WO2005017185A2 - HEPATOCYTE NUCLEAR FACTOR 4α MODULATOR COMPOUNDS - Google Patents

HEPATOCYTE NUCLEAR FACTOR 4α MODULATOR COMPOUNDS Download PDF

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WO2005017185A2
WO2005017185A2 PCT/US2004/022907 US2004022907W WO2005017185A2 WO 2005017185 A2 WO2005017185 A2 WO 2005017185A2 US 2004022907 W US2004022907 W US 2004022907W WO 2005017185 A2 WO2005017185 A2 WO 2005017185A2
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Prior art keywords
optionally substituted
compound
halogens
naphthalenyl
tetrahydro
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PCT/US2004/022907
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French (fr)
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WO2005017185A3 (en
Inventor
Pierre Michellys
Jyun-Hung Chen
Christopher Mapes
Daniel Ruppar
Donald Karanewsky
Anthony Thompson
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Ligand Pharmceuticals Incorporated
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Publication of WO2005017185A2 publication Critical patent/WO2005017185A2/en
Publication of WO2005017185A3 publication Critical patent/WO2005017185A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans

Definitions

  • This invention relates to compounds that bind to and/or modulate hepatocyte nuclear factor 4 ⁇ receptors and to methods for making and using such compounds.
  • Hepatocyte nuclear factor 4 ⁇ (HNF-4 ) has been described as a member of the steroid/thyroid superfamily of transcription factors that is expressed in liver, kidney, intestine and pancreas. Sladeket al, (1990) Genes Dev. 4, 2353-2365; Miquerol et al, (1994) J. Biol Chem. 269:8944-8951. No ligand has been identified at present and therefore HNF-4 ⁇ is referred to as an orphan member of the intracellular receptor family (3-5). Tsai & O'Malley (1994) Annu. Rev. Biochem.
  • HNF-4 ⁇ has been described as being capable of activating transcription in tissue culture cells under certain conditions. Kou et al, (1992) Nature 355:457-461;
  • HNF-4 ⁇ plays a role in one or more metabolic pathways, including glucose and lipid homeostasis. Ladias et al, (1992) J. Biol. Chem. 267:15849- 15860; Montgomery-Snyder et al, (1992) Mol. Cell. Biol. 12:1708-1718; Metzger et al, (1993) J. Biol. Chem. 268:16831-16838; Yamagata et al, (1996) Nature 384, 458-460; Stoffel & Duncan (1997) Proc. Natl.
  • HNF-4 HNF-4 ⁇ plays a role in metabolic gene regulation.
  • Yamagata et al (1996) Nature 384;458-460.
  • Liver-specific knockouts demonstrate that HNF-4 plays a role in liver development and function. Li et al, (2000) Genes & Dev. 14:464-474; Hayhurst et al, (2001) Mol. Cell. Biol. 21:1393-1403; Fraser (1998) Nuc. Acids Res. 26:2702-2707.
  • the present invention provides a compound of formula I:
  • R 1 is selected from H, a halogen, SH, and OH;
  • R 2 is selected from H, a halogen, a NR 12 R 13 , a sulfonamide, a nitro, a formyl, an acyl, a C 1 -C 3 alkyl optionally substituted with one or more fluorines, a C 2 -C 3 alkenyl optionally substituted with one or more fluorines, a C 2 -C 3 akynyl optionally substituted with one or more fluorines, a C ⁇ -C 2 alkoxy optionally substituted with one or more fluorines, a C ⁇ -C 2 thioalkyl optionally substituted with one or more fluorines, a C 2 thioalkenyl optionally substituted with one or more fluorines, a C 2 thioakynyl optionally substituted with one or more fluorines, and a hydroxylamine optionally substituted with a C ⁇ -C 2
  • R 3 is selected from H, a halogen, a nitro, a -C10 alkyl optionally substituted with one or more halogens, a C 2 -C ⁇ o alkenyl optionally substituted with one or more halogens, a C 2 -C ⁇ o akynyl optionally substituted with one or more halogens, a C1-C10 alkoxy optionally substituted with one or more halogens, a Cj-Cio thioalkyl optionally substituted with one or more halogens, a C 2 -C ⁇ o thioalkenyl optionally substituted with one or more halogens, a C 2 -C ⁇ o thioakynyl optionally substituted with one or more fluorines, a NR 14 R 15 , and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with up to two R 19 groups;
  • R 4 is selected from H, a halogen, and OH;
  • R 5 is selected from CH 2 OH, CHO, COOH, and a C(R 5' )( R 5" )(COOH);
  • R 5 ' and R 5 are each independently selected from H, O, S and F; or R 5 and R 5" together form an O or S;
  • R 6 and R 7 are each independently selected from H, a halogen, a C ⁇ -C ⁇ 2 alkyl optionally substituted with one or more R , a C 2 -C ⁇ 2 alkenyl optionally substituted with one or more R 19 , a C 2 -C ⁇ 2 akynyl optionally substituted with one or more R 19 , a Ci-C 12 alkoxy optionally substituted with one or more R , a -C ⁇ thioalkyl optionally substituted with one or more R 19 , a C 2 -C ⁇ 2 thioalkenyl optionally substituted with one or more R 19 , a C 2 -C 12 thioakynyl optionally substituted with one or more R 19 , a NR 16 R 17 , a NHC(O)R 18 and null; or R 6 and
  • R 8 and R 9 are each independently selected from H, a halogen, a methyl optionally substituted with one or more halogens, and null; or R 8 and R 9 taken together with Y form a tliree to five-membered optionally substituted carbocyclic ring; each R 10 is independently selected from H, a halogen, and a methyl optionally substituted with one or more halogens;
  • R 11 and R 11' are each independently selected from H, a halogen and OH; or R 11 and R 11 taken together form an O;
  • R 12 and R 13 are each independently a C ⁇ -C 3 alkyl optionally substituted with one or more halogens, a C 2 -C 3 alkenyl optionally substituted with one or more halogens, or a C 2 -C 3 akynyl optionally substituted with one or more halogens; or R 12 and R 13 taken together with the nitrogen atom to which they are both bound form a five to six- membered heterocyclic ring;
  • R 14 and R 15 are each independently a C ⁇ -C 2 alkyl optionally substituted with one or more halogens, a C 2 alkenyl optionally substituted with one or more halogens, or a C 2 akynyl optionally substituted with one or more halogens;
  • R 16 and R 17 are each independently selected from a -C ⁇ alkyl optionally substituted with one or more R 19 , a C 2 -C ⁇ 2 alkenyl optionally substituted with one or more R 19 , a C 2 -C ⁇ 2 akynyl optionally substituted with one or more R 19 , and a five to six- membered carbocyclic or heterocyclic ring optionally substituted with one or more R 19 ; or R 16 and R 17 taken together with the nitrogen atom to which they are both bound form a five to six-membered heterocyclic ring;
  • R 18 is selected from a Ci- o alkyl optionally substituted with one or more halogens, a C 2 -C ⁇ o alkenyl optionally substituted with one or more halogens, a C 2 -C 10 akynyl optionally substituted with one or more halogens, and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with one or more R 19 ;
  • R 19 is selected from a halogen, a C ⁇ -C 4 alkyl optionally substituted with one or more fluorines, a C 2 -C 4 alkenyl optionally substituted with one or more fluorines, a C 2 - C 4 akynyl optionally substituted with one or more fluorines, a -C 4 alkoxy optionally substituted with one or more halogens, a C 1 -C 3 thioalkyl optionally substituted with one or more halogens, a C 2 -C 3 thioalkenyl optionally substituted with one or more halogens, C 2 -C 3 thioakynyl optionally substituted with one or more halogens, a formyl and a nitro;
  • X and Y are each independently selected from O, S, N and C; wherein: if X is O or S, then each of R 6 and R 7 is null; if X is N, then one of R 6 and R 7 is null; if Y is O or S, then each of R and R is null; and if Y is N, then one of R s and R 9 is null.
