the mixture was concentrated and the residue was dissolved in EtOAc and treated with 1 M aqueous HCl (3 mL). The organic phase was separated, washed with brine, dried and concentrated. The residue was purified by preparative HPLC (Method E, gradient 40-80% B, 19 min; then Method F, gradient 30-70% B, 27 min) to provide (1s,4s)-4-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)carbamoyl)-4-hydroxycyclohexane-1-carboxylic acid (9.7 mg, 35% yield). LCMS m/z 684.1 (M+H).sup.+; HPLC t.sub.R 2.11 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.93 (br d, J=8.5 Hz, 1H), 7.62-7.56 (m, 1H), 7.54-7.48 (m, 1H), 7.36-7.29 (m, 3H), 7.29-7.22 (m, 2H), 4.04-3.93 (m, 1H), 3.07-2.97 (m, 1H), 2.91-2.81 (m, 1H), 2.70-2.60 (m, 1H), 2.35-2.24 (m, 1H), 2.23-2.13 (m, 1H), 2.03-1.87 (m, 3H), 1.87-1.48 (m, 9H), 1.26 (br s, 1H).
(176) The Examples in Table 9 were prepared using the procedures used to prepare Example 191, or similar procedures, from the appropriate carboxylic acid and amine starting materials.
(177) TABLE-US-00010 TABLE 9 Ex. LCMS m/z HPLC t.sub.R HPLC number Structure observed (min) method 192
Example 195
N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,a3a4,59b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-4-hydroxypiperidine-4-carboxamide
(178) ##STR00290##
(179) A mixture of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine trifluoroacetate (Example 114, 110 mg, 0.175 mmol), 1-(tert-butoxycarbonyl)-4-hydroxypiperidine-4-carboxylic acid (64.5 mg, 0.263 mmol), DMF (3 mL), DIEA (306 L, 1.75 mmol) and HATU (100 mg, 0.263 mmol) was stirred at rt. After 1 h the mixture was diluted with EtOAc and water and the layers were separated. The organic phase was washed sequentially with saturated aqueous Na.sub.2CO.sub.3, 10% aqueous LiCl and brine, then was dried and concentrated. The residue was dissolved in DCM (5 mL) and treated with HCl (4 M in 1,4-dioxane; 394 L, 1.58 mmol). After standing overnight at rt, the mixture was concentrated under vacuum. A sample of the residue (19.6 mg) was purified by preparative HPLC (Method E, gradient 30-70% B, 20 min) to provide N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-4-hydroxypiperidine-4-carboxamide (15.9 mg, 86% yield). LCMS m/z 641.2 (M+H).sup.+; HPLC t.sub.R 1.81 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.00 (br d, J=8.5 Hz, 1H), 7.63-7.56 (m, 1H), 7.52 (br d, J=8.2 Hz, 1H), 7.32 (br s, 3H), 7.29-7.21 (m, 2H), 4.04-3.92 (m, 1H), 3.07-2.97 (m, 1H), 2.93-2.79 (m, 4H), 2.70-2.60 (m, 1H), 2.34-2.24 (m, 1H), 2.04-1.85 (m, 6H), 1.55-1.39 (m, 2H), 1.31-1.19 (m, 1H), 1.00 (d, J=6.4 Hz, 1H).
(180) The Examples in Table 10 were prepared using the procedures used to prepare Example 195, or similar procedures, from the appropriate carboxylic acid and amine starting materials.
(181) TABLE-US-00011 TABLE 10 Ex. LCMS m/z HPLC t.sub.R HPLC number Structure observed (min) method 196
Example 201
N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)methanesulfonamide
(182) ##STR00296##
(183) A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine trifluoroacetate (Example 114; 40 mg, 0.078 mmol) in DCM (2 mL) was treated with methanesulfonyl chloride (11.6 mg, 0.101 mmol) and TEA (11 L, 0.078 mmol) at rt and stirred for 2 h. The mixture was diluted with water and saturated aqueous NaHCO.sub.3 and extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative HPLC (Method B, gradient 41-81% B, 20 min) to provide N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)methanesulfonamide (6.8 mg, 15% yield). LCMS m/z 592.1 (M+H).sup.+; HPLC t.sub.R 1.10 min (Method A). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.53-7.43 (m, 3H), 7.39-7.25 (m, 5H), 3.19-3.15 (m, 1H), 3.03-2.96 (m, 1H), 2.93-2.90 (m, 3H), 2.83-2.76 (m, 1H), 2.70-2.61 (m, 1H), 2.21-2.13 (m, 1H), 2.12-2.03 (m, 3H), 1.90-1.82 (m, 1H), 1.40-1.32 (m, 1H).
Example 202
2-hydroxy-2-methylpropyl ((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)carbamate
(184) ##STR00297##
(185) A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine trifluoroacetate (Example 114 trifluoroacetate; 40 mg, 0.078 mmol) in DCM (2 mL) was stirred on an ice-water bath, treated with phosgene (42.4 mg, 0.086 mmol) and TEA (43 L, 0.312 mmol) and stirred at 0 C. for 0.5 h. The mixture was warmed to rt and concentrated, and the residue was dissolved in DCM (4 mL) and treated with 2-methylpropane-1,2-diol (35.1 mg, 0.390 mmol) and TEA (43 L, 0.312 mmol). The mixture was stirred at rt for 5 h, then was diluted with water and saturated aqueous NaHCO.sub.3 and extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative HPLC (Method B, gradient 40-100% B, 20 min) to provide 2-hydroxy-2-methylpropyl ((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)carbamate (2.1 mg, 4% yield). LCMS m/z 630.2 (M+H).sup.+; HPLC t.sub.R 2.34 min (Method B). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.51 (s, 1H), 7.43 (br d, J=7.6 Hz, 1H), 7.37-7.24 (m, 5H), 3.75 (s, 2H), 3.73-3.60 (m, 1H), 3.07-2.95 (m, 1H), 2.92-2.80 (m, 1H), 2.70-2.60 (m, 1H), 2.21 (ddd, J=14.3, 11.0, 7.0 Hz, 1H), 2.06-1.91 (m, 3H), 1.87-1.75 (m, 1H), 1.36-1.21 (m, 2H), 1.12 (s, 6H).
Example 203
1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3-(2-hydroxy-2-methylpropyl)urea
(186) ##STR00298##
(187) A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine trifluoroacetate (Example 114 trifluoroacetate; 50 mg, 0.097 mmol) in DCM (2 mL) was stirred on an ice-water bath and treated with phosgene (53.0 mg, 0.107 mmol) and TEA (54 L, 0.390 mmol) and stirred at 0 C. for 30 min. The mixture was warmed to rt and concentrated, and the residue was dissolved in DCM (4 mL). The mixture was treated 1-amino-2-methylpropan-2-ol (43.4 mg, 0.487 mmol) and TEA (54 L, 0.390 mmol), and stirred at rt for 2 h. The mixture was diluted with water and saturated aqueous NaHCO.sub.3 and extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative HPLC (Method B, gradient 39-79% B, 20 min) to provide 1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3-(2-hydroxy-2-methylpropyl)urea (11.4 mg, 18% yield). LCMS m/z 629.1 (M+H).sup.+; HPLC t.sub.R 1.06 min (Method A). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.51-7.46 (m, 2H), 7.36-7.31 (m, 1H), 7.30-7.22 (m, 4H), 6.41-6.37 (m, 1H), 5.92-5.85 (m, 1H), 4.56-4.52 (m, 1H), 3.90-3.82 (m, 1H), 3.52-3.45 (m, 1H), 3.06-2.98 (m, 1H), 2.97-2.92 (m, 2H), 2.70-2.60 (m, 2H), 2.23-2.15 (m, 1H), 2.08-2.02 (m, 1H), 2.01-1.91 (m, 2H), 1.79-1.69 (m, 1H), 1.31-1.23 (m, 1H), 1.07-1.03 (m, 6H).
(188) The Examples in Table 11 were prepared using the procedures used to prepare Example 203, or similar procedures, from the appropriate carboxylic acid and amine starting materials.
(189) TABLE-US-00012 TABLE 11 Ex. LCMS m/z HPLC t.sub.R HPLC number Structure observed (min) method 204
Examples 208 and 209
2-(((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)amino)-N-methylacetamide and 2,2-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)azanediyl)bis(N-methylacetamide)
(190) ##STR00303##
(191) A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine trifluoroacetate (Example 114 trifluoroacetate; 26.4 mg, 0.042 mmol) in DMF (1 mL) was treated with 2-chloro-N-methylacetamide (5.9 mg, 0.055 mmol) and DIEA (95 L, 0.546 mmol). The reaction was stirred at rt for 3 h, then at 80 C. Two additional portions of 2-chloro-N-methylacetamide (10 mg, 0.093 mmol) were added after 3 h and after heating overnight. The mixture was cooled to rt and subjected to preparative LCMS (Method E, gradient 40-80% B, 22 min) to provide 2-(((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)amino)-N-methylacetamide (Example 208; 9.1 mg, 35% yield). LCMS m/z 585.1 (M+H).sup.+; HPLC t.sub.R 1.89 min (Method A). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.83 (br d, J=4.3 Hz, 1H), 7.50-7.41 (m, 2H), 7.30 (s, 1H), 7.28-7.16 (m, 4H), 3.77 (br s, 1H), 3.74 (br s, 1H), 3.24-3.10 (m, 2H), 3.00 (br dd, J=14.3, 4.0 Hz, 1H), 2.85-2.75 (m, 1H), 2.75-2.67 (m, 1H), 2.63 (d, J=4.6 Hz, 3H), 2.23-2.06 (m, 2H), 1.97-1.85 (m, 2H), 1.75-1.59 (m, 1H), 1.21-1.12 (m, 1H).
(192) A second product was isolated and purified again by preparative LCMS (Method F, gradient 40-65% B, 25 min) to provide 2,2-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)azanediyl)bis(N-methylacetamide) (Example 209; 4.4 mg, 16% yield). LCMS m/z 656.4 (M+H).sup.+; HPLC t.sub.R 1.89 min (Method A).
(193) The Examples in Table 12 were prepared using procedures used to prepare Examples 208 and 209, or similar procedures.
(194) TABLE-US-00013 TABLE 12 Ex. LCMS m/z HPLC t.sub.R HPLC number Structure observed (min) method 210
Example 214
3-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)amino)-2,2-dimethylpropan-1-ol
(195) ##STR00308##
(196) A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine (Example 114; 20.0 mg, 0.039 mmol) in DCM (1 mL) was treated with DIEA (14 L, 0.078 mmol) and 3-hydroxy-2,2-dimethylpropanal (39.8 mg, 0.390 mmol) and stirred at rt. After 45 min the mixture was treated with sodium triacetoxyborohydride (33.0 mg, 0.156 mmol) and stirred at rt overnight. The mixture was treated with a drop of saturated aqueous NaHCO.sub.3, concentrated and purified by preparative HPLC (Method E, gradient 48-88% B, 20 min) to provide 3-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)amino)-2,2-dimethylpropan-1-ol (7.2 mg, 30% yield). LCMS m/z 600.2 (M+H).sup.+; HPLC t.sub.R 1.91 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.48 (s, 2H), 7.36-7.20 (m, 5H), 3.25-3.14 (m, 2H), 2.98 (br dd, J=10.8, 3.5 Hz, 1H), 2.82 (q, J=7.2 Hz, 1H), 2.73-2.66 (m, 1H), 2.61 (br d, J=15.6 Hz, 1H), 2.48-2.32 (m, 2H), 2.22-2.06 (m, 2H), 2.03-1.82 (m, 3H), 1.75-1.60 (m, 1H), 1.35-1.17 (m, 1H), 0.82 (2s, 6H).