  • the invention provides a compound of formula II:
  • R 1 is selected from H, a halogen, SH, and OH;
  • R 2 is selected from H, a halogen, a NR 12 R 13 , a sulfonamide, a nitro, a formyl, an acyl optionally substituted with one or more halogens, a C ⁇ -C 3 alkyl optionally substituted with one or more fluorines, a C 2 -C 3 alkenyl optionally substituted with one or more fluorines, a C 2 -C 3 akynyl optionally substituted with one or more fluorines, a C ⁇ -C 2 alkoxy optionally substituted with one or more fluorines, a d-C 2 thioalkyl optionally substituted with one or more fluorines, a C 2 thioalkenyl optionally substituted with one or more fluorines, a C 2 thioakynyl optionally substituted with one or more fluorines, and a hydroxylamine optionally substituted with a d-C 2 alkyl, a C 2 alken
  • R 3 is selected from H, a halogen, a nitro, a Cj-Cio alkyl optionally substituted with one or more halogens, a C 2 -C ⁇ 0 alkenyl optionally substituted with one or more halogens, a C 2 -C 10 akynyl optionally substituted with one or more halogens, a Ci-Cio alkoxy optionally substituted with one or more halogens, a d-Cio thioalkyl optionally substituted with one or more halogens, a C 2 -C ⁇ o thioalkenyl optionally substituted with one or more halogens, a C 2 -C ⁇ o thioakynyl optionally substituted with one or more halogens, a NR 1 R 15 , and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with up to two R groups;
  • R 4 is selected from H, a halogen, and OH;
  • R 5 is selected from CH 2 OH, CHO, COOH, and a C(R 5' )( R 5" )(COOH);
  • R 5' and R 5" are each independently selected from H, O, S and F; or R 5' and R 5 together form an O or S;
  • R 6 and R 7 are each independently selected from H, a halogen, a C ⁇ -C 12 alkyl optionally substituted with one or more R 19 , a C 2 -C 12 alkenyl optionally substituted with one or more R 19 , a C 2 -C 12 akynyl optionally substituted with one or more R , a C ⁇ -C ⁇ 2 alkoxy optionally substituted with one or more R 19 , a Ct-Cn thioalkyl optionally substituted with one or more R 19 , a C 2 -C ⁇ 2 thioalkenyl optionally substituted with one or more R 19 , a C 2 -C 12 thioakynyl optionally substituted with one or more R 19 , a NR 1 R 17 , a NHC(O)R 18 and null; or R 6 and R 7 taken together form an O, S, NH or CH 2 ;
  • R 8 and R 9 are each independently selected from H, halogen, a methyl optionally substituted with one or more halogens, and null; or R 8 and R 9 taken together with Y form a tliree to five-membered optionally substituted carbocyclic ring;
  • R 12 and R 13 are each independently a C ⁇ -C 3 alkyl optionally substituted with one or more halogens, a C 2 -C 3 alkenyl optionally substituted with one or more halogens, or a C 2 -C 3 akynyl optionally substituted with one or more halogens; or R 12 and R 13 taken together with the nitrogen atom to which they are both bound form a five to six- membered heterocyclic ring;
  • R 14 and R 15 are each independently a C ⁇ -C 2 alkyl optionally substituted with one or more halogens, a C 2 alkenyl optionally substituted with one or more halogens, or a C 2 akynyl optionally substituted with one or more halogens;
  • R 16 and R 17 are each independently selected from a C ⁇ -C 12 alkyl optionally substituted with one or more R 19 , a C 2 -C ⁇ 2 alkenyl optionally substituted with one or more R 19 , a C 2 -C ⁇ 2 akynyl optionally substituted with one or more R 19 , and a five to six- membered carbocyclic or heterocyclic ring optionally substituted with one or more R 19 ; or R 16 and R 17 taken together with the nitrogen atom to which they are both bound form a five to six-membered heterocyclic ring;
  • R 18 is selected from a C 1 -C 10 alkyl optionally substituted with one or more halogens, a C 2 -C ⁇ o alkenyl optionally substituted with one or more halogens, a C 2 -C 10 akynyl optionally substituted with one or more halogens, and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with one or more R ;
  • R 19 is selected from a halogen, a C ⁇ -C 4 optionally substituted with one or more fluorines, a C 2 -C 4 alkenyl optionally substituted with one or more fluorines, a C 2 -C 4 akynyl optionally substituted with one or more fluorines, a Q-C 4 alkoxy optionally substituted with one or more halogens, a C ⁇ -C 3 thioalkyl optionally substituted with one or more halogens, a C 2 -C 3 thioalkenyl optionally substituted with one or more halogens, a C 2 -C 3 thioakynyl optionally substituted with one or more halogens, a formyl and a nitro; X and Y are each independently selected from O, S, N and C; wherein: if X is O or S, then each of R 6 and R 7 is null; if X is N, then one of R 6 and R 7 is
  • the invention provides a compound of formula III:
  • R 1 is selected from H, a halogen, SH, and OH;
  • R 2 is selected from H, a halogen,a NR 12 R 13 , a sulfonamide, a nitro, a formyl, an acyl optionally substituted with one or more halogens, a d-d alkyl optionally substituted with one or more fluorines, a C 2 -C 3 alkenyl optionally substituted with one or more fluorines, a C 2 -C 3 akynyl optionally substituted with one or more fluorines, a d-C 2 alkoxy optionally substituted with one or more fluorines, a d-C 2 thioalkyl optionally substituted with one or more fluorines, a thioC 2 alkenyl optionally substituted with one or more fluorines, a C 2 thioakynyl optionally substituted with one or more fluorines, and a hydroxylamine optionally substituted with a C ⁇ -C 2 alkyl, a d- C 2 al
  • R 3 is selected from H, a halogen, a nitro, a d-C ⁇ 0 alkyl optionally substituted with one or more halogens, a d-Cio alkenyl optionally substituted with one or more halogens, a C 2 -C 10 akynyl optionally substituted with one or more halogens, a d-C 10 alkoxy optionally substituted with one or more halogens, a Ci-do thioalkyl optionally substituted with one or more halogens, a C 2 -C ⁇ o thioalkenyl optionally substituted with one or more halogens, C 2 -C 10 thioakynyl optionally substituted with one or more halogens, a NR 14 R 15 , and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with up to two R 19 groups;
  • R 4 is selected from H, a halogen, and OH;
  • R 5 is selected from CH 2 OH, CHO, COOH, and a C(R 5' )( R 5 ")(COOH);
  • R 5 and R 5 are each independently selected from H, O, S and F; or R 5 and R 5 together form an O or S;
  • R 8 and R 9 are each independently selected from H, a halogen, a methyl optionally substituted with one or more halogens, and null; or R 8 and R 9 taken together with Y form a three to five-membered optionally substituted carbocyclic ring;
  • R 12 and R 13 are each independently a C ⁇ -C 3 alkyl optionally substituted with one or more halogens, a C 2 -C 3 alkenyl optionally substituted with one or more halogens, or a C 2 -C 6 akynyl optionally substituted with one or more halogens; or R 12 and R 13 taken together with the nitrogen atom to which they are both bound form a five to six- membered heterocyclic ring;
  • R 14 and R 15 are each independently a C ⁇ -C 2 alkyl optionally substituted with one or more halogens, a C 2 alkenyl optionally substituted with one or more halogens, or a C 2 akynyl optionally substituted with one or more halogens;
  • R 19 is selected from a halogen, a C ⁇ -C 4 alkyl optionally substituted with one or more fluorines, a C 2 -C 4 alkenyl optionally substituted with one or more fluorines, a C 2 - C 4 akynyl optionally substituted with one or more fluorines, a C 1 -C 4 alkoxy optionally substituted with one or more halogens, a C 1 -C 3 thioalkyl optionally substituted with one or more halogens, a C 2 -C 3 thioalkenyl optionally substituted with one or more halogens, a C 2 -C 3 thioakynyl optionally substituted with one or more halogens, a formyl and a nitro;
  • Y is selected from O, S, N and C; wherein: if Y is O or S, then each of R 8 and R 9 is null; and if Y is N, then one of R 8 and R 9 is null.