Example 215
(3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-N-phenyl-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine
(197) ##STR00309##
(198) A mixture of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine trifluoroacetate (Example 114 trifluoroacetate; 20 mg, 0.032 mmol), bromobenzene (10.0 mg, 0.064 mmol) and toluene (1 mL) was purged with nitrogen for 2 min. Palladium(II) acetate (1.4 mg, 6.37 mol), BINAP (6.0 mg, 9.56 mol) and sodium tert-butoxide (12.3 mg, 0.127 mmol) were added and the mixture was heated at 105 C. under nitrogen overnight. The mixture was cooled to rt, diluted with ethyl acetate and washed with brine. The organic phase was dried and concentrated, and the residue was purified by preparative HPLC (Method F, gradient 52-92% B, 19 min; then Method E, gradient 58-98% B, 20 min) to provide (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-N-phenyl-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine (3.2 mg, 17% yield). LCMS m/z 590.2 (M+H).sup.+; HPLC t.sub.R 2.55 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.54-7.41 (m, 2H), 7.36 (br s, 1H), 7.33-7.20 (m, 4H), 7.06 (br t, J=7.5 Hz, 2H), 6.62 (br d, J=7.9 Hz, 2H), 6.51 (br t, J=7.2 Hz, 1H), 5.82 (br d, J=7.6 Hz, 1H), 3.69-3.57 (m, 1H), 3.11-2.90 (m, 2H), 2.63 (br d, J=16.2 Hz, 1H), 2.33-2.21 (m, 1H), 2.20-2.06 (m, 2H), 2.00 (br t, J=12.2 Hz, 1H), 1.77-1.65 (m, 1H), 1.39-1.25 (m, 1H).
Example 216
(3R,3 aR,9bS)-9b-((4-fluorophenyl)sulfonyl)-N-(2-hydroxy-2-methylpropyl)-5-methyl-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[c]quinoline-3-carboxamide
(199) ##STR00310##
Step A: (3R,3aR,9bS)-9b-((4-fluorophenyl)sulfonyl)-N-(2-hydroxy-2-methylpropyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[c]quinoline-3-carboxamide
(200) ##STR00311##
(201) A solution of (3R,3aR,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[c]quinoline-3-carboxylic acid hydrochloride (Intermediate 16; 50 mg, 0.092 mmol) in DMF (920 L) was treated with 1-amino-2-methylpropan-2-ol (8.2 mg, 0.092 mmol), DIEA (64 L, 0.37 mmol), and HATU (53 mg, 0.14 mmol). The mixture was stirred at rt for 30 min, then was purified by preparative HPLC (Method E, gradient 45-90% B, 20 min) to provide (3R,3aR,9bS)-9b-((4-fluorophenyl)sulfonyl)-N-(2-hydroxy-2-methylpropyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[c]quinoline-3-carboxamide (14 mg, 48% yield). LCMS m/z 615.0 (M+1).sup.+; HPLC t.sub.R 0.99 min (Method A). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.82 (br t, J=5.8 Hz, 1H), 7.64 (br dd, J=8.2, 5.2 Hz, 2H), 7.42 (br t, J=8.5 Hz, 2H), 7.32 (d, J=8.2 Hz, 1H), 6.83 (s, 1H), 6.74 (br d, J=7.9 Hz, 1H), 6.62 (br s, 1H), 4.39 (s, 1H), 3.29-3.12 (m, 1H), 3.09-3.00 (m, 1H), 3.00-2.87 (m, 3H), 2.65-2.54 (m, 2H), 2.32 (br t, J=4.9 Hz, 1H), 1.79-1.63 (m, 1H), 1.60 (br d, J=10.1 Hz, 1H), 1.01 (d, J=2.4 Hz, 6H).
Step B: (3R,3aR,9bS)-9b-((4-fluorophenyl)sulfonyl)-N-(2-hydroxy-2-methylpropyl)-5-methyl-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[c]quinoline-3-carboxamide
(202) ##STR00312##
(203) A solution of (3R,3aR,9bS)-9b-((4-fluorophenyl)sulfonyl)-N-(2-hydroxy-2-methylpropyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[c]quinoline-3-carboxamide (30 mg, 0.049 mmol) in MeOH (0.5 mL) was treated with formaldehyde (40 mg, 0.49 mmol), acetic acid (56 L, 0.98 mmol) and sodium cyanoborohydride (31 mg, 0.49 mmol). The mixture was stirred at rt for 30 min, then was purified by preparative HPLC (Method E, gradient 45-90% B, 20 min) to provide (3R,3aR,9bS)-9b-((4-fluorophenyl)sulfonyl)-N-(2-hydroxy-2-methylpropyl)-5-methyl-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[c]quinoline-3-carboxamide (11 mg, 36% yield). LCMS m/z 629.0 (M+1).sup.+; HPLC t.sub.R 1.04 min (Method A). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.82 (br t, J=5.8 Hz, 1H), 7.55 (t, J=6.4 Hz, 2H), 7.46-7.31 (m, 3H), 6.89 (br d, J=8.5 Hz, 1H), 6.66 (s, 1H), 3.07-2.90 (m, 4H), 2.74 (s, 3H), 2.72-2.55 (m, 4H), 2.48-2.28 (m, 1H), 1.77-1.61 (m, 2H), 1.03 (s, 6H).
(204) The Examples in Table 13 were prepared using procedures used to prepare Example 216 or similar procedures.
(205) TABLE-US-00014 TABLE 13 Ex. LCMS m/z HPLC t.sub.R HPLC number Structure observed (min) method 217
Example 219
N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[c]quinolin-3-yl)-pyridin-4-yl)acetamide
(206) ##STR00315##
Step A: (3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[c]quinolin-3-amine bis-trifluoroacetate
(207) ##STR00316##
(208) A solution of (3R,3aR,9bS)-5-(tert-butoxycarbonyl)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[c]quinoline-3-carboxylic acid (Intermediate 15; 1.0 g, 1.9 mmol) in toluene (20 mL) was stirred on an ice-water bath and treated with triethylamine (1.1 mL, 7.8 mmol). The mixture was stirred at 0 C. for 5 min, then diphenyl phosphorazidate (1.8 mL, 7.8 mmol) was added and the mixture was allowed to warm to rt and stirred for 1 h. The mixture was treated with water and extracted with EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was suspended in 2-(trimethylsilyl)ethanol (6.0 mL, 42 mmol) and stirred at 80 C. for 3 h. The mixture was cooled to rt, diluted with water, and extracted with EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was subjected to column chromatography on silica gel, eluting with EtOAc-hexanes, to provide tert-butyl (3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-3-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)-1,2,3,3a,4,9b-hexahydro-5H-cyclopenta[c]quinoline-5-carboxylate. This material was dissolved in DCM (8 mL) and treated with TFA (5 mL). The mixture was stirred at rt for 2 h, then was concentrated. The residue was dissolved in EtOAc, washed with brine, dried and concentrated to provide (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[c]quinolin-3-amine bis-trifluoroacetate (1.0 g, 87% yield), used without further purification. LCMS m/z 515.0 (M+1).sup.+; HPLC t.sub.R 0.85 min (Method A).
Step B: N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[c]quinolin-3-yl)-2-(pyridin-4-yl)acetamide
(209) ##STR00317##
(210) A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[c]quinolin-3-amine bis-trifluoroacetate (50 mg, 0.097 mmol) was dissolved in DMF (970 L) and treated with 2-(pyridin-4-yl)acetic acid (53 mg, 0.39 mmol), DIEA (100 L, 0.58 mmol), and HATU (55 mg, 0.15 mmol). The mixture was stirred at room temperature for 30 min, then was purified by preparative HPLC (Method E, gradient 45-90% B, 20 min) to provide N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[c]quinolin-3-yl)-2-(pyridin-4-yl)acetamide (11 mg, 17% yield). LCMS m/z 634.1 (M+1).sup.+; HPLC t.sub.R 0.84 min (Method B). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.54-8.47 (m, 2H), 8.44 (br d, J=8.2 Hz, 1H), 7.62-7.52 (m, 2H), 7.39 (br t, J=8.5 Hz, 2H), 7.34-7.25 (m, 3H), 6.82-6.68 (m, 2H), 6.50 (s, 1H), 3.86 (br t, J=8.9 Hz, 1H), 3.49 (br s, 1H), 3.11 (br dd, J=12.2, 4.0 Hz, 1H), 3.02-2.86 (m, 1H), 2.82-2.67 (m, 1H), 2.60 (br s, 1H), 2.56 (s, 1H), 2.38-2.18 (m, 1H), 1.85 (br dd, J=12.5, 7.3 Hz, 1H), 1.56-1.45 (m, 1H).
(211) The Examples in Table 14 were prepared using procedures used to prepare Example 219 or similar procedures.
(212) TABLE-US-00015 TABLE 14 Ex. LCMS m/z HPLC t.sub.R HPLC number Structure observed (min) method 220
Example 222
2-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)propan-2-ol
(213) ##STR00320##
(214) A mixture of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylic acid (Intermediate 14; 20 mg, 0.037 mmol), BOP (19.6 mg, 0.044 mmol), and DCM (1 mL) was treated with DIEA (19 L, 0.111 mmol). The solution obtained was stirred at rt for 1.5 h. The mixture was filtered through a pad of silica gel, the solids were rinsed with EtOAc and the combined filtrate were concentrated. The residue was dissolved in THF (2 mL) and cooled on an ice-water bath. The solution was treated dropwise with methylmagnesium bromide (3 M in diethyl ether; 31 L, 0.092 mmol) and the mixture was stirred at rt for 3 days. The mixture was treated with saturated aqueous NH.sub.4Cl (1 mL) and extracted with EtOAc (21 mL). The combined organic phases were dried and concentrated. The residue was purified by preparative HPLC (Method E, gradient 46-90% B, 20 min) to provide 2-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)propan-2-ol (4.1 mg, 20% yield). LCMS m/z 579.1 (M+H).sup.+; HPLC t.sub.R 2.46 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.52-7.41 (m, 2H), 7.36-7.16 (m, 5H), 3.03-2.80 (m, 2H), 2.67-2.56 (m, 1H), 2.35-2.24 (m, 1H), 2.19-2.06 (m, 1H), 2.04-1.93 (m, 1H), 1.90-1.78 (m, 2H), 1.68-1.59 (m, 1H), 1.31-1.21 (m, 2H), 1.19-1.12 (m, 6H).
Examples 223 and 224
N-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)methyl)-2-hydroxy-2-methylpropanamide and N-(((3R,3aS,9bS)-9b-((4-aminophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)methyl)-2-hydroxy-2-methylpropanamide trifluoroacetate
(215) ##STR00321##
Step A: ((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)methanol
(216) ##STR00322##
(217) A mixture of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylic acid hydrochloride (Intermediate 14 hydrochloride; 100 mg, 0.184 mmol) in DCM (2 mL) was treated with BOP (98 mg, 0.221 mmol) and DIEA (129 L, 0.737 mmol) at rt. The solution obtained was stirred for 3 h. NaBH.sub.4 (14.0 mg, 0.369 mmol) was added, followed by ethanol (1 mL). The mixture was stirred at rt for 3 days, then was treated with saturated aqueous NH.sub.4Cl (6 mL). The mixture was extracted with EtOAc (32 mL) and the combined organic phases were dried and concentrated. The residue was subjected to column chromatography on silica gel to provide ((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)methanol (80 mg, 82% yield). LCMS m/z 570.1 (M+H+MeCN).sup.+; HPLC t.sub.R 1.35 min (Method D).
Step B: N-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)methyl)-2-hydroxy-2-methylpropanamide and N-(((3R,3aS,9bS)-9b-((4-aminophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)methyl)-2-hydroxy-2-methylpropanamide trifluoroacetate
(218) ##STR00323##
(219) A solution of ((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)methanol (80 mg, 0.151 mmol) in DCM (4 mL) was stirred on an ice-water bath and treated with methanesulfonyl chloride (23 L, 0.303 mmol). DIEA (106 L, 0.606 mmol) was then added dropwise and the mixture was stirred at 0 C. After 2 h the mixture was treated with aqueous ammonia. The mixture was extracted with EtOAc, and the combined organic phases were dried and concentrated. The residue was dissolved in DMF (0.5 mL) and treated with sodium azide (49.2 mg, 0.757 mmol). The mixture was stirred at rt for several days, then was diluted with water and extracted with EtOAc. The organic phase was dried and concentrated, and the residue was subjected to column chromatography on silica gel. The isolated azide intermediate (40 mg) was dissolved in MeOH (2 mL). Palladium on carbon (20 mg, 0.019 mmol) and 1 M aqueous HCl (72 L, 0.072 mmol) were added, and the mixture was stirred at rt under a hydrogen atmosphere (balloon pressure) for 4 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in DCM (1 mL) and treated with DIEA (101 L, 0.578 mmol), 2-hydroxy-2-methylpropanoic acid (15.0 mg, 0.145 mmol), and BOP (63.9 mg, 0.145 mmol). The mixture was stirred at rt for 4 h, concentrated, and the residue was subjected preparative HPLC (Method F, gradient 42-82% B, 25 min) to provide N-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)methyl)-2-hydroxy-2-methylpropanamide (Example 223; 6 mg, 11% yield). LCMS m/z 614.4 (M+H).sup.+; HPLC t.sub.R 2.30 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.92-7.87 (m, 1H), 7.52-7.44 (m, 2H), 7.30-7.23 (m, 3H), 7.23-7.16 (m, 2H), 5.39-5.35 (m, 1H), 3.36-3.28 (m, 1H), 3.27-3.20 (m, 1H), 3.07-3.00 (m, 1H), 2.79-2.73 (m, 1H), 2.59-2.51 (m, 1H), 2.20-2.06 (m, 2H), 2.02-1.94 (m, 1H), 1.80-1.65 (m, 3H), 1.29-1.23 (m, 6H), 1.17-1.04 (m, 1H).
(220) Also isolated was N-(((3R,3aS,9bS)-9b-((4-aminophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)methyl)-2-hydroxy-2-methylpropanamide trifluoroacetate (Example 224; 18.8 mg, 35% yield). LCMS m/z 611.4 (M+H).sup.+; HPLC t.sub.R 2.01 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.85-7.80 (m, 1H), 7.52-7.48 (m, 1H), 7.47-7.43 (m, 1H), 7.23-7.19 (m, 1H), 6.38-6.31 (m, 2H), 6.13-6.07 (m, 2H), 5.46-5.43 (m, 1H), 3.33-3.25 (m, 1H), 3.24-3.18 (m, 1H), 3.02-2.93 (m, 1H), 2.65-2.56 (m, 1H), 2.49-2.42 (m, 1H), 2.11-2.00 (m, 2H), 1.96-1.87 (m, 1H), 1.75-1.61 (m, 3H), 1.28-1.22 (m, 6H), 1.09-0.97 (m, 1H).
Examples 225 and 226
1-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)ethan-1-amine (two single diastereomers)
(221) ##STR00324##
Step A: (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-N-methoxy-N-methyl-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide
(222) ##STR00325##
(223) A mixture of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylic acid (Intermediate 14, 300 mg, 0.553 mmol), N,O-dimethylhydroxylamine hydrochloride (64.7 mg, 0.664 mmol), DIEA (386 L, 2.21 mmol), and DCM (5 mL) was treated with BOP (294 mg, 0.664 mmol). The solution obtained was stirred at rt for 1.5 h. Saturated aqueous NaHCO.sub.3 (5 mL) was added, and the aqueous layer was separated and extracted with EtOAc (33 mL). The combined organic phases were dried and concentrated, and the residue was subjected to column chromatography on silica gel (12 g), eluting with EtOAc-hexanes (gradient from 0-100%) to provide (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-N-methoxy-N-methyl-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide (255 mg, 79% yield). LCMS m/z 586.3 (M+H).sup.+; HPLC t.sub.R 1.42 min (Method D).
Step B: 1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)ethan-1-one
(224) ##STR00326##
(225) A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-N-methoxy-N-methyl-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide (255 mg, 0.436 mmol) in THF (5 mL) was cooled on an ice-water bath and treated dropwise with methylmagnesium bromide (3 M in diethyl ether; 726 L, 2.18 mmol). The mixture was stirred at rt for 1 h, then was cooled again to 0 C. and treated with saturated aqueous NH.sub.4Cl (3 mL). The mixture was extracted with EtOAc (34 mL) and the combined organic phases were dried and concentrated. The residue was subjected to column chromatography on silica gel (4 g), eluting with EtOAc-hexanes (gradient from 0-100%), to provide 1-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)ethan-1-one (220 mg, 93% yield). LCMS m/z 541.2 (M+H).sup.+; HPLC t.sub.R 1.44 min (Method D). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.63-7.50 (m, 1H), 7.50-7.42 (m, 1H), 7.23-7.12 (m, 3H), 6.99-6.88 (m, 2H), 3.53-3.33 (m, 2H), 2.78-2.65 (m, 1H), 2.51-2.36 (m, 2H), 2.32-2.20 (m, 5H), 2.19-2.08 (m, 1H), 1.81-1.67 (m, 1H), 1.20-1.06 (m, 1H).
Step C: 1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)ethan-1-amine (two single diastereomers)
(226) ##STR00327##
(227) A mixture of 1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)ethan-1-one (200 mg, 0.370 mmol), ammonium acetate (285 mg, 3.70 mmol), methanol (5 mL), and DCM (1.5 mL) was sonicated, then cooled on an ice-water bath. Sodium cyanoborohydride (93 mg, 1.48 mmol) was added, and the mixture was stirred at 0 C. for 1 h, then overnight at rt. The mixture was concentrated and the residue was mixed with EtOAc (2 mL) and water (3 mL), then treated with K.sub.2CO.sub.3 to make the pH basic. The aqueous layer was separated and extracted with EtOAc (31 mL). The combined organic phases were dried and concentrated. The residue was separated by preparative chiral SFC on a Lux Cellulose-4 column (30250 mm, 5 m) at 50 C.; eluting with CO.sub.2-MeOH (80:20) with 0.1% aqueous NH.sub.4OH at 160 mL/min and 100 bars. Peak 1 eluted with t.sub.R 2.85 min, and peak 2 eluted with t.sub.R 3.55 min.
(228) Peak 1 (Example 225, 74 mg): LCMS m/z 520.0 (M+H).sup.+; HPLC t.sub.R 1.87 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.55-7.45 (m, 2H), 7.33-7.27 (m, 2H), 7.26 (s, 1H), 7.18 (br t, J=8.5 Hz, 2H), 3.13-3.03 (m, 1H), 3.03-2.95 (m, 1H), 2.94-2.85 (m, 1H), 2.60-2.54 (m, 1H), 2.33-2.22 (m, 1H), 2.21-2.10 (m, 1H), 1.96-1.90 (m, 1H), 1.82-1.69 (m, 3H), 1.21-1.11 (m, 1H), 1.08 (d, J=6.3 Hz, 3H).
(229) Peak 2 (Example 226, 110 mg): LCMS m/z 520.0 (M+H).sup.+; HPLC t.sub.R 1.89 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.58-7.42 (m, 2H), 7.33-7.20 (m, 3H), 7.19-7.08 (m, 2H), 3.26-3.15 (m, 1H), 3.14-3.05 (m, 1H), 2.86-2.72 (m, 1H), 2.58-2.53 (m, 1H), 2.26-2.06 (m, 2H), 1.94-1.80 (m, 4H), 1.27-1.19 (m, 3H), 1.18-1.09 (m, 1H).
(230) The absolute configurations of the 1-aminoethyl substituents were not determined.
Examples 227 and 228
(4R)-4-fluoro-N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-1-(2-hydroxy-2-methylpropyl)-5-oxopyrrolidine-2-carboxamide (2 single diastereomers)
(231) ##STR00328##
(232) A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine (Example 114; 50 mg, 0.097 mmol), (2S,4R)-4-fluoro-5-oxopyrrolidine-2-carboxylic acid (Intermediate 20; 15.8 mg, 0.107 mmol), HATU (40.7 mg, 0.107 mmol) and DIEA (51 L, 0.292 mmol) in DMF (1.5 mL) was stirred at rt for 1 h. The mixture was diluted with EtOAc, submitted to standard aqueous washes, dried and concentrated. The residue was treated with 2,2-dimethyloxirane (35.1 mg, 0.487 mmol), K.sub.2CO.sub.3 (26.9 mg, 0.195 mmol) and tert-butanol (1 mL) and the mixture was stirred in a sealed vial at 110 C. for 2 h. After cooling to rt, the mixture was purified by preparative HPLC (Method E, gradient 39-79% B, 20 min) to provide two separated diastereomers of (4R)-4-fluoro-N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-1-(2-hydroxy-2-methylpropyl)-5-oxopyrrolidine-2-carboxamide.
(233) Peak 1 (Example 227, 1.6 mg, 2.3% yield): LCMS m/z 715.2 (M+H).sup.+; HPLC t.sub.R 2.16 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.53-8.43 (m, 1H), 7.53-7.42 (m, 2H), 7.36 (s, 1H), 7.28 (br d, J=6.7 Hz, 4H), 5.32-5.13 (m, 1H), 4.57-4.49 (m, 1H), 4.04-3.94 (m, 1H), 3.60 (br d, J=13.7 Hz, 1H), 3.09-3.00 (m, 1H), 2.93-2.75 (m, 2H), 2.72-2.63 (m, 2H), 2.56 (s, 1H), 2.33-2.24 (m, 1H), 2.08-1.97 (m, 3H), 1.95-1.87 (m, 1H), 1.81 (s, 1H), 1.26 (br d, J=11.9 Hz, 1H), 1.12 (s, 3H), 1.02 (s, 3H).
(234) Peak 2 (Example 228, 6.5 mg, 9.3% yield): LCMS m/z 715.2 (M+H).sup.+; HPLC t.sub.R 2.14 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.70-8.60 (m, 1H), 7.52-7.34 (m, 3H), 7.26 (d, J=6.7 Hz, 4H), 5.35-5.13 (m, 1H), 4.67-4.56 (m, 1H), 3.99-3.91 (m, 1H), 3.08-2.95 (m, 1H), 2.92-2.81 (m, 1H), 2.75-2.54 (m, 4H), 2.42-2.20 (m, 3H), 2.14-2.00 (m, 2H), 1.96 (br s, 1H), 1.88 (s, 1H), 1.33-1.22 (m, 1H), 1.14 (s, 3H), 1.09 (s, 3H).
(235) The absolute configurations at the 2-position of the pyrrolidinone ring were not determined.
Example 229
N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,59b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-(2-hydroxy-2-methylpropyl)-3-oxopyrazolidin-1-carboxamide
(236) ##STR00329##
(237) A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine (Example 114; 100 mg, 0.195 mmol) in DCM (5 mL) was cooled in a dry ice-acetone bath and treated dropwise with phosgene (38.5 mg, 0.390 mmol), then with DIEA (136 L, 0.779 mmol). The mixture was stirred at 78 C. for 20 min, then was warmed to rt and concentrated. The residue was dissolved in DCM (5 mL) and treated with DIEA (136 L, 0.779 mmol) and pyrazolidin-3-one hydrochloride (23.9 mg, 0.195 mmol). The mixture was stirred at rt for 2 h, then was washed sequentially with 0.5 M aqueous HCl, water and brine, dried and concentrated. The residue was mixed with 2,2-dimethyloxirane (111 L, 1.28 mmol) and K.sub.2CO.sub.3 (35.4 mg, 0.256 mmol) in tert-BuOH (1 mL) and heated in a sealed vial at 110 C. for 4 h. The mixture was cooled to rt and purified by preparative HPLC (Method E, gradient 45-90% B, 20 min) to provide N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-(2-hydroxy-2-methylpropyl)-3-oxopyrazolidin-1-carboxamide (3.6 mg, 2.6% yield). LCMS m/z 698.3 (M+H).sup.+; HPLC t.sub.R 2.23 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.95 (s, 1H), 7.61-7.47 (m, 2H), 7.36-7.20 (m, 5H), 6.59 (br d, J=8.2 Hz, 1H), 4.01-3.89 (m, 2H), 3.76 (br t, J=9.9 Hz, 1H), 3.04-2.95 (m, 1H), 2.93-2.85 (m, 3H), 2.74 (s, 1H), 2.66 (br d, J=14.6 Hz, 1H), 2.56 (s, 1H), 2.32-2.22 (m, 1H), 2.04-1.90 (m, 3H), 1.82 (br d, J=8.2 Hz, 1H), 1.33-1.23 (m, 1H), 1.17 (s, 6H).