  • the invention provides a compound of formula IV: rv
  • R 1 is selected from H, a halogen, SH, and OH;
  • R 2 is selected from H, a halogen, a NR I2 R 13 , a sulfonamide, a nitro, a formyl, an acyl, a d-C 3 alkyl optionally substituted with one or more fluorines, a C 2 -C 3 alkenyl optionally substituted with one or more fluorines, a C 2 -C 3 akynyl optionally substituted with one or more fluorines, a d-C 2 alkoxy optionally substituted with one or more fluorines, a C ⁇ -C 2 thioalkyl optionally substituted with one or more fluorines, a C 2 thioalkenyl optionally substituted with one or more fluorines, a C 2 thioakynyl optionally substituted with one or more fluorines, and a hydroxylamine optionally substituted with a C]-C 2 alkyl, a C 2 alkenyl, a C 2 akyn
  • R 3 is selected from H, a halogen, a nitro, a d-Cio alkyl optionally substituted with one or more halogens, a C 2 -C ⁇ o alkenyl optionally substituted with one or more halogens, a C 2 -C ⁇ o akynyl optionally substituted with one or more halogens, a d-C 10 alkoxy optionally substituted with one or more halogens, a C ⁇ -C 10 thioalkyl optionally substituted with one or more halogens, a C 2 -C ⁇ o thioalkenyl optionally substituted with one or more halogens, C 2 -C ⁇ o thioakynyl optionally substituted with one or more halogens, a NR R , and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with up to two R 19 groups;
  • R 4 is selected from H, a halogen, and OH;
  • R 5 is selected from CH 2 OH, CHO, COOH, and a C(R 5' )( R 5" )(COOH);
  • R 5 and R 5' are each independently selected from H, O, S or F; and R 5' and R 5" together form an O or S;
  • R 6 is selected from H, a halogen, a C ⁇ -C ⁇ 2 alkyl optionally substituted with one or more R 19 , a C 2 -C ⁇ 2 alkenyl optionally substituted with one or more R 19 , a C 2 -C ⁇ 2 akynyl optionally substituted with one or more R 19 , a C ⁇ -C 12 alkoxy optionally substituted with one or more R 19 , a d-C ⁇ 2 thioalkyl optionally substituted with one or more R 19 , a C 2 -C 12 thioalkenyl optionally substituted with one or more R , a C 2 -C 12 thioakynyl optionally substituted with one or more R 19 ,a NR 16 R 17 , a NHC(O)R 18 and null;
  • R and R are each independently selected from H, a halogen, a methyl optionally substituted with one or more halogens, and null; or R 8 and R 9 taken together with Y form a three to five-membered optionally substituted carbocyclic ring;
  • R 12 and R 13 are each independently a d-C 3 alkyl optionally substituted with one or more halogens, a C 2 -C 3 alkenyl optionally substituted with one or more halogens, or C 2 -C 3 akynyl optionally substituted with one or more halogens; or R 12 and R 13 taken together with the nitrogen atom to which they are both bound form a five to six- membered heterocyclic ring; R 14 and R 15 are each independently a C ⁇ -C 2 alkyl optionally substituted with one or more halogens, a C 2 alkenyl optionally substituted with one or more halogens, or a C 2 akynyl optionally substituted with one or more halogens;
  • R 16 and R 17 are each independently selected from a C ⁇ -C 12 alkyl optionally substituted with one or more R , a C 2 -C ⁇ 2 alkenyl optionally substituted with one or more R 19 , a C 2 -C ⁇ 2 akynyl optionally substituted with one or more R 19 , and a five to six- membered carbocyclic or heterocyclic ring optionally substituted with one or more R 19 ; or R 16 and R 17 taken together with the nitrogen atom to which they are both bound form a five to six-membered heterocyclic ring;
  • R 18 is selected from a Ci-do alkyl optionally substituted with one or more halogens, a C 2 -C ⁇ o alkenyl optionally substituted with one or more halogens, a C 2 -C 10 akynyl optionally substituted with one or more halogens, and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with one or more R 19 ;
  • R 19 is selected from a halogen, a d-C 4 alkyl optionally substituted with one or more fluorines, a C 2 -C alkeny optionally substituted with one or more fluorines 1, a C 2 - C 4 akynyl optionally substituted with one or more fluorines, a d-d alkoxy optionally substituted with one or more halogens, a Cj-C thioalkyl optionally substituted with one or more halogens, a C 2 -C 3 thioalkenyl optionally substituted with one or more halogens, a C 2 -C 3 thioakynyl optionally substituted with one or more halogens, a formyl and a nitro;
  • R 20 is selected from a C 4 -C 5 alkyl optionally substituted with one or more halogens, a C 4 -C 5 alkenyl optionally substituted with one or more halogens, a C 4 -C 5 akynyl optionally substituted with one or more halogens, a phenyl optionally substituted with one or more fluorines, a thienyl optionally substituted with one or more fluorines, and a benzyl optionally substituted with one or more R 19 ;
  • X is selected from O and NH
  • Y is selected from O, S, N, and C;
  • Z is selected from CH 2 , NH, and phenylene; wherein: if Y is O or S, then each of R 8 and R 9 is null; and if Y is N, then one of R and R is null.
  • the invention provides a compound of formula V:
  • R 1 is selected from H, a halogen, SH, and OH;
  • R 2 is selected from H, a halogen, a NR 12 R 13 , a sulfonamide, a nitro, a formyl, an acyl, a Cj-C 3 alkyl optionally substituted with one or more fluorines, a C 2 -C 3 alkenyl optionally substituted with one or more fluorines, a C 2 -C akynyl optionally substituted with one or more fluorines , a d-C 2 alkoxy optionally substituted with one or more fluorines, a d-C 2 thioalkyl optionally substituted with one or more fluorines, a C 2 thioalkenyl optionally substituted with one or more fluorines, a C 2 - thioakynyl optionally substituted with one or more fluorines, and a hydroxylamine optionally substituted with a C ⁇ -C 2 alkyl, a C 2 alkenyl, a C 2 aky
  • R 3 is selected from H, a halogen, a nitro, a Cj-Cio alkyl optionally substituted with one or more halogens C 2 -C 10 alkenyl optionally substituted with one or more halogens, C 2 -do akynyl optionally substituted with one or more halogens, a Ci-Cio alkoxy optionally substituted with one or more halogens, a C I -C I Q thioalkyl optionally substituted with one or more halogens, a C 2 -C ⁇ o thioalkenyl optionally substituted with one or more halogens, a C 2 -C 10 thioakynyl optionally substituted with one or more halogens, a NR 14 R 15 , and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with up to two R 19 groups;
  • R 4 is selected from H, a halogen, and OH;
  • R 5 is selected from CH 2 OH, CHO, COOH, and a C(R 5' )( R 5" )(COOH);
  • R 5 and R 5' are each independently selected from H, O, S and F; or R 5 and R 5 together form an O or S;
  • R 8 and R 9 are each independently selected from H, a halogen, a methyl optionally substituted with one or more halogens, and null; or R 8 and R 9 taken together with Y form a three to five-membered optionally substituted carbocyclic ring;
  • R 12 and R 13 are each independently a C 1 -C 3 alkyl optionally substituted with one or more halogens, a C 2 -C 3 alkenyl optionally substituted with one or more halogens, or a C 2 -C 3 akynyl optionally substituted with one or more halogens; or R 12 and R 13 taken together with the nitrogen atom to which they are both bound form a five to six- membered heterocyclic ring;
  • R 14 and R 15 are each independently a C ⁇ -C 2 alkyl optionally substituted with one or more halogens, a C 2 alkenyl optionally substituted with one or more halogens, or a C 2 akynyl optionally substituted with one or more halogens;
  • R 19 is selected from a halogen, a C ⁇ -C 4 alkyl optionally substituted with one or more fluorines, a C 2 -C 4 alkenyl optionally substituted with one or more fluorines, a C 2 - C 4 akynyl optionally substituted with one or more fluorines, a C ⁇ -C 4 alkoxy optionally substituted with one or more halogens, a C ⁇ -C 3 thioalkyl optionally substituted with one or more halogens, a C 2 -C 3 thioalkenyl optionally substituted with one or more halogens, a C 2 -C 3 thioakynyl optionally substituted with one or more halogens , a formyl and a nitro;
  • R 20 is selected from a d-C 5 alkyl optionally substituted with one or more halogens a C 4 -C 5 alkenyl optionally substituted with one or more halogens, a C 4 -C 5 akynyl optionally substituted with one or more halogens, a phenyl optionally substituted with one or more fluorines, a thienyl optionally substituted with one or more fluorines, and a benzyl optionally substituted with one or more R 19 ;
  • Y is selected from O, S, N, and C;
  • Z is selected from CH 2 , NH, and phenylene; wherein: if Y is O or S, then each of R and R is null; and if Y is N, then one of R and R is null.
  • the invention provides a compound of formula VI:
  • R 1 is selected from H, a halogen, SH, and OH;
  • R is selected from H, a halogen, a NR 12 R 13 , a sulfonamide, a nitro, a formyl, an acyl optionally substituted with one or more halogens, a d-C 3 alkyl optionally substituted with one or more fluorines, a C 2 -C 3 alkenyl optionally substituted with one or more fluorines, a C 2 -C akynyl optionally substituted with one or more fluorines, a C ⁇ -C 2 alkoxy optionally substituted with one or more fluorines, a C ⁇ -C 2 thioalkyl optionally substituted with one or more fluorines, a C 2 thioalkenyl optionally substituted with one or more fluorines, a C 2 thioakynyl optionally substituted with one or more fluorines, and a hydroxylamine optionally substituted with a C ⁇ -C 2 alkyl, a C 2 alkenyl
  • R 4 is selected from H, a halogen, and OH;
  • R 5 is selected from CH 2 OH, CHO, COOH, and a C(R 5' )( R 5" )(COOH);
  • R 5' and R 5" are each independently selected from H, O, S and F; or R 5 and R 5 together form an O or S;
  • R 12 and R 13 are each independently a d-C 3 alkyl optionally substituted with one or more halogens; a C 2 -C alkenyl optionally substituted with one or more halogens, or a C 2 -C 3 akynyl optionally substituted with one or more halogens; or R 12 and R 13 taken together with the nitrogen atom to which they are both bound form a five to six- membered heterocyclic ring;
  • R 14 and R 15 are each independently a d-C 2 alkyl optionally substituted with one or more halogens, a C 2 alkenyl optionally substituted with one or more halogens, or C akynyl optionally substituted with one or more halogens;
  • R 19 is selected from a halogen, a C 1 -C 4 alkyl optionally substituted with one or more fluorines, a C 2 -C 4 alkenyl optionally substituted with one or more fluorines, a C 2 - C 4 akynyl optionally substituted with one or more fluorines, a d-d alkoxy optionally substituted with one or more halogens, a d-C thioalkyl optionally substituted with one or more halogens, a C 2 -C 3 thioalkenyl optionally substituted with one or more halogens, a C 2 -C 3 thioakynyl optionally substituted
  • A is selected from O, CH 2 , CF 2 , and S.
  • the invention provides a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, and/or Formula VI.
  • the invention provides a method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, and/or Fo ⁇ nula VI.
  • the invention provides a selective HNF-4 ⁇ modulator of Formula I, Formula II, Formula III, Formula IV, Formula V, and/or Formula VI.
  • the invention provides an HNF-4 ⁇ selective binding agent of Formula I, Formula II, Formula III, Formula IV, Formula V, and/or Formula VI. DETAILED DESCRIPTION OF THE INVENTION
  • Standard chemical symbols are used interchangeably with the full names represented by such symbols. Thus, for example, the terms "hydrogen” and “H” are understood to have identical meaning.
  • Standard techniques may be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, delivery, and treatment of patients. ' Standard techniques may be used for recombinant DNA methodology, oligonucleotide synthesis, tissue culture and transformation (e.g., electroporation, lipofection).
  • Reactions and purification techniques may be performed e.g., using kits according to manufacturer's specifications, as commonly accomplished in the art or as described herein.
  • the foregoing techniques and procedures may be generally performed according to conventional methods well known in the art and as described in various general or more specific references that are cited and discussed throughout the present specification. See e.g., Sambrook et al. Molecular- Cloning: A Laboratoi ⁇ Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)), which is incorporated herein by reference for any purpose.
  • selective binding compound refers to a compound that selectively binds to any portion of one or more target receptors.
  • selective HNF-4 ⁇ receptor binding compound refers to a compound that selectively binds to any portion of an HNF-4 ⁇ receptor.
  • selectively binds refers to the ability of a selective binding compound to bind to a target receptor with greater affinity than it binds to a non-target receptor.
  • selective binding refers to binding to a target with an affinity that is at least 10, 50, 100, 250, 500, or 1000 times greater than the affinity for a non-target.
  • target receptor refers to a receptor or a portion of a receptor capable of being bound by a selective binding compound.
  • a target receptor is an HNF-4 receptor.
  • modulator refers to a compound that alters or elicits an activity of a molecule. For example, a modulator may cause an increase or decrease in the magnitude of a certain activity of a molecule compared to the magnitude of the activity in the absence of the modulator.
  • a modulator is an inhibitor, which decreases the magnitude of one or more activities of a molecule. In certain embodiments, an inhibitor completely prevents one or more activities of a molecule. In certain embodiments, a modulator is an activator, which increases the magnitude of at least one activity of a molecule. In certain embodiments the presence of a modulator results in an activity that does not occur in the absence of the modulator. [024]
  • the term “selective modulator” refers to a compound that selectively modulates a target activity.
  • selective HNF-4 ⁇ receptor modulator refers to a compound that selectively modulates at least one activity associated with an HNF-4a receptor.
  • target activity refers to a biological activity capable of being modulated by a selective modulator. Certain exemplary target activities include, but are not limited to, changes in binding affinity, signal transduction, enzymatic activity, transcription of one or more genes, tumor growth, changes in blood glucose concentration, and inflammation or inflammation-related processes.
  • receptor-mediated activity refers to any biological activity that results, either directly or indirectly, from binding of a ligand to a receptor.
  • agonist refers to a compound, the presence of which results in a biological activity of a receptor that is the same as the biological activity resulting from the presence of a naturally occurring ligand for the receptor.
  • partial agonist refers to a compound the presence of which results in a biological activity of a receptor that is of the same type as that resulting from the presence of a naturally occurring ligand for the receptor, but of a lower magnitude.
  • antagonist refers to a compound, the presence of which results in a decrease in the magnitude of a biological activity of a receptor. In certain embodiments, the presence of an antagonist results in complete inhibition of a biological activity of a receptor.
  • alkyl refers to an optionally substituted straight-chain or branched-chain alkyl radical having from 1 to about 12 carbon atoms.
  • the term also includes substituted straight-chain or branched-chain alkyl radicals having from 1 to about 6 carbon atoms as well as those having from 1 to about 4 carbon atoms.
  • alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the like.
  • alkenyl refers to an optionally substituted straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon double-bonds and having from 2 to about 18 carbon atoms.
  • the term also includes substituted straight-chain or branched-chain alkyl radicals having one or more carbon-carbon double bonds and having from 2 to about 6 carbon atoms as well as those having from 2 to about 4 carbon atoms.
  • alkenyl radicals include ethenyl, propenyl, 1,4-butadienyl and the like.
  • alkynyl refers to an optionally substituted straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon triple-bonds and having from 2 to about 12 carbon atoms.
  • the term also includes substituted straight-chain or branched-chain alkyl radicals having one or more carbon-carbon tyriple bonds and having from 2 to about 6 carbon atoms as well as those having from 2 to about 4 carbon atoms.
  • alkynyl radicals include ethynyl, propynyl, butynyl and the like.