Examples 230 and 231
1-(acetyl-d3)-3-(2-(((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)amino)-2-oxoethyl)azetidin-3-yl acetate-d3 and 2-(1-(acetyl-d3)-3-hydroxyazetidin-3-yl)-N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)acetamide
(238) ##STR00330##
Part A: N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-(3-hydroxyazetidin-3-yl)acetamide hydrochloride
(239) ##STR00331##
(240) A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine (Example 114; 40 mg, 0.078 mmol) in DMF (1 mL) was treated with 2-(1-(tert-butoxycarbonyl)-3-hydroxyazetidin-3-yl)acetic acid (23.4 mg, 0.101 mmol), DIEA (109 L, 0.623 mmol) and HATU (38.5 mg, 0.101 mmol). The mixture was stirred at rt for 3 h, then was partitioned between EtOAc and water. The organic phase was washed with saturated aqueous Na.sub.2CO.sub.3, 10% aqueous LiCl and brine, then was dried and concentrated to give crude tert-butyl 3-(2-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)amino)-2-oxoethyl)-3-hydroxyazetidine-1-carboxylate. LCMS m/z 727.2 (M+H).sup.+; HPLC t.sub.R 1.09 min (Method A). The residue was dissolved in DCM (5 mL) and treated with HCl (4 M in 1,4-dioxane; 1.2 mL, 4.67 mmol). The mixture was stirred at rt overnight, then was concentrated to provide crude N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-(3-hydroxyazetidin-3-yl)acetamide hydrochloride, which was used without further purification. LCMS m/z 627.1 (M+H).sup.+; HPLC t.sub.R 0.80 min (Method A).
Part B: 1-(acetyl-d3)-3-(2-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)amino)-2-oxoethyl)azetidin-3-yl acetate-d3 and 2-(1-(acetyl-d3)-3-hydroxyazetidin-3-yl)-N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)acetamide
(241) ##STR00332##
(242) A solution of crude N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-(3-hydroxyazetidin-3-yl)acetamide hydrochloride (24.4 mg, 0.039 mmol) in DMF (1 mL) was treated with DIEA (102 L, 0.585 mmol) and acetic anhydride-d.sub.6 (25.3 mg, 0.234 mmol). The reaction was stirred at rt. After 1 h, additional acetic anhydride-d.sub.6 (25.3 mg, 0.234 mmol) and DIEA (102 L, 0.585 mmol) were added. After 3 h, the mixture was purified by preparative HPLC (Method E, gradient 30-80% B, 19 min) to provide 1-(acetyl-d.sub.3)-3-(2-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)amino)-2-oxoethyl)azetidin-3-yl acetate-d.sub.3 (Example 230; 2.6 mg, 9% yield). LCMS m/z 717.4 (M+H).sup.+; HPLC t.sub.R 2.12 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.36 (br t, J=7.8 Hz, 1H), 7.51-7.41 (m, 2H), 7.35 (br s, 1H), 7.28 (br s, 4H), 4.41 (br t, J=8.7 Hz, 1H), 4.25 (br d, J=10.1 Hz, 1H), 4.14 (br dd, J=10.7, 4.0 Hz, 1H), 3.97-3.86 (m, 2H), 3.00 (br dd, J=7.3, 3.7 Hz, 1H), 2.93-2.84 (m, 2H), 2.83-2.74 (m, 1H), 2.65 (br d, J=14.3 Hz, 1H), 2.28-2.16 (m, 1H), 2.09-1.89 (m, 3H), 1.85-1.77 (m, 1H), 1.28-1.21 (m, 1H).
(243) Also isolated was 2-(1-(acetyl-d.sub.3)-3-hydroxyazetidin-3-yl)-N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)acetamide (Example 231; 1.7 mg, 5% yield). LCMS m/z 672.2 (M+H).sup.+; HPLC t.sub.R 2.14 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.09 (br s, 1H), 7.48 (br s, 2H), 7.39-7.28 (m, 3H), 7.28-7.21 (m, 2H), 4.28-4.20 (m, 1H), 4.02-3.89 (m, 3H), 3.67 (br d, J=7.4 Hz, 1H), 3.09-2.99 (m, 1H), 2.89-2.79 (m, 1H), 2.74-2.63 (m, 1H), 2.55 (s, 2H), 2.24 (ddd, J=14.4, 10.7, 6.9 Hz, 1H), 2.15-1.92 (m, 3H), 1.90-1.78 (m, 1H), 1.37-1.25 (m, 1H).
Example 232
1-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3-(2-hydroxyethyl-2,2-d2)urea
(244) ##STR00333##
(245) A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine (Example 114; 100 mg, 0.195 mmol) in DCM (3 mL) was stirred on an ice-water bath and treated with phosgene (123 L, 0.234 mmol), then with TEA (109 L, 0.779 mmol). The mixture was stirred 0 C. for 0.5 h, then was warmed to rt for 0.5 h. The mixture was concentrated and the residue was dissolved in DCM (4 mL) and treated with methyl glycinate (17.4 mg, 0.195 mmol) and TEA (109 L, 0.779 mmol), and stirred at rt for 16 h. The mixture was diluted with water and saturated aqueous NaHCO.sub.3 and extracted with EtOAc. The organic layer was dried and concentrated to give methyl (((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)carbamoyl)glycinate, which was used without further purification. LCMS m/z 629.1 (M+H).sup.+; HPLC t.sub.R 1.05 min (Method A).
(246) This material was dissolved in THF (4 mL) and MeOH (1 mL) and treated with sodium borodeuteride (51.6 mg, 1.363 mmol). After 16 h at rt, the mixture was diluted with water and saturated aqueous NaHCO.sub.3 and extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative HPLC (Method F, gradient 50-72% B, 25 min) to provide 1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3-(2-hydroxyethyl-2,2-d.sub.2)urea (5.6 mg, 4.8% yield). LCMS m/z 603.1 (M+H).sup.+; HPLC t.sub.R 1.01 min (Method A). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.48-7.42 (m, 2H), 7.32-7.19 (m, 5H), 6.27-6.21 (m, 1H), 3.83 (br s, 1H), 3.64-3.55 (m, 2H), 3.12-3.05 (m, 2H), 3.03-2.96 (m, 1H), 2.71-2.60 (m, 2H), 2.21-2.12 (m, 1H), 2.07-2.01 (m, 2H), 2.01-1.92 (m, 1H), 1.77-1.68 (m, 1H), 1.31-1.22 (m, 2H).
Example 233
N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-hydroxy-2-(4-hydroxytetrahydro-2H-pyran-4-yl)acetamide (mixture of diastereomers)
(247) ##STR00334##
(248) A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine (Example 114; 80 mg, 0.156 mmol) and 2-(tetrahydro-4H-pyran-4-ylidene)acetic acid (28.8 mg, 0.203 mmol) in DMF (2 mL) was treated with HATU (77 mg, 0.203 mmol) and TEA (65 L, 0.467 mmol) and stirred at rt for 3 h. The mixture was diluted with water and saturated aqueous NaHCO.sub.3 and extracted with EtOAc. The organic layer was dried and concentrated to give N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-(tetrahydro-4H-pyran-4-ylidene)acetamide which was used without further purification. LCMS m/z 638.1 (M+H).sup.+; HPLC t.sub.R 1.13 min (Method A).
(249) This material was dissolved in acetone (4 mL) and water (0.4 mL) and treated with OsO.sub.4 (2.5% in tert-butanol, 196 L, 0.016 mmol) and 4-methylmorpholine 4-oxide (27.4 mg, 0.234 mmol). After stirring overnight, the mixture was treated with saturated aqueous Na.sub.2S.sub.2O.sub.3 stirred at rt for 1 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative HPLC (Method E, gradient 39-79% B, 20 min) to provide a mixture of diastereomers of N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-hydroxy-2-(4-hydroxytetrahydro-2H-pyran-4-yl)acetamide (20.3 mg, 19% yield). LCMS m/z 673.1 (M+H).sup.+; HPLC t.sub.R 1.05 min (Method A). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.05-7.94 (m, 2H), 7.55-7.47 (m, 4H), 7.33-7.18 (m, 11H), 5.92-5.83 (m, 1H), 4.76-4.71 (m, 1H), 4.07-3.98 (m, 2H), 3.85-3.78 (m, 2H), 3.71-3.54 (m, 6H), 3.07-2.95 (m, 2H), 2.91-2.81 (m, 3H), 2.66-2.56 (m, 3H), 2.31-2.22 (m, 2H), 2.08-1.65 (m, 14H), 1.43-1.20 (m, 7H).
(250) The Examples in Table 15 were prepared using procedures used to prepare Example 233 or similar procedures.
(251) TABLE-US-00016 TABLE 15 Ex. LCMS m/z HPLC t.sub.R HPLC number Structure observed (min) method 234
Example 239
1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3-(pyridin-4-yl)pyrrolidin-2-one (mixture of two diastereomers)
(252) ##STR00340##
Part A: ethyl 2-(pyridin-4-yl)pent-4-enoate (racemic)
(253) ##STR00341##
(254) A solution of ethyl 2-(pyridin-4-yl)acetate (460 L, 3.03 mmol) in THF (10 mL) was cooled on a dry ice-acetone bath and treated with 3-bromoprop-1-ene (290 L, 3.3 mmol) and lithium bis(trimethylsilyl)amide (1.0 M in THF; 6 mL, 6.00 mmol). The mixture was stirred at 78 C. for 2 h, then was warmed to rt. Celite was added and the mixture was concentrated. The residue was subjected to column chromatography on silica gel, eluting with EtOAc-hexanes, to provide ethyl 2-(pyridin-4-yl)pent-4-enoate (250 mg, 40% yield). LCMS m/z 206.1 (M+1).sup.+; HPLC t.sub.R 0.57 min (Method A). .sup.1H NMR (499 MHz, CDCl.sub.3) 8.58 (d, J=5.1 Hz, 2H), 7.34-7.16 (m, 2H), 5.86-5.63 (m, 1H), 5.14-4.91 (m, 2H), 4.27-4.06 (m, 2H), 3.66-3.56 (m, 1H), 2.88-2.70 (m, 1H), 2.57-2.47 (m, 1H), 1.38-1.17 (m, 3H).
Part B: racemic ethyl 4-oxo-2-(pyridin-4-yl)butanoate
(255) ##STR00342##
(256) A solution of ethyl 2-(pyridin-4-yl)pent-4-enoate (250 mg, 1.2 mmol) in a mixture of 1,4-dioxane (9 mL) and water (3 mL) was treated with 2,6-lutidine (280 L, 2.4 mmol), OsO.sub.4 (2.5% in water, 770 L, 0.061 mmol) and sodium periodate (1.0 g, 4.9 mmol). The mixture was stirred at rt overnight, then was diluted with EtOAc and washed 3 times with water. The organic layer was dried and concentrated to provide racemic ethyl 4-oxo-2-(pyridin-4-yl)butanoate, used without further purification. LCMS m/z 208.1 (M+1).sup.+; HPLC t.sub.R 0.43 min (Method A).
Part C: 1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3-(pyridin-4-yl)pyrrolidin-2-one (mixture of 2 diastereomers)
(257) ##STR00343##
(258) A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine (Example 114; 60 mg, 0.12 mmol) in 1,2-dichloroethane (2.3 mL) was treated with ethyl 4-oxo-2-(pyridin-4-yl)butanoate (48 mg, 0.23 mmol) and sodium triacetoxyborohydride (50 mg, 0.23 mmol). The mixture was stirred at rt for 30 min, then for 2 h at 60 C. The mixture was cooled to rt and purified by preparative HPLC (Method E, gradient 45-90% B, 20 min) to provide a mixture of diastereomers of 1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3-(pyridin-4-yl)pyrrolidin-2-one (3.4 mg, 4% yield). LCMS m/z 659.1 (M+1).sup.+; HPLC t.sub.R 0.92 min (Method A). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.84-8.51 (m, 2H), 7.75-7.42 (m, 4H), 7.42-7.17 (m, 5H), 4.47-4.26 (m, 1H), 4.07-3.90 (m, 1H), 3.82-3.39 (m, 1H), 3.26-2.98 (m, 2H), 2.77-2.57 (m, 4H), 2.49-2.21 (m, 2H), 2.14-2.03 (m, 1H), 2.03-1.75 (m, 2H), 1.41-1.16 (m, 2H).
Example 240
3-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)oxazolidin-2-one
(259) ##STR00344##
(260) A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine (Example 114; 30 mg, 0.058 mmol) in DCM (3 mL) was treated with DIEA (31 L, 0.175 mmol) and 2-chloroethyl carbonochloridate (8.4 mg, 0.058 mmol) and stirred at rt for 2 h. The mixture was concentrated and the residue was dissolved in DMF (1 mL) and treated with NaH (mineral oil dispersion; 7.0 mg, 0.175 mmol). The mixture was stirred at rt for 1.5 h, treated with water and purified by preparative HPLC (Method E, gradient 40-80% B, 20 min) to provide 3-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)oxazolidin-2-one (12.2 mg, 36% yield). LCMS m/z 584.0 (M+H).sup.+; HPLC t.sub.R 1.05 min (Method A). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.59-7.46 (m, 2H), 7.34-7.17 (m, 3H), 6.94-6.81 (m, 1H), 6.49 (br d, J=8.9 Hz, 1H), 4.41-4.31 (m, 2H), 4.13-3.98 (m, 1H), 3.85-3.72 (m, 1H), 3.60 (br d, J=7.9 Hz, 1H), 3.17-3.00 (m, 1H), 2.97 (s, 1H), 2.56 (s, 1H), 2.34-2.03 (m, 3H), 1.88-1.72 (m, 2H), 1.30-1.13 (m, 1H).
Examples 241 and 242
5-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-5-methylimidazolidine-2,4-dione (two single diastereomers)
(261) ##STR00345##
(262) A mixture of (NH.sub.4).sub.2CO.sub.3 (14.2 mg, 0.148 mmol), sodium cyanide (3.6 mg, 0.074 mmol), 1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)ethan-1-one (Examples 225 and 226, Part B; 20 mg, 0.037 mmol), 95% ethanol (0.6 mL), and water (0.2 mL) was stirred at 85 C. under a nitrogen atmosphere for 1 day. The mixture was cooled, diluted with EtOAc (3 mL), dried and concentrated. The residue was separated by preparative chiral SFC on a Lux Cellulose-4 column (30250 mm, 5 m) at 50 C., eluting with CO.sub.2-MeOH (83:17) at 160 mL/min and 100 bars. Peak 1 eluted with t.sub.R 2.40 min, and peak 2 eluted with t.sub.R 3.30 min.
(263) Peak 1 (Example 241, 12 mg, 52% yield): LCMS m/z 628.1 (M+NH.sub.4).sup.+; HPLC t.sub.R 1.27 min (Method D). .sup.1H NMR (400 MHz, MeOH-d.sub.4) 7.62-7.55 (m, 1H), 7.54-7.46 (m, 1H), 7.24 (s, 1H), 7.22-7.13 (m, 2H), 7.11-7.04 (m, 2H), 3.29-3.22 (m, 1H), 2.75 (dt, J=11.5, 7.2 Hz, 1H), 2.46 (dt, J=16.0, 3.6 Hz, 1H), 2.34 (dt, J=11.2, 7.7 Hz, 1H), 2.27-2.10 (m, 2H), 2.10-1.96 (m, 2H), 1.66-1.49 (m, 1H), 1.45 (s, 3H), 1.23-1.08 (m, 1H).
(264) Peak 2 (Example 242, 6 mg, 26% yield): LCMS m/z 628.2 (M+NH.sub.4).sup.+; HPLC t.sub.R 1.28 min (Method D). .sup.1H NMR (400 MHz, MeOH-d.sub.4) 7.43 (s, 1H), 7.42-7.37 (m, 1H), 7.32 (dd, J=8.6, 5.1 Hz, 2H), 7.28 (s, 1H), 7.08 (t, J=8.7 Hz, 2H), 3.24-3.12 (m, 1H), 3.05-2.95 (m, 1H), 2.60-2.52 (m, 1H), 2.40-2.31 (m, 1H), 2.28-2.00 (m, 4H), 1.78-1.68 (m, 1H), 1.56-1.51 (m, 3H), 0.93-0.82 (m, 1H).
(265) The absolute configurations at the 5-position of the imidazolidinedione ring were not determined.
Example 243
(R)-3-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,33a,4,59b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-5-(2-hydroxy-2-methylpropyl)imidazolidine-2,4-dione
(266) ##STR00346##
Step A: tert-butyl (R)-3-((tert-butoxycarbonyl)amino)-4-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)amino)-4-oxobutanoate
(267) ##STR00347##
(268) A solution of (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine (Example 114; 200 mg, 0.390 mmol) and (R)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid (113 mg, 0.390 mmol) in DMF (2 mL) was treated with HATU (222 mg, 0.584 mmol) and TEA (217 L, 1.56 mmol). The mixture was stirred at rt overnight, then was partitioned between EtOAc (40 mL) and water (30 mL). The organic layer was washed sequentially with water (30 mL) and brine (30 mL), dried and concentrated. The residue was subjected to column chromatography on silica gel, eluting with EtOAc-hexanes (gradient from 0-100%) to give tert-butyl (R)-3-((tert-butoxycarbonyl)amino)-4-(((3R,3aS,9bS)-9b-((4-fluorophenyl)-sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)amino)-4-oxobutanoate as a white solid (225 mg, 74% yield). LCMS m/z 785.4 (M+H).sup.+; HPLC t.sub.R 1.23 min (Method A). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.76 (br d, J=8.2 Hz, 1H), 7.63 (br d, J=8.5 Hz, 1H), 7.55-7.47 (m, 1H), 7.15 (br s, 3H), 6.92 (t, J=8.5 Hz, 2H), 5.71 (br d, J=8.7 Hz, 1H), 4.68-4.47 (m, 1H), 4.39-4.25 (m, 1H), 3.39-3.23 (m, 1H), 2.99 (br d, J=5.1 Hz, 1H), 2.81-2.64 (m, 2H), 2.54-2.45 (m, 1H), 2.43-2.33 (m, 1H), 2.20-2.02 (m, 3H), 1.53-1.46 (m, 18H), 1.35-1.28 (m, 2H).
Step B: methyl 2-((R)-1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2,5-dioxoimidazolidin-4-yl)acetate
(269) ##STR00348##
(270) A solution of tert-butyl (R)-3-((tert-butoxycarbonyl)amino)-4-(((3R,3aS,9bS)-9b-((4-fluorophenyl)-sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)amino)-4-oxobutanoate (220 mg, 0.280 mmol) in DCM (5 mL) was treated with HCl (4 M in 1,4-dioxane; 170 L, 5.60 mmol). The mixture was stirred at rt for 4 hr, then was concentrated. The residue was dissolved in MeOH (5 mL) and treated with thionyl chloride (250 L) and the mixture was stirred at rt overnight. The mixture was concentrated, and the residue was dissolved in DCM (10 mL). The solution was cooled on an ice-water bath and treated with triphosgene (40.6 mg, 0.137 mmol) and pyridine (457 L, 5.65 mmol). The mixture was allowed to warm to rt over 30 min, stirred 30 min more at rt, then was heated at 50 C. overnight. The mixture was concentrated and the residue was purified by preparative HPLC (Method G, gradient 0-100% B, 10 min) to provide methyl 2-((R)-1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2,5-dioxoimidazolidin-4-yl)acetate as a white solid (60 mg, 26% yield). LCMS m/z 669.2 (M+H).sup.+; HPLC t.sub.R 1.08 min (Method A).
Step C: (R)-3-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-5-(2-hydroxy-2-methylpropyl)imidazolidine-2,4-dione
(271) ##STR00349##
(272) A solution of methyl 2-((R)-1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2,5-dioxoimidazolidin-4-yl)acetate (30 mg, 0.045 mmol) in THF (1 mL) was cooled on an ice-water bath and treated with methyllithium (1.0 M in THF; 135 L, 0.135 mmol). The mixture was stirred at 0 C. for 2 h, then was treated with a few drops of saturated aqueous NH.sub.4Cl. The mixture was partitioned between EtOAc (25 mL) and water (20 mL). The organic layer was separated, washed with brine (15 mL), dried and concentrated. The residue was purified by preparative HPLC (Method E, gradient 42-82% B, 20 min) to provide (R)-3-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-5-(2-hydroxy-2-methylpropyl)imidazolidine-2,4-dione (5.9 mg, 19% yield). LCMS m/z 669.3 (M+H).sup.+; HPLC t.sub.R 2.24 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.89 (s, 1H), 7.58-7.42 (m, 5H), 7.38-7.29 (m, 2H), 4.58 (s, 1H), 4.13 (br d, J=8.9 Hz, 1H), 4.00 (br d, J=7.9 Hz, 1H), 3.49-3.40 (m, 1H), 3.02-2.90 (m, 1H), 2.79-2.65 (m, 1H), 2.38-2.23 (m, 2H), 1.97-1.79 (m, 2H), 1.77-1.65 (m, 1H), 1.55 (dd, J=14.2, 9.3 Hz, 1H), 1.34 (br dd, J=13.6, 6.3 Hz, 1H), 1.16 (s, 6H).
Example 244
(3R,3aS,9bS)N-((1s,3S)-3-acetamidocyclobutyl)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2.3.3a4.5.9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide
(273) ##STR00350##
(274) A solution of (3R,3aS,9bS)N-((1s,3S)-3-aminocyclobutyl)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide (Example 110; 25 mg, 0.041 mmol) in DMF (410 L) was treated with DIEA (29 L, 0.16 mmol) and acetyl chloride (6 L, 0.082 mmol). The mixture was stirred at rt for 30 min, then was purified by preparative HPLC (Method E, gradient 45-90% B, 20 min) to provide (3R,3aS,9bS)N-((1s,3S)-3-acetamidocyclobutyl)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide (12 mg, 43% yield). LCMS m/z 653.1 (M+1).sup.+; HPLC t.sub.R 1.00 min (Method A). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.11 (br d, J=7.0 Hz, 1H), 8.09 (br d, J=7.6 Hz, 1H), 7.49-7.37 (m, 3H), 7.37-7.20 (m, 4H), 3.84 (br s, 2H), 3.59-3.48 (m, 2H), 3.23-3.09 (m, 2H), 3.02-2.95 (m, 1H), 2.64-2.55 (m, 1H), 2.46-2.38 (m, 1H), 2.32-2.11 (m, 3H), 2.01-1.94 (m, 1H), 1.91-1.83 (m, 2H), 1.82-1.70 (m, 4H).
Example 245
1-(acetyl-d3)-N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-4-hydroxypiperidine-4-carboxamide
(275) ##STR00351##
(276) A solution of N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-4-hydroxypiperidine-4-carboxamide (Example 195; 23.4 mg, 0.0365 mmol) in DMF (1 mL) was treated with acetic anhydride-d.sub.6 (19.7 mg, 0.183 mmol) and DIEA (960 L, 0.548 mmol). The mixture was stirred at rt for 2 h, then was purified by preparative HPLC (Method E, gradient 40-80% B, 20 min) to provide 1-(acetyl-d.sub.3)-N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-4-hydroxypiperidine-4-carboxamide (18.8 mg, 74% yield). LCMS m/z 686.2 (M+1).sup.+; HPLC t.sub.R 2.02 min (Method B). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.02 (br d, J=5.8 Hz, 1H), 7.62-7.55 (m, 1H), 7.55-7.48 (m, 1H), 7.32 (br s, 3H), 7.28-7.20 (m, 2H), 5.60 (s, 1H), 4.21 (br d, J=11.3 Hz, 1H), 4.05-3.93 (m, 1H), 3.67 (br d, J=12.8 Hz, 1H), 3.52-3.41 (m, 1H), 3.38-3.22 (m, 1H), 3.10-2.96 (m, 1H), 2.94-2.77 (m, 2H), 2.72-2.58 (m, 1H), 2.30 (dt, J=14.5, 7.1 Hz, 1H), 2.05-1.80 (m, 4H), 1.80-1.67 (m, 1H), 1.59-1.41 (m, 2H), 1.31-1.18 (m, 1H).