  • an alkyl comprises 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that an alkyl group may comprise only 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the term “alkyl” also includes instances where no numerical range of carbon atoms is designated).
  • the term “lower alkyl” refers to an alkyl comprising 1 to 6 carbon atoms.
  • the term “medium alkyl” refers to an alkyl comprising 7 to 12 carbon atoms.
  • alkyl may be designated as "C 1 -C 4 alkyl” or similar designations.
  • "d-d alkyl”, “ -d alkenyl” and"d-d alkynyl” indicate a radical having one, two, three, or four carbon atoms (e.g., methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, and butynyl).
  • haloalkyl refers to an alkyl in which at least one hydrogen atom is replaced with a halogen atom. In certain of the embodiments in which two or more hydrogen atom are replaced with halogen atoms, the halogen atoms are all the same as each other. In certain of such embodiments, the halogen atoms are not all the same as each other.
  • heteroalkyl refers to a group comprising an alkyl and one or more heteroatoms. Certain heteroalkyls are acylalkyls, in which the one or more heteroatoms are within an alkyl chain.
  • heterohaloalkyl refers to a heteroalkyl in which at least one hydrogen atom is replaced with a halogen atom.
  • Carbocycle refers to a group comprising a covalently closed ring, wherein each of the atoms forming the ring is a carbon atom. Carbocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Carbocycles may be optionally substituted. [040]
  • the term “heterocycle” refers to a group comprising a covalently closed ring wherein at least one atom forming the ring is a heteroatom. Heterocyclic rings may be formed by tliree, four, five, six, seven, eight, nine, or more than nine atoms.
  • heterocyclic rings may comprise one, two, three, four, five, six, seven, eight, nine, or more than nine heteroatoms.
  • those two or more heteroatoms may be the same as or different from each other.
  • Heterocycles may be optionally substituted. Binding to a heterocycle can be at a heteroatom or via a carbon atom. For example, binding for benzo-fused derivatives, may be via a carbon of the benzenoid ring.
  • heterocycles include, but are not limited to the following:
  • D, E, F, and G each independently represent a heteroatom.
  • D, E, F, and G may be the same as or different from each other.
  • heteroatom refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from oxygen, sulfur, nitrogen, and phosphorus, but are not limited to those atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms may all be the same, or some or all of the two or more heteroatoms may each be different from the others.
  • aromatic refers to a group comprising a covalently closed ring having a delocalized ⁇ -electron system. Aromatic rings may be formed by five, six, seven, eight, nine, or more than nine atoms. Aromatics may be optionally substituted.
  • aromatic groups include, but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl.
  • aromatic includes, for example, benzenoid groups, connected via one of the ring-forming carbon atoms, and optionally carrying one or more substituents selected from an aryl, a heteroaryl, a cycloalkyl, a non-aromatic heterocycle, a halo, a hydroxy, an amino, a cyano, a nitro, an alkylamido, an acyl, a C ⁇ -6 alkoxy, a d -6 alkyl, a C] -6 hydroxyalkyl, a d- 6 aminoalkyl, a d- 6 alkylamino, an alkylsulfenyl, an alkylsulfinyl, an alkylsulfon
  • an aromatic group is substituted at one or more of the para, meta, and or ortho positions.
  • aromatic groups comprising substitutions include, but are not limited to, phenyl, 3- halophenyl, 4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl, 4- aminophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4- trifluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl, (trifluoromethyl)phenyl, alkoxyphenyl, 4- morpholin-4-ylphenyl, 4-pyrcolidin-l-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl, and 4-(2-oxopyrrolidin- 1 -yl)phenyl.
  • aryl refers to an aromatic group wherein each of the atoms forming the ring is a carbon atom.
  • Aryl rings may be formed by five, six, seven, eight, nine, or more than nine carbon atoms.
  • Aryl groups may be optionally substituted.
  • heteroaryl refers to an aromatic group wherein at least one atom forming the aromatic ring is a heteroatom. Heteroaryl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Heteroaryl groups may be optionally substituted.
  • heteroaryl groups include, but are not limited to, aromatic C 3-8 heterocyclic groups comprising one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and their substituted as well as benzo- and pyrido-fused derivatives, for example, connected via one of the ring-forming carbon atoms.
  • heteroaryl groups are optionally substituted with one or more substituents, independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, C 1-6 alkoxy, d_ 6 alkyl, C 1-6 hydroxyalkyl, d- 6 aminoalkyl, C ⁇ -6 alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, and trifluoromethyl.
  • substituents independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, C 1-6 alkoxy, d_ 6 alkyl, C 1-6 hydroxyalkyl, d- 6 aminoalkyl, C ⁇ -6 alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, and triflu
  • heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidme, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthala
  • the substituents are halo, hydroxy, cyano, O-C ⁇ -6 alkyl, C ⁇ -6 alkyl, hydroxy-C ⁇ -6 alkyl, or ammo-C ⁇ -6 alkyl.
  • non-aromatic ring refers to a group comprising a covalently closed ring that does not have a delocalized ⁇ -electron system.
  • cycloalkyl alone or in combination, refers to a monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety has from 3 to about 8 carbon atoms.
  • cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Cycloalkyl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Cycloalkyls may be optionally substituted.
  • non-aromatic heterocycle refers to a group comprising a non- aromatic ring wherein one or more atoms forming the ring is a heteroatom. Non- aromatic heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Non-aromatic heterocycles may be optionally substituted.
  • non-aromatic heterocycles comprise one or more carbonyl or thiocarbonyl groups such as, for example, oxo- and thio-containing groups.
  • non-aromatic heterocycles include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane, tetrahydro- 1,4-thiazme, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hy
  • arylalkyl refers to a group comprising an aryl group bound to an alkyl group.
  • carbocyclic cycloalkyl ring refers to a group comprising a carbocyclic cycloalkyl ring. Carbocycloalkyl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Carbocycloalkyl groups may be optionally substituted.
  • ring refers to any covalently closed structure.
  • Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non-aromatic heterocycles), aromatics (e.g., aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and non-aromatic heterocycles). Rings may be optionally substituted. Rings may form part of a ring system. [051]
  • ring system refers to two or more rings, wherein two or more of the rings are fused.
  • fused refers to structures in which two or more rings share one or more bonds.
  • R refers to a substituent selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon).
  • null refers to a group being absent from a structure. For R' R" example, in the structure ⁇ - ⁇ , if X is C, then both R' and R" exist, but if X is N, then one of those R groups is null, meaning that only tliree groups are bound to the N.
  • cyano refers to a group of formula -CN.
  • isocyanato refers to a group of formula -NCO.
  • thiocyanato refers to a group of formula -CNS.
  • isothiocyanato refers to a group of formula -NCS.
  • esters refers to a chemical moiety with formula -(R) n -COOR', where R and R' are independently selected from alkenyl, alkynyl,, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl (bonded through a ring carbon) and non- aromatic heterocycle (bonded through a ring carbon), where n is 0 or 1.
  • amide refers to a chemical moiety with formula -(R) n -C(O)NHR' or -(R) n -NHC(O)R, where R and R' are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), where n is 0 or 1.
  • an amide may be an amino acid or a peptide.
  • alkoxy refers to an alkyl ether radical.
  • alkoxy radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
  • formyl includes aldehydes attached to a compound via an alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl group (e.g., -alkyl-CHO, -aryl-CHO, • arylalkyl-CHO or -heteroarylalkyl-CHO, etc.).
  • oxime refers to a group of formula:
  • hydrozone refers to a group of formula:
  • hydroxylamine refers to a group of formula:
  • sulfonamide refers to a group of formula:
  • halogen includes F, CI, Br and I
  • amine includes F, CI, Br and I
  • hydroxy includes F, CI, Br and I
  • carboxyl include such groups that have been esterified or amidified. Procedures and specific groups used to achieve esterification and amidification are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, which is inco ⁇ orated by reference herein in its entirety.