Examples 246 and 247
N((S)-1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)ethyl)-1H-imidazole-5-carboxamide trifluoroacetate (single diastereomer) and 2-((S)-1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)ethyl)guanidine trifluoroacetate (single diastereomer)
(277) ##STR00352##
(278) A mixture of a single diastereomer of 1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)ethan-1-amine (Example 225; 16 mg, 0.030 mmol), 1H-imidazole-4-carboxylic acid (4.3 mg, 0.038 mmol), HATU (14.6 mg, 0.038 mmol), DIEA (210 L, 0.118 mmol), and anhydrous DMF (0.3 mL) was sonicated and then stirred at rt for 22 h. The mixture was purified by preparative HPLC (Method F, gradient 31-80% B, 20 min) to provide a single diastereomer of N-(1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)ethyl)-1H-imidazole-4-carboxamide trifluoroacetate (Example 246; 3.4 mg, 15% yield). LCMS m/z 636.2 (M+H).sup.+; HPLC t.sub.R 1.95 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.06-7.95 (m, 2H), 7.82-7.75 (m, 1H), 7.53-7.49 (m, 1H), 7.48-7.43 (m, 1H), 7.28-7.21 (m, 2H), 7.20-7.10 (m, 3H), 4.30-4.22 (m, 1H), 3.10 (br dd, J=14.2, 5.6 Hz, 1H), 2.88-2.81 (m, 1H), 2.46-2.39 (m, 1H), 2.20-2.10 (m, 2H), 2.04-1.96 (m, 2H), 1.88-1.79 (m, 2H), 1.57-1.48 (m, 1H), 1.20-1.15 (m, 2H), 1.15-1.07 (m, 1H).
(279) Also isolated was a single diastereomer of 2-(1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)ethyl)-1,1,3,3-tetramethylguanidine trifluoroacetate (Example 247; 2.3 mg, 10% yield). LCMS m/z 639.9 (M+H).sup.+; HPLC t.sub.R 2.13 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.46-7.39 (m, 2H), 7.35-7.31 (m, 1H), 7.31-7.28 (m, 1H), 7.26-7.00 (m, 3H), 3.75-3.67 (m, 1H), 3.09-3.01 (m, 1H), 2.95-2.91 (m, 12H), 2.81-2.72 (m, 1H), 2.64-2.57 (m, 1H), 2.27-2.13 (m, 1H), 2.04-1.94 (m, 2H), 1.91-1.76 (m, 2H), 1.38-1.13 (m, 5H).
Example 248
2-amino-N((S)-1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)ethyl)-2-methylpropanamide (single diastereomer)
(280) ##STR00353##
(281) A stirred solution of a single diastereomer of 1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)ethan-1-amine (Example 226; 8 mg, 0.015 mmol) and 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (6.0 mg, 0.030 mmol) in DMF (0.3 mL) was treated with BOP (13.1 mg, 0.030 mmol) and DIEA (10 L, 0.059 mmol). The mixture was stirred at rt for 2 h, then was treated with 10% aqueous LiCl (3 mL) and extracted with EtOAc (31 mL). The combined organic phases were dried and concentrated. The residue was dissolved in 1,2-dichloroethane (1 mL) and treated with TFA (0.5 mL). The mixture was stirred at rt for 1 h, then was concentrated. The residue was purified by preparative HPLC (Method E, gradient 42-85% B, 20 min) to provide a single diastereomer of 2-amino-N-(1-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)ethyl)-2-methylpropanamide (7.8 mg, 82% yield). LCMS m/z 627.2 (M+H).sup.+; HPLC t.sub.R 2.14 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.43-7.39 (m, 1H), 7.37-7.32 (m, 1H), 7.29-7.24 (m, 1H), 7.19-7.15 (m, 4H), 4.10-4.03 (m, 1H), 3.04-2.98 (m, 1H), 2.78-2.71 (m, 1H), 2.60-2.54 (m, 1H), 2.22-2.07 (m, 2H), 1.98-1.71 (m, 7H), 1.30-1.27 (m, 3H), 1.26-1.21 (m, 4H), 1.17-1.12 (m, 3H).
(282) The Examples in Table 16 were prepared using procedures used to prepare Examples 244 through 248 or similar procedures, starting from the appropriate Example amine and an appropriate carboxylic acid, acyl chloride or acid anhydride.
(283) TABLE-US-00017 TABLE 16 Ex. LCMS m/z HPLC t.sub.R HPLC number Structure observed (min) method 249
Example 272
N-(1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)ethyl)-1-methyl-1H-pyrazole-4-sulfonamide
(284) ##STR00377##
(285) A stirred solution of a single diastereomer of 1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)ethan-1-amine (Example 225; 8 mg, 0.015 mmol) in DMSO (0.3 mL) was treated with 1-methyl-1H-pyrazole-4-sulfonyl chloride (5.3 mg, 0.030 mmol) and DIEA (10 L, 0.059 mmol). The mixture was stirred at rt for 2 h, then was purified by preparative HPLC (Method E, gradient 43-83% B, 20 min) to provide N-(1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)ethyl)-1-methyl-1H-pyrazole-4-sulfonamide (4.3 mg, 41% yield). LCMS m/z 686.2 (M+H).sup.+; HPLC t.sub.R 2.36 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.26-8.21 (m, 1H), 7.74 (s, 1H), 7.54 (d, J=8.5 Hz, 2H), 7.52-7.47 (m, 1H), 7.22 (s, 1H), 7.18-7.13 (m, 3H), 3.90-3.86 (m, 5H), 3.37-3.30 (m, 1H), 3.13-3.06 (m, 1H), 2.86-2.78 (m, 1H), 2.28-2.18 (m, 1H), 2.18-2.08 (m, 1H), 1.81-1.72 (m, 2H), 1.71-1.62 (m, 1H), 1.57-1.46 (m, 1H), 1.08-0.97 (m, 1H), 0.91-0.85 (m, 3H).
(286) The Examples in Table 17 were prepared using procedures used to prepare Example 272 or similar procedures, starting from the appropriate Example amine and an appropriate sulfonyl chloride.
(287) TABLE-US-00018 TABLE 17 Ex. LCMS m/z HPLC t.sub.R HPLC number Structure observed (min) method 273
Example 280
(3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-N-((1s,3S)-3-(sulfamoylamino)cyclobutyl)-2,3,3a,4,5 0.9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide
(288) ##STR00385##
(289) A solution of (3R,3aS,9bS)N-((1s,3S)-3-aminocyclobutyl)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide hydrochloride (Example 110; 25 mg, 0.041 mmol) in DMF (410 L) was treated with DIEA (29 L, 0.16 mmol) and sulfuric diamide (20 mg, 0.20 mmol). The mixture was stirred at rt for 30 min, then was purified by preparative HPLC (Method E, gradient 45-90% B, 20 min) to provide (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-N-((1s,3S)-3-(sulfamoylamino)cyclobutyl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxamide (3.8 mg, 13% yield). LCMS m/z 690.1 (M+1).sup.+; HPLC t.sub.R 1.02 min (Method B). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.17-8.06 (m, 1H), 7.53-7.18 (m, 6H), 6.55-6.41 (m, 1H), 3.88-3.73 (m, 1H), 3.60-3.47 (m, 1H), 3.47-3.29 (m, 1H), 3.22-3.08 (m, 1H), 3.03-2.90 (m, 2H), 2.77-2.62 (m, 2H), 2.50-2.34 (m, 2H), 2.34-2.08 (m, 2H), 2.03-1.88 (m, 2H), 1.88-1.72 (m, 4H), 1.32-1.15 (m, 1H).
(290) The Examples in Table 18 were prepared using procedures used to prepare Example 280 or similar procedures, starting from the appropriate Example amine.
(291) TABLE-US-00019 TABLE 18 Ex. LCMS m/z HPLC t.sub.R HPLC number Structure observed (min) method 281
Example 284
1-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)amino)-2-methyl-1-oxopropan-2-yl dihydrogen phosphate
(292) ##STR00389##
Step A: dibenzyl (1-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-perfluoropropan-2-yl)-2,3,3a,4,5 0.9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)amino)-2-methyl-1-oxopropan-2-yl) phosphate
(293) ##STR00390##
(294) A solution of N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-2-hydroxy-2-methylpropanamide (Example 137; 400 mg, 0.667 mmol) and 5-methyl-1H-tetrazole (337 mg, 4.00 mmol) in DCM (13.3 mL) was purged with nitrogen and cooled in an ice-water bath, then was treated with dibenzyl diisopropylphosphoramidite (732 L, 2.00 mmol) and the mixture was stirred at 0 C. for 5 min, then at rt for 2 h. The mixture was cooled again in an ice-water bath and treated with 30% aqueous hydrogen peroxide (750 L, 7.34 mmol). After 1 h, the mixture was partitioned between DCM and saturated aqueous NaHCO.sub.3. The organic phase was washed with brine, dried and concentrated. The residue was subjected to column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient from 0-100%), to provide dibenzyl (1-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)amino)-2-methyl-1-oxopropan-2-yl) phosphate as a white solid (500 mg, 87% yield). LCMS m/z 860.4 (M+H).sup.+, HPLC t.sub.R 1.24 min (method A). .sup.1H NMR (499 MHz, MeOH-d.sub.4) 7.73 (d, J=8.5 Hz, 1H), 7.55 (br d, J=9.3 Hz, 1H), 7.45-7.31 (m, 10H), 7.26 (s, 1H), 7.25-7.20 (m, 2H), 7.00 (t, J=8.8 Hz, 2H), 5.24-5.14 (m, 4H), 4.24-4.16 (m, 1H), 3.25-3.16 (m, 1H), 2.99 (ddd, J=11.9, 5.9, 4.0 Hz, 1H), 2.58 (dt, J=16.1, 3.7 Hz, 1H), 2.53-2.45 (m, 1H), 2.19-2.12 (m, 1H), 2.12-1.97 (m, 2H), 1.87-1.79 (m, 1H), 1.76 (s, 3H), 1.71 (s, 3H), 1.35-1.26 (m, 1H).
Step B: 1-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)amino)-2-methyl-1-oxopropan-2-yl dihydrogen phosphate
(295) ##STR00391##
(296) A solution of dibenzyl (1-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)amino)-2-methyl-1-oxopropan-2-yl) phosphate (450 mg, 0.523 mmol) in MeOH-EtOAc (2:1, 20.9 mL) was treated with palladium on carbon (195 mg) and stirred under a hydrogen atmosphere (balloon pressure). After 3 h, the mixture was filtered, the solids were washed with methanol and the filtrates were concentrated. The residue was stirred at rt overnight in MeCN, and the solid was collected, washed with cold MeCN and dried to provide 1-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)amino)-2-methyl-1-oxopropan-2-yl dihydrogen phosphate as a white solid (330 mg, 88% yield). LCMS m/z 680.2 (M+H).sup.+, HPLC t.sub.R 1.02 min (method A). .sup.1H NMR (499 MHz, MeOH-d.sub.4) 7.61 (d, J=8.4 Hz, 1H), 7.52 (br d, J=8.0 Hz, 1H), 7.36-7.28 (m, 3H), 7.11 (t, J=8.8 Hz, 2H), 4.21-4.13 (m, 1H), 3.24 (ddd, J=14.6, 7.3, 5.2 Hz, 1H), 3.04 (dt, J=10.9, 6.3 Hz, 1H), 2.64 (dt, J=16.1, 4.2 Hz, 1H), 2.38 (ddd, J=14.5, 9.3, 7.4 Hz, 1H), 2.21-2.06 (m, 3H), 2.06-1.97 (m, 1H), 1.73 (s, 3H), 1.69 (s, 3H), 1.40-1.30 (m, 1H).
Example 285
1-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carbonyl)-2-(methyl-d3)pyrazolidin-3-one
(297) ##STR00392##
(298) A solution of 1-((3R,3aS,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carbonyl)pyrazolidin-3-one (Example 75; 30 mg, 0.049 mmol) in MeCN (1 mL) was treated with iodomethane-d.sub.3 (71 mg, 0.49 mmol) and Cs.sub.2CO.sub.3 (18 mg, 0.054 mmol). The mixture was stirred at 40 C. for 2 h, then purified by preparative HPLC (Method E, gradient 45-90% B, 20 min) to provide 1-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carbonyl)-2-(methyl-d.sub.3)pyrazolidin-3-one (2 mg, 5% yield). LCMS m/z 628.1 (M+1).sup.+; HPLC t.sub.R 2.26 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.60-7.13 (m, 7H), 4.02-3.80 (m, 2H), 3.26-3.12 (m, 1H), 3.12-2.95 (m, 1H), 2.95-2.81 (m, 2H), 2.77-2.65 (m, 1H), 2.35-2.13 (m, 2H), 2.09-1.79 (m, 3H), 1.33-1.14 (m, 1H), 1.06-0.90 (m, 1H).