  • the term “optionally substituted,” refers to a group in which none, one, or more than one of the hydrogen atoms has been replaced with one or more group(s) individually and independently selected from: alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, haloalkenyl, haloalkynyl, heterohaloalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkyl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, alkenylthio, alkynylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O
  • protective derivatives and protecting groups that may form such protective derivatives
  • carrier refers to a compound that facilitates the inco ⁇ oration of another compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • pharmaceutical agent refers to a chemical compound or composition capable of inducing a desired therapeutic effect in a patient.
  • a pharmaceutical agent comprises an active agent, which is the agent that induces the desired therapeutic effect.
  • a pharmaceutical agent comprises a prodrug.
  • a pharmaceutical agent comprises inactive ingredients such as carriers, excipients, and the like.
  • therapeutically effective amount refers to an amount of a pharmaceutical agent sufficient to achieve a desired therapeutic effect.
  • prodrug refers to a pharmaceutical agent that is converted from a less active form into a corresponding more active form in vivo.
  • the term “phannaceutically acceptable” refers to a formulation of a compound that does not significantly abrogate a biological activity, a pharmacological activity and/or other properties of the compound when the formulated compound is administered to a patient. In certain embodiments, a pharmaceutically acceptable formulation does not cause significant irritation to a patient.
  • co-administer refers to administering more than one pharmaceutical agent to a patient. In certain embodiments, co-administered pharmaceutical agents are administered together in a single dosage unit. In certain embodiments, co-administered pharmaceutical agents are administered separately. In certain embodiments, co-administered pharmaceutical agents are administered at the same time.
  • co-administered pharmaceutical agents are administered at different times.
  • the term "patient” includes human and animal subjects.
  • the term "substantially pure” means an object species (e.g., compound) is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition).
  • a substantially pure composition is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all species present.
  • a substantially pure composition is a composition wherein the object species comprises more than about 80%, 85%, 90%), 95%o, or 99%> of all species present in the composition.
  • tissue-selective refers to the ability of a compound to modulate a biological activity in one tissue to a greater or lesser degree than it modulates a biological activity in another tissue.
  • the biological activities modulated in the different tissues may be the same or they may be different.
  • the biological activities modulated in the different tissues may be mediated by the same type of target receptor.
  • a tissue-selective compound may modulate an HNF-4 ⁇ receptor-mediated biological activity in one tissue and fail to modulate, or modulate to a lesser degree, an HNF-4 ⁇ receptor-mediated biological activity in another tissue type.
  • monitoring refers to observing an effect or absence of any effect.
  • cells are monitored after contacting those cells with a compound of the present invention. Examples of effects that may be monitored include, but are not limited to, changes in cell phenotype, cell proliferation, an HNF-4 ⁇ receptor activity, or the interaction between an HNF-4 ⁇ receptor and a natural binding partner.
  • cell phenotype refers to physical or biological characteristics.
  • cell proliferation refers to the rate at which cells divide.
  • the number of cells growing in a vessel can be quantified by a person skilled in the art (e.g., by counting cells in a defined area using a light microscope, or by using laboratory apparatus that measure the density of cells in an appropriate medium).
  • One skilled in that art can calculate cell proliferation by determining the number of cells in a sample at two or more times.
  • contacting refers to bringing two or more materials into close enough proximity that they may interact. In certain embodiments, contacting can be accomplished in a vessel such as a test tube, a petri dish, or the like. In certain embodiments, contacting may be performed in the presence of additional materials. In certain embodiments, contacting may be performed in the presence of cells. In certain of such embodiments, one or more of the materials that are being contacted may be inside a cell. Cells may be alive or may dead. Cells may or may not be intact. Certain compounds
  • Certain compounds that bind to HNF-4 ⁇ receptors and/or certain compounds that modulate an activity of such receptors play a role in health (e.g., normal growth, development, and/or absence of disease).
  • compounds of the present invention are useful for treating any of a variety of diseases or conditions.
  • Certain compounds have been previously described as receptor modulators. See e.g., U. S. Patent Nos. 6,462,038, 5,693,646; 6,380,207; 6,506,766;
  • Patent Application No. 10/209,461 (Pub. No. US 2003/0055094); International Patent Application Nos. WO 01/27086 and WO 02/22585; Zhi, et al. Bioorganic & Med. Chem. Lett. 2000, 10:415-418; Pooley, et al, J. Med. Chem. 1998, 41:3461; Hamann, etal J. Med. Chem. 1998, 41:623; and Yin, et al, Molec. Pharmacol, 2003, 63:211-223 the entire disclosures of which are inco ⁇ orated by reference herein in their entirety.
  • cyclothiocarbamate analogues have been described as progesterone receptor modulators (e.g., U.S. Pat. Nos. 6,436,929 and 6,509,334). Certain cyclocarbamate analogues have been described as progesterone receptor antagonists (e.g., U.S. Pat. Nos. 6,306,851, 6,380,178, 6,441,019, 6,444,668, 6,509,334, and 6,566,358; Zhang, et al. J. Med. Chem. 45:4379 (2002)). [098] In certain embodiments, the invention provides a compound of formula I, II, III, IV, V, or VI:
  • R 1 is selected from H, a halogen, SH, and OH.
  • R 2 is selected from H, a halogen, an optionally substituted d-d alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 akynyl, an optionally substituted d-d heteroalkyl, an optionally substituted C 2 - heteroalkenyl, an optionally substituted C 2 -C 6 heteroakynyl, an optionally substituted C ⁇ -C 6 haloalkyl, an optionally substituted C 2 -C 6 haloalkenyl, an optionally substituted C 2 -C 6 haloakynyl, an optionally substituted C ⁇ -C 6 heterohaloalkyl, an optionally substituted C 2 -C 6 heterohaloalkenyl, an optionally substituted C 2 -C 6 heterohaloakynyl
  • R 2 is an optionally substituted d-C 8 alkyl, an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 akynyl, an optionally substituted C 2 -C 8 thioalkyl, an optionally substituted C 2 -C 8 thioalkenyl, an optionally substituted C 2 -C 8 thioakynyl, or an optionally substituted C 3 -C 8 cycloalkyl.
  • R 2 is an optionally substituted C ⁇ -C 8 alkyl, an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 akynyl, an optionally substituted C 2 -C 8 thioalkyl, an optionally substituted C 2 -C 8 thioalkenyl, an optionally substituted C 2 -C 8 thioakynyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 -C 8 cycloalkenyl, or an optionally substituted C 3 -C 8 cycloakynyl.
  • R 2 is selected from an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 2 -C 3 thioalkenyl, an optionally substituted C 2 -C 3 thioalkynyl, an optionally substituted C 3 -C 8 cycloalkenyl, and an optionally substituted C 3 -C 8 cycloalkynyl.
  • R 2 is selected from an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert- butyl.
  • R 2 is F or CI.
  • R 2 is selected from an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, thioalkenyl, thioalkynyl, aldehyde and ketone, those groups are optionally substituted with one or more fluorines.
  • R 2 is selected from an optionally substituted hydroxylamine, that group is optionally substituted with a C ⁇ -C 2 alkyl, a C 2 alkenyl, a C 2 akynyl, a d-C 2 fluoroalkyl, a C 2 a fluoroalkenyl, or a C 2 fluoroakynyl,.
  • R 3 is selected from H, a halogen, a nitro, an optionally substituted d-do alkyl, an optionally substituted C 2 -C ⁇ o alkenyl, an optionally substituted C 2 -C ⁇ o akynyl, an optionally substituted d-Cio alkoxy, an optionally substituted d-do thioalkyl, an optionally substituted C 2 -do thioalkenyl, an optionally substituted C 2 -C ⁇ o thioakynyl, a NR 14 R 15 , and an optionally substituted five to six-membered carbocyclic or heterocyclic ring.
  • R 3 is an optionally substituted d-C 8 alkyl, an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 akynyl, an optionally substituted C 2 -C 8 thioalkyl, an optionally substituted C 2 -C 8 thioalkenyl, an optionally substituted C 2 -C 8 thioakynyl, or an optionally substituted C 3 -C 8 cycloalkyl.