(299) The Examples in Table 19 were prepared using procedures used to prepare Example 285 or similar procedures, starting from the appropriate Example starting material and an appropriate alkyl halide.
(300) TABLE-US-00020 TABLE 19 Ex. LCMS m/z HPLC t.sub.R HPLC number Structure observed (min) method 286
Example 289
(S)N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-1-(2-hydroxyethyl-2,2-d2)-5-oxopyrrolidine-3-carboxamide
(301) ##STR00396##
Part A: ethyl 2-((S)-4-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)carbamoyl)-2-oxopyrrolidin-1-yl)acetate
(302) ##STR00397##
(303) A solution of (3S)N-((3R,3aS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-5-oxopyrrolidine-3-carboxamide (Example 176; 30 mg, 0.048 mmol) in DMF (0.5 mL) was treated with Cs.sub.2CO.sub.3 (47.0 mg, 0.144 mmol) and ethyl 2-bromoacetate (16.0 mg, 0.096 mmol). The mixture was stirred at 75 C. for 3 h. After cooling to rt, the mixture was partitioned between EtOAc (30 mL) and water (20 mL). The organic layer was washed sequentially with water (310 mL) and brine (15 mL), dried and concentrated. The residue was subjected to silica gel chromatography, eluting with EtOAc-hexanes (gradient from 0-100%), to give ethyl 2-((S)-4-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)carbamoyl)-2-oxopyrrolidin-1-yl)acetate as a beige solid (20 mg, 59% yield). LCMS m/z 711.3 (M+1).sup.+; HPLC t.sub.R 1.05 min (Method A). .sup.1H NMR (499 MHz, CDCl.sub.3) 7.73 (d, J=8.5 Hz, 1H), 7.52 (br d, J=8.3 Hz, 1H), 7.25 (br d, J=8.0 Hz, 1H), 7.18-7.08 (m, 3H), 6.94 (br t, J=8.5 Hz, 2H), 4.40-4.29 (m, 1H), 4.25 (q, J=7.2 Hz, 2H), 4.19-4.03 (m, 2H), 3.86-3.66 (m, 2H), 3.25 (dt, J=15.1, 7.6 Hz, 2H), 2.86-2.77 (m, 3H), 2.55-2.41 (m, 2H), 2.26-2.15 (m, 1H), 2.11-1.99 (m, 2H), 1.67-1.53 (m, 1H), 1.32 (t, J=7.2 Hz, 4H).
Part B: (S)N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-1-(2-hydroxyethyl-2,2-d2)-5-oxopyrrolidine-3-carboxamide
(304) ##STR00398##
(305) A solution of ethyl 2-((S)-4-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)carbamoyl)-2-oxopyrrolidin-1-yl)acetate (20 mg, 0.028 mmol) in THF (0.5 mL) and DMF (0.5 mL) was treated with NaBD.sub.4 (5.9 mg, 0.141 mmol) and stirred at rt overnight. The mixture was treated with saturated aqueous NH.sub.4Cl (1 mL) and partitioned between EtOAc (30 mL) and water (20 mL). The organic layer was washed with brine (15 mL), dried and concentrated. The residue was purified by preparative HPLC (Method F, gradient 34-74% B, 20 min) to provide (S)N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-1-(2-hydroxyethyl-2,2-d.sub.2)-5-oxopyrrolidine-3-carboxamide (4.9 mg, 26% yield). LCMS m/z 671.3 (M+1).sup.+; HPLC t.sub.R 1.97 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.33 (br d, J=7.6 Hz, 1H), 7.53-7.39 (m, 2H), 7.34 (s, 1H), 7.29-7.20 (m, 4H), 3.92 (br d, J=7.9 Hz, 1H), 3.57 (br s, 1H), 3.46-3.36 (m, 1H), 3.29-3.11 (m, 3H), 3.09-2.97 (m, 1H), 2.83 (br d, J=6.7 Hz, 1H), 2.64 (br d, J=15.9 Hz, 1H), 2.50-2.44 (m, 2H), 2.30-2.17 (m, 1H), 2.10-1.93 (m, 3H), 1.83 (br s, 1H), 1.24 (br d, J=10.4 Hz, 1H).
Example 290
N-((3R3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-4-hydroxy-1-methylpiperidine-4-carboxamide
(306) ##STR00399##
(307) A solution of N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-4-hydroxypiperidine-4-carboxamide (Example 195; 23.4 mg, 0.0365 mmol) in DCM (1 mL) was treated with 37% aqueous formaldehyde (41 L, 0.548 mmol) and stirred at rt. After 1.5 h, the mixture was treated with sodium triacetoxyborohydride (30.9 mg, 0.146 mmol), and the mixture was stirred at rt for 2 h. A drop of saturated aqueous Na.sub.2CO.sub.3 was added and the mixture was concentrated. The residue was purified by preparative HPLC (Method E, gradient 30-70% B, 20 min) to provide N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-4-hydroxy-1-methylpiperidine-4-carboxamide (14.6 mg, 59% yield). LCMS m/z 655.1 (M+H).sup.+; HPLC t.sub.R 1.85 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.94 (br d, J=8.5 Hz, 1H), 7.62-7.56 (m, 1H), 7.55-7.48 (m, 1H), 7.32 (br s, 3H), 7.29-7.21 (m, 2H), 4.03-3.93 (m, 1H), 3.08-2.97 (m, 1H), 2.91-2.81 (m, 1H), 2.71-2.61 (m, 1H), 2.36-2.25 (m, 1H), 2.24-2.18 (m, 2H), 2.17 (s, 3H), 2.03-1.87 (m, 7H), 1.87-1.74 (m, 1H), 1.53-1.37 (m, 2H), 1.31-1.18 (m, 1H).
(308) The Example in Table 20 was prepared using the procedures used to prepare Example 290, or similar procedures, from the appropriate Example starting material and an appropriate carbonyl compound.
(309) TABLE-US-00021 TABLE 20 Ex. LCMS m/z HPLC t.sub.R HPLC number Structure observed (min) method 291
Example 292
(S)N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-1-(2-hydroxy-2-methylpropyl)-5-oxopyrrolidine-3-carboxamide
(310) ##STR00401##
(311) A mixture of (S)N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-5-oxopyrrolidine-3-carboxamide (Example 176; 25 mg, 0.040 mmol), Cs.sub.2CO.sub.3 (13.0 mg, 0.040 mmol), IPA (0.8 mL) and 2,2-dimethyloxirane (28.9 mg, 0.400 mmol) was heated in a sealed vial at 100 C. After 1 h, the mixture was cooled to rt and purified by preparative HPLC (Method F, gradient 37-77% B, 20 min) to provide (S)N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-1-(2-hydroxy-2-methylpropyl)-5-oxopyrrolidine-3-carboxamide (8.8 mg, 30% yield). LCMS m/z 697.1 (M+H).sup.+; HPLC t.sub.R 2.05 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.80-9.70 (m, 1H), 8.38-8.21 (m, 1H), 7.46 (br d, J=6.4 Hz, 2H), 7.34 (s, 1H), 7.29-7.20 (m, 4H), 4.60 (d, J=3.1 Hz, 1H), 3.94 (br s, 1H), 3.82-3.65 (m, 1H), 3.51 (br s, 1H), 3.21-2.95 (m, 4H), 2.83 (br s, 1H), 2.66 (br s, 1H), 2.49-2.41 (m, 2H), 2.23 (dt, J=6.7, 3.7 Hz, 1H), 2.10-1.92 (m, 3H), 1.84 (br d, J=9.5 Hz, 1H), 1.24 (br d, J=11.0 Hz, 1H), 1.11-0.98 (m, 6H).
(312) The Example in Table 21 was prepared using the procedures used to prepare Example 292, or similar procedures, from the appropriate Example starting material.
(313) TABLE-US-00022 TABLE 20 Ex. LCMS m/z HPLC t.sub.R HPLC number Structure observed (min) method 293
Example 294
(S)-1-(2-cyanoethyl)-N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-5-oxopyrrolidine-3-carboxamide
(314) ##STR00403##
(315) A mixture of (S)N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-5-oxopyrrolidine-3-carboxamide (Example 176; 15 mg, 0.024 mmol), Cs.sub.2CO.sub.3 (7.8 mg, 0.024 mmol), DMF (0.5 mL) and acrylonitrile (2.6 mg, 0.048 mmol) was heated in a sealed vial at 60 C. for 5 h. The mixture was cooled to rt and purified by preparative HPLC (Method E, gradient 37-77% B, 20 min) to provide (S)-1-(2-cyanoethyl)-N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-5-oxopyrrolidine-3-carboxamide (6.9 mg, 42% yield). LCMS m/z 678.3 (M+H).sup.+; HPLC t.sub.R 2.13 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.35 (br d, J=7.6 Hz, 1H), 7.54-7.42 (m, 2H), 7.35 (s, 1H), 7.27 (br d, J=7.0 Hz, 4H), 3.95 (br s, 1H), 3.69-3.58 (m, 1H), 3.18 (br d, J=6.7 Hz, 1H), 3.08-2.98 (m, 1H), 2.84 (br d, J=6.4 Hz, 1H), 2.74 (t, J=6.6 Hz, 2H), 2.69-2.61 (m, 1H), 2.51 (br s, 5H), 2.24 (dt, J=6.7, 3.7 Hz, 1H), 2.10-1.93 (m, 3H), 1.86 (br d, J=8.5 Hz, 1H), 1.25 (br d, J=11.0 Hz, 1H).
Example 295
3-((S)-4-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)carbamoyl)-2-oxopyrrolidin-1-yl)propanoic acid
(316) ##STR00404##
Step A: methyl 3-((S)-4-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)carbamoyl)-2-oxopyrrolidin-1-yl)propanoate
(317) ##STR00405##
(318) A mixture of (S)N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-5-oxopyrrolidine-3-carboxamide (Example 176; 20 mg, 0.032 mmol), Cs.sub.2CO.sub.3 (31.3 mg, 0.096 mmol), DMF (0.5 mL) and methyl acrylate (5.5 mg, 0.064 mmol) was heated in a sealed vial at 85 C. for 1 h. The mixture was cooled to rt and partitioned between EtOAc (30 mL) and water (10 mL). The organic layer was washed sequentially with water (310 mL) and brine (15 mL), dried and concentrated. The residue was subjected to column chromatography on silica gel, eluting with MeOH-DCM (gradient from 0-10%), to give methyl 3-((S)-4-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)carbamoyl)-2-oxopyrrolidin-1-yl)propanoate as a yellow solid (19 mg, 83% yield). LCMS m/z 711.3 (M+H).sup.+; HPLC t.sub.R 1.02 min (Analytical HPLC Method A). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.75 (d, J=8.5 Hz, 1H), 7.52 (s, 1H), 7.16 (s, 4H), 6.95 (br d, J=8.1 Hz, 2H), 4.36 (br dd, J=7.9, 2.8 Hz, 1H), 3.73 (s, 4H), 3.68 (d, J=8.6 Hz, 1H), 3.65-3.60 (m, 2H), 3.31-3.10 (m, 2H), 2.83-2.68 (m, 3H), 2.64 (br d, J=2.5 Hz, 2H), 2.48 (s, 2H), 2.25-2.15 (m, 1H), 2.12-2.03 (m, 2H), 1.59 (br s, 1H), 1.34-1.22 (m, 1H).
Step B: 3-((S)-4-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)carbamoyl)-2-oxopyrrolidin-1-yl)propanoic acid
(319) ##STR00406##
(320) A mixture of 3-((S)-4-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)carbamoyl)-2-oxopyrrolidin-1-yl)propanoate (10 mg, 0.014 mmol), THF (0.5 mL), water (0.5 mL) and LiOH hydrate (0.89 mg, 0.021 mmol) was stirred at rt for 5 h. The mixture was concentrated and purified by preparative HPLC (Method F, gradient 35-75% B, 20 min) to provide 3-((S)-4-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)carbamoyl)-2-oxopyrrolidin-1-yl)propanoic acid (5.4 mg, 55% yield). LCMS m/z 697.1 (M+H).sup.+; HPLC t.sub.R 1.92 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.33 (br d, J=7.6 Hz, 1H), 7.51-7.41 (m, 2H), 7.34 (s, 1H), 7.29-7.21 (m, 4H), 3.98-3.89 (m, 1H), 3.44-3.31 (m, 2H), 3.16-3.09 (m, 1H), 3.01 (br d, J=5.5 Hz, 1H), 2.83 (br d, J=6.4 Hz, 1H), 2.64 (br d, J=15.9 Hz, 1H), 2.51 (br s, 2H), 2.47-2.38 (m, 4H), 2.23 (br s, 1H), 2.09-1.93 (m, 3H), 1.84 (br d, J=8.2 Hz, 1H), 1.23 (br d, J=10.4 Hz, 1H).
Example 296
(S)N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-1-(3-hydroxypropyl)-5-oxopyrrolidine-3-carboxamide
(321) ##STR00407##
(322) A solution of methyl 3-((S)-4-(((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)carbamoyl)-2-oxopyrrolidin-1-yl)propanoate (Example 295, Step A; 10 mg, 0.014 mmol) in THF (0.5 mL) was treated with LiBH.sub.4 (2.0 M in THF; 14 L, 0.028 mmol). The mixture was stirred at rt for 2 h. The mixture was treated with saturated aqueous NH.sub.4Cl (1 mL) and partitioned between EtOAc (20 mL) and water (15 mL). The organic layer was washed sequentially with water (10 mL) and brine (15 mL), dried and concentrated. The residue was purified by preparative HPLC (Method E, gradient 35-75% B, 20 min) to provide (S)N-((3R,3 aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-1-(3-hydroxypropyl)-5-oxopyrrolidine-3-carboxamide (5.0 mg, 50% yield). LCMS m/z 683.1 (M+H).sup.+; HPLC t.sub.R 2.92 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.31 (br d, J=7.3 Hz, 1H), 7.53-7.41 (m, 2H), 7.35 (s, 1H), 7.27 (br d, J=7.0 Hz, 4H), 4.51 (t, J=5.0 Hz, 1H), 4.04-3.88 (m, 1H), 3.55-3.32 (m, 2H), 3.25-3.08 (m, 3H), 3.06-2.97 (m, 1H), 2.83 (br d, J=6.7 Hz, 1H), 2.65 (br d, J=15.9 Hz, 1H), 2.50-2.40 (m, 2H), 2.31-2.17 (m, 1H), 2.09-1.92 (m, 3H), 1.85 (br d, J=8.9 Hz, 1H), 1.59 (br t, J=6.7 Hz, 2H), 1.25 (br d, J=10.7 Hz, 1H).
(323) The Example in Table 22 was prepared using the procedures used to prepare Examples 295 and 296, or similar procedures, from the appropriate Example starting material.
(324) TABLE-US-00023 TABLE 22 Ex. LCMS m/z HPLC t.sub.R HPLC number Structure observed (min) method 297
Examples 298 and 299
4-fluoro-N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide and N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3,6-dihydro-2H-thiopyran-4-carboxamide 1,1-dioxide
(325) ##STR00409##
(326) Following the procedure of Example 118, (3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-amine trifluoroacetate (Example 114 trifluoroacetate; 39.5 mg, 0.063 mmol) was converted into N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-4-hydroxytetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (Example 123). Without purification, the crude material was dissolved in DCM (3 mL) and treated with DAST (42 L, 0.315 mmol). The mixture was stirred at rt for 30 min, then stored in a freezer overnight. The mixture was treated with saturated aqueous NaHCO.sub.3 (1.5 mL) and extracted with EtOAc (21 mL). The combined organic phases were dried and concentrated. The residue was purified by preparative HPLC (Method E, gradient 53-78% B, 25 min; then Method F, gradient 40-80% B, 19 min) to provide 4-fluoro-N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (Example 298; 2.5 mg, 6% yield). LCMS m/z 692.1 (M+H).sup.+; HPLC t.sub.R 2.24 min (Method B). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.51 (br d, J=5.8 Hz, 1H), 7.60-7.55 (m, 1H), 7.54-7.49 (m, 1H), 7.37-7.23 (m, 5H), 4.01-3.92 (m, 1H), 3.20 (br d, J=16.2 Hz, 1H), 3.04-2.98 (m, 1H), 2.65 (br d, J=15.3 Hz, 1H), 2.60-2.23 (m, J=19.5 Hz, 8H), 2.04-1.83 (m, 4H), 1.32-1.20 (m, 2H).
(327) Also obtained was N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-3,6-dihydro-2H-thiopyran-4-carboxamide 1,1-dioxide (Example 299; 5.5 mg, 13% yield). LCMS m/z 672.1 (M+H).sup.+; HPLC t.sub.R 2.09 min (Method C). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.23 (br d, J=7.3 Hz, 1H), 7.50 (s, 2H), 7.39-7.22 (m, 5H), 6.44 (br s, 1H), 3.99 (quin, J=7.7 Hz, 1H), 3.91 (br s, 2H), 3.31-3.22 (m, 1H), 3.09-2.93 (m, 2H), 2.87 (br s, 2H), 2.72-2.60 (m, 1H), 2.32-2.20 (m, 1H), 2.10-1.93 (m, 3H), 1.93-1.82 (m, 1H), 1.34-1.18 (m, 2H).
Example 300
N-((3R,3aS,9bS)-7-(perfluoropropan-2-yl)-9b-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide
(328) ##STR00410##
(329) A solution of N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (Example 149; 60 mg, 0.089 mmol) in THF (3 mL) was stirred on an ice-water bath and treated with bis(tricyclohexylphosphine)nickel(II) chloride (6.2 mg, 8.9 mol), then with lithium tri-tert-butoxyaluminum hydride (1.0 M in THF; 891 L, 0.891 mmol). The mixture was heated with stirring at 65 C. for 16 h, then was cooled to rt. The mixture was filtered, and the filtrate was treated with 1 M aqueous HCl and extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative HPLC (Method E, gradient 54-78% B, 20 min) to provide N-((3R,3aS,9bS)-7-(perfluoropropan-2-yl)-9b-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (2.4 mg, 4% yield). LCMS m/z 556.1 (M+H).sup.+; HPLC t.sub.R 1.05 min (Method A).
(330) The Examples in Table 23 were prepared using the procedures used to prepare Example 1, or similar procedures, from the appropriate carboxylic acid and amine starting materials.
(331) TABLE-US-00024 TABLE 23 Ex. LCMS m/z HPLC t.sub.R HPLC number Structure observed (min) method 301
General ROR Gal4 Reporter Assay
(332) Inverse agonist activity of potential ligands to ROR was measured by inhibition of luminescence in a Gal4-luciferase reporter assay in Jurkat cells.
(333) Jurkat cells stably over-expressing the ROR receptor, Jurkat pEx/Gal/hROR CLBD/HYG pG5luc/blast, were plated at a concentration of 10,000 cells/well in a 384-well solid white cell culture plate (Perkin Elmer #6007899) in assay buffer RPMI 1640 (Gibco 11875-085 1L) containing 0.1% BSA, 100HEPES (Gibco 15360-080), 100 mM sodium pyruvate (Gibco 11360-040), 50 mg/mL Hygromycin B (Invitrogen 10687-010) and 10 mg/mL blasticidin (Invitrogen R210-01). 100 nL of test compound in a 3-fold serial dilution, with final concentrations ranging from 40 M to 0.67 nM, were added to the cells which were then incubated overnight.
(334) The following day, cells were lysed with 10 L of Steady-Glo Luciferase Assay System (Promega Cat. No. EZ550), and analyzed immediately. IC.sub.50 values were determined. The IC.sub.50 value is defined as the concentration of test compound needed to reduce luciferase activity by 50% and is calculated using the four parameter logistic equation to fit the normalized data.
(335) IC.sub.50 values for compounds of the invention in the ROR Gal4 reporter assay are provided below.
(336) TABLE-US-00025 Example # ROR Gal4, IC.sub.50 (m) 1 2.845 2 1.788 3 0.026 4 0.019 5 2.914 6 1.545 7 3.337 8 0.007 9 1.919 10 0.061 11 0.034 12 0.031 13 0.033 14 0.017 15 0.017 16 0.012 17 0.061 18 0.250 19 0.082 20 0.070 21 0.043 22 0.039 23 0.013 24 0.047 25 0.021 26 0.082 27 0.048 28 0.009 29 0.014 30 0.005 31 0.014 32 0.019 33 0.025 34 0.008 35 0.008 36 0.011 37 0.013 38 0.020 39 0.019 40 0.014 41 0.034 42 0.034 43 0.181 44 0.026 45 0.044 46 0.033 47 0.027 48 0.394 49 0.023 50 0.010 51 0.004 52 0.012 53 0.004 54 0.003 55 0.005 56 0.008 57 0.010 58 0.006 59 0.016 60 0.007 61 0.010 62 0.009 63 0.021 64 0.037 65 0.013 66 0.015 67 0.073 68 0.009 69 0.006 70 0.006 71 0.004 72 0.004 73 0.009 74 0.043 75 0.033 76 0.001 77 0.004 78 0.493 79 0.272 80 0.421 81 3.435 82 0.018 83 0.009 84 0.005 85 0.014 86 0.033 87 0.029 88 0.037 89 0.025 90 0.048 91 0.040 92 0.041 93 0.027 94 0.419 95 0.026 96 0.013 97 0.018 98 0.022 99 0.014 100 0.053 101 0.007 102 0.033 103 0.031 104 1.024 105 0.042 106 0.188 107 0.088 108 0.130 109 0.138 110 0.101 111 0.445 112 0.212 113 0.128 114 0.421 115 0.561 116 2.519 117 2.556 118 0.021 119 0.009 120 0.005 121 0.776 122 0.005 123 0.002 124 0.007 125 0.015 126 0.024 127 0.019 128 0.533 129 3.707 130 0.013 131 0.007 132 0.005 133 0.009 134 0.006 135 0.006 136 0.007 137 0.006 138 0.009 139 0.024 140 0.184 141 0.007 142 0.261 143 0.034 144 0.040 145 0.011 146 0.013 147 0.009 148 0.010 149 0.009 150 0.009 151 0.010 152 0.004 153 0.068 154 0.004 155 0.001 156 0.004 157 0.013 158 0.014 159 0.003 160 0.008 161 0.016 162 0.022 163 0.008 164 0.002 165 0.006 166 0.006 167 0.007 168 0.028 169 0.012 170 0.002 171 0.009 172 0.015 173 0.009 174 0.005 175 0.004 176 0.008 177 0.011 178 0.009 179 0.007 180 0.008 181 0.003 182 0.003 183 0.006 184 0.003 185 0.005 186 0.002 187 0.027 188 0.009 189 0.009 190 0.023 191 0.054 192 0.024 193 0.097 194 0.032 195 0.026 196 0.048 197 0.030 198 0.017 199 0.018 200 0.063 201 0.007 202 0.009 203 0.003 204 0.009 205 0.003 206 0.004 207 0.012 208 0.016 209 0.166 210 0.107 211 0.204 212 0.160 213 0.075 214 0.042 215 0.008 216 3.000 217 0.082 218 0.113 219 0.070 220 0.610 221 0.045 222 0.026 223 0.006 224 0.158 225 0.132 226 0.222 227 0.006 228 0.013 229 0.005 230 0.035 231 0.065 232 0.017 233 0.002 234 0.002 235 0.009 236 0.004 237 0.003 238 0.006 239 0.128 240 0.009 241 0.051 242 0.035 243 0.070 244 0.007 245 0.002 246 0.037 247 0.767 248 0.073 249 0.079 250 0.011 251 0.014 252 0.159 253 0.019 254 0.007 255 0.009 256 0.004 257 0.027 258 0.344 259 0.312 260 0.083 261 0.034 262 0.087 263 0.022 264 0.082 265 0.016 266 0.003 267 0.015 268 0.021 269 0.009 270 0.004 271 0.045 272 0.027 273 0.026 274 0.062 275 0.065 276 0.052 277 0.006 278 0.007 279 0.019 280 0.022 281 0.058 282 0.018 283 0.006 284 0.234 285 0.060 286 0.003 287 0.015 288 0.003 289 0.008 290 0.012 291 0.002 292 0.011 293 0.010 294 0.004 295 0.146 296 0.004 297 0.003 298 0.007 299 0.005 300 0.017 301 6.531 302 0.151 303 0.153 304 7.025