  • R is an optionally substituted C ⁇ -C 8 alkyl, an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 akynyl, an optionally substituted C 2 -C 8 thioalkyl, an optionally substituted C 2 -C 8 thioalkenyl, an optionally substituted C 2 -C 8 thioakynyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 -C 8 cycloalkenyl, or an optionally substituted C 3 - C 8 cycloakynyl.
  • R 3 is selected from an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 2 -C 3 thioalkenyl, an optionally substituted C 2 -C 3 thioalkynyl, an optionally substituted C 3 -C 8 cycloalkenyl, and an optionally substituted C 3 -C 8 cycloalkynyl.
  • R 3 is selected from an optionally substituted methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.
  • R 3 is F or CI.
  • R 3 is selected from an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, thioalkenyl, thioalkynyl, aldehyde and ketone, those groups are optionally substituted with one or more halogens.
  • R 3 is selected from an optionally substituted carboxylic or heterocyclic ring, that ring is optionally substituted with a one or two R 19 groups.
  • R 4 is selected from H, a halogen, and OH.
  • R 5 is selected from CH 2 OH, CHO, COOH, and a C(R 5' )(R 5" )(COOH).
  • R 5' and R 5 are each independently selected from H, O, S and F. In certain embodiments, R 5 and R 5 together are O or S.
  • R 6 and R 7 are each independently selected from H, a halogen, a NHC(O)R 18 , an optionally substituted d-C 6 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 akynyl, an optionally substituted C 2 -C 6 alkenyl, C ⁇ -C 6 heteroalkyl, an optionally substituted C 2 -C 6 heteroalkenyl, an optionally substituted C 2 -C 6 heteroakynyl, an optionally substituted d- d haloalkyl, an optionally substituted C 2 -C 6 haloalkenyl, an optionally substituted C 2 -C 6 haloakynyl, an optionally substituted C ⁇ -C 6 heterohaloalkyl, an optionally substituted C 2 - heterohaloalkenyl, an optionally substituted C 2 -C 6 heterohaloakyny
  • R 6 and/or R 7 is an optionally substituted d-C 8 alkyl, an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 akynyl, an optionally substituted C 2 -C 8 thioalkyl, an optionally substituted C 2 -C 8 thioalkenyl, an optionally substituted C 2 -C 8 thioakynyl, or an optionally substituted C 3 -C 8 cycloalkyl.
  • R 6 and/or R 7 is an optionally substituted d-C 8 alkyl, an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 akynyl, an optionally substituted C 2 -C 8 thioalkyl, an optionally substituted C 2 -C 8 thioalkenyl, an optionally substituted C 2 -C 8 thioakynyl, or an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 -C 8 cycloalkenyl,or an optionally substituted C 3 -C 8 cycloakynyl .
  • R 6 and/or R 7 is selected from an optionally substituted d-C 8 alkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 2 -C 3 thioalkenyl, an optionally substituted C 2 -C 3 thioalkynyl, an optionally substituted C 3 -C 8 cycloalkenyl, and an optionally substituted C 3 -C 8 cycloalkynyl.
  • R 6 and/or R 7 is selected from an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl.
  • R 6 and/or R 7 is F or CI.
  • R 6 and/or R 7 is selected from an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, thioalkenyl, thioalkynyl, aldehyde and ketone, those groups are optionally substituted with one or more fluorines.
  • R and/or R is selected from an optionally substituted hydroxylamine
  • that hydroxylamine is optionally substituted with a C ⁇ -C 2 alkyl, a C 2 alkenyl, a C 2 akynyl, a C ⁇ -C 2 fluoroalkyl, a C 2 fluoroalkenyl, or a C 2 fluoroakynyl,.
  • R 6 and R 7 taken together form a group selected from O, S, NH and CH 2 .
  • R 8 and R 9 are each independently selected from H, a halogen, an optionally substituted C ⁇ -C 2 alkyl, an optionally substituted C 2 alkenyl, an optionally substituted C 2 akynyl, and null.
  • R 8 and/or R 9 is methyl optionally substituted with one or more halogens.
  • R and R 9 taken together with Y form a three to five-membered optionally substituted carbocyclic ring.
  • R 10 is selected from H, a halogen, an optionally substituted d-C 2 alkyl, an optionally substituted C 2 alkenyl, and an optionally substituted C 2 akynyl. In certain embodiments, R 10 is a methyl optionally substituted with one or more halogens.
  • R 11 and R n are each independently selected from H, a halogen and OH. In certain embodiments, R n and R 11' taken together form an O. In certain embodiments, if R 11 is OH, then R 11 is H.
  • R and R are each independently selected from a C 1 -C 3 alkyl optionally substituted with one or more halogens, C 2 -C 3 alkenyl optionally substituted with one or more halogens, and a C 2 -C 3 akynyl optionally substituted with one or more halogens.
  • R 12 and R 13 taken together with the nitrogen atom to which they are both bound form a five to six-membered optionally substituted heterocyclic ring.
  • R 14 and R 15 are each independently selected from a C ⁇ -C 2 alkyl optionally substituted with one or more halogens, an C 2 -C 6 alkenyl optionally substituted with one or more halogens, and a C 2 -C 6 akynyl optionally substituted with one or more halogens.
  • R 16 and R 17 are each independently selected from an optionally substituted C ⁇ -C ⁇ 2 alkyl, optionally substituted C 2 -C ⁇ 2 alkenyl, optionally substituted C 2 -C 12 akynyl, an optionally substituted Cj-Cn heteroalkyl, an optionally substituted C 2 -C 12 heteroalkenyl, an optionally substituted C 2 -C 12 akynyl, an optionally substituted d-C 12 haloalkyl, an optionally substituted C 2 -C ⁇ 2 haloalkenyl, an optionally substituted C 2 -C ⁇ 2 haloakynyl, an optionally substituted C ⁇ -C 12 heterohaloalkyl, an optionally substituted C 2 -C ⁇ 2 heterohaloalkenyl, an optionally substituted C 2 -C 12 heterohaloakynyl, an optionally substituted C 3 -C 12 cycloalkyl, an optionally substituted
  • R 16 and/or R 17 is an optionally substituted C ⁇ -C ⁇ 2 alkyl, optionally substituted C 2 -C ⁇ 2 alkenyl, optionally substituted C 2 -C ⁇ 2 akynyl, an optionally substituted C 3 -C 12 cycloalkyl, an optionally substituted C 3 -C ⁇ 2 cycloalkenyl, or an optionally substituted C 3 -C ⁇ 2 cycloakynyl.
  • R 16 and/or R 17 is an optionally substituted C ⁇ -C 12 alkyl optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C ⁇ 2 akynyl, an optionally substituted C 3 -C 12 cycloalkyl, an optionally substituted C 3 -C 12 cycloalkenyl, or an optionally substituted C -C ⁇ 2 cycloakynyl.
  • R 16 and or R 17 is selected from an optionally substituted C 2 -C ⁇ 2 alkenyl, an optionally substituted C 2 -C ⁇ 2 alkynyl, an optionally substituted C 3 -C 12 cycloalkenyl, and an optionally substituted C 3 -C ⁇ 2 cycloalkynyl.
  • R 16 and/or R 17 is selected from an optionally substituted methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments where R 16 and/or R 17 is optionally substituted with one or more R 19 .
  • R 16 and R 17 taken together with the nitrogen atom to which they are both bound form a five to six-membered optionally substituted heterocyclic ring.
  • R 18 is selected from an optionally substituted Cv- C 12 alkyl, optionally substituted C 2 -C ⁇ 2 alkenyl, optionally substituted C 2 -C 12 akynyl, an optionally substituted C ⁇ -C ⁇ 2 heteroalkyl, an optionally substituted C 2 -C 12 heteroalkenyl, an optionally substituted C 2 -C ⁇ 2 heteroakynyl, an optionally substituted C ⁇ -C 12 haloalkyl, an optionally substituted C 2 -C 12 haloalkenyl, an optionally substituted C 2 -C ⁇ 2 haloakynyl, an optionally substituted d-C ⁇ 2 heterohaloalkyl, an optionally substituted C 2 -C 12 heterohaloalkenyl, an optionally substituted C 2 -C 12 heterohaloalken
  • R 18 is an optionally substituted C ⁇ -C 12 alkyl, an optionally substituted C 2 -C ⁇ 2 alkenyl, an optionally substituted C 2 -C 12 akynyl, or an optionally substituted C 3 -C ⁇ 2 cycloalkyl .
  • R 18 is an optionally substituted C ⁇ -C ⁇ 2 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 - C ⁇ akynyl, an optionally substituted C 3 -C 12 cycloalkyl, an optionally substituted C 3 -C ⁇ 2 cycloalkenyl, or an optionally substituted C 3 -C ⁇ 2 cycloakynyl .
  • R 18 is selected from an optionally substituted C 2 -C 12 alkenyl, an optionally substituted C 2 -C ⁇ 2 alkynyl, an optionally substituted C -C ⁇ 2 cycloalkenyl, and an optionally substituted C 3 -Cj 2 cycloalkynyl.
  • R 18 is selected from an optionally substituted methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.
  • R 8 is optionally substituted with one or more R 1 .
  • R 19 is selected from a halogen, an optionally substituted C1-C4 alkyl, optionally substituted C 2 -d alkenyl, optionally substituted C 2 -d akynyl, an optionally substituted C 1 -C 4 alkoxy, an optionally substituted d-C 3 thioalkyl, optionally substituted C 2 -C 3 thioalkenyl, optionally substituted C 2 -C 3 thioakynyl, an optionally substituted formyl, and an optionally substituted nitro.
  • R i9 is a -d alkyl optionally substituted with one or more fluorines, a C 2 -d alkenyl optionally substituted with one or more fluorines, or a C 2 -d akynyl optionally substituted with one or more fluorines.
  • R 19 is a - alkoxy optionally substituted with one or more halogens.
  • R 19 is a C ⁇ -C 3 thioalkyl optionally substituted with one or more halogens, a C 2 -C 3 thioalkenyl optionally substituted with one or more halogens, or a C 2 -C 3 thioakynyl optionally substituted with one or more halogens.
  • R 20 is selected from a C 4 -C 5 alkyl optionally substituted with one or more halogens, a C 4 -d alkenyl optionally substituted with one or more halogens, a C 4 -C 5 akynyl optionally substituted with one or more halogens, a phenyl optionally substituted with one or more fluorines, a thienyl optionally substituted 91 with one or more fluorines, and a benzyl optionally substituted with one or more R .
  • R 21 is selected from a halogen, a methyl optionally substituted with one or more fluorines, and a thiomethyl optionally substituted with one or more halogens.
  • X and Y are each independently selected from O, S, N and C.
  • A is selected from O, CH 2 , CF 2 and S.
  • Z is selected from C, N and phenylene.
  • each of R 6 and R 7 is null; if X is O or S, then each of R 6 and R 7 is null; if Y is O or S, then each of the R 8 and R 9 is null; and if Y is N, then one of R 8 and R 9 is null.
  • R 6 is selected from a halogen, a C ⁇ -C 12 alkyl a C 2 -C ⁇ 2 alkenyl, a C 2 -C 12 alkynyl or a C 2 -C ⁇ 2 alkoxy any of which is optionally substituted with one or more R 19 , or a C ⁇ -C 12 thioalkyl C ⁇ -C 12 thioalkenyl or d-C ⁇ 2 thioalkynyl any of which is optionally substituted with one or more R 19 , NR 16 R 17 or HNC(O)R 18 , then R 7 is H or F.
  • R 19 is selected from a - alkyl substituted with one or more halogens, a C 2 -C 4 alkenyl substituted with one or more halogens, a C 2 - d akynyl substituted with one or more halogens, a - alkoxy group substituted with one or more halogens, a d-C 3 thioalkyl substituted with one or more halogens, a C 2 -C 3 thioalkenyl substituted with one or more halogens, and C 2 -C 3 akynyl substituted with one or more halogens, group substituted with one or more halogens, then each of R 3 , R and R 17 is substituted with no more than two R 19 groups.
  • R 3 is a methyl substituted with one or more fluorines
  • neither R 1 nor R 2 is either hydrogen or a halogen.
  • R 4 is a halogen
  • R 3 is an ethoxy optionally substituted with one or more fluorines.
  • Y is nitrogen then neither R 8 nor R 9 is a halogen.
  • R is null and R is null.
  • certain compounds of the invention comprise two or more R 19 groups.
  • the identities of those two or more R 19 groups are each selected independently.
  • those R 19 groups are all the same aseach other; in certain embodiments, those R 19 groups are all different fromeach other; and in certain embodiments, some of those R 19 groups are the same as each other and some are different from the others. This independent selection applies to any group that is present in a compound more than once.
  • Certain compounds of the present inventions may exist as stereoisomers including, but not limited to, optical isomers.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations.
  • enantiomer refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
  • chiral center refers to a carbon atom to which four different groups are attached.
  • diastereomers refers to stereoisomers which are not enantiomers.
  • two diastereomers which have a different configuration at only one chiral center are referred to herein as “epimers.”
  • racemate refers to a mixture of equal parts of enantiomers.
  • the compounds of the present invention may be chiral, and it is intended that any enantiomers, as separated, pure or partially purified enantiomers or racemic mixtures thereof are included within the scope of the invention.
  • diastereomers when a double bond or a fully or partially saturated ring system or more than one center of asymmetry or a bond with restricted rotatability is present in the molecule diastereomers may be formed. It is intended that any diastereomers, as separated, pure or partially purified diastereomers or mixtures thereof are included within the scope of the invention. Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms, which the compounds are able to form, are included within the scope of the present invention. Thus, as one skilled in the art knows, certain aryls may exist in tautomeric forms. The mvention also includes tautomers, enantiomers and other stereoisomers of the compounds of Formula I.
  • R and S are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center.
  • the term “R” (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the term “S” (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the priority of groups is based upon their atomic number (in order of decreasing atomic number).
  • the compounds of Formula I when existing as a diastereomeric mixture, may be separated into diastereomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof.
  • a suitable solvent for example methanol or ethyl acetate or a mixture thereof.
  • the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent.
  • any enantiomer of a compound of Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration or through enantioselective synthesis.
  • enantiomeric enrichment refers to the increase in the amount of one enantiomer as compared to the other.
  • the ee with respect to the first enantiomer is 40%>.
  • the ee with respect to the first enantiomer is 80%>.
  • Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art.
  • the specific stereoisomers and enantiomers of compounds of Formula I can be prepared by one of ordinary skill in the art utilizing well known techniques and processes, such as those disclosed by J. Jacques, et al., "Enantiomers. Racemates.
  • the invention provides compounds selected from: 4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl]benzoyl benzoic acid (Compound 103); 4-[5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-l-hydroxy-2-naphthalenyl]benzoyl benzoic acid (Compound 104);
  • a compound of Formula I, II, III, IV, V, or VI is a selective HNF-4 ⁇ receptor modulator. In certain embodiments, a compound of Formula I, II, III, IV, V, or VI is a selective HNF-4 ⁇ receptor agonist. In certain embodiments, a compound of Formula I, II, III, IV, V, or VI is a selective HNF-4 ⁇ receptor antagonist. In certain embodiments, a compound of Formula I, II, III, IV, V, or VI is a selective HNF-4 ⁇ receptor partial agonist. In certain embodiments, a compound of Formula I, II, III, IV, V, or VI is a tissue-specific selective HNF-4 ⁇ receptor modulator.
  • a compound of Formula I, II, III, IV, V, or VI is a gene-specific selective HNF-4 ⁇ receptor modulator. In certain embodiments, a compound of Formula I, II, III, IV, V, or VI is a selective HNF-4 ⁇ receptor binding compound. [0142] In certain embodiments, the present invention provides selective HNF-4 ⁇ receptor modulators. In certain embodiments, the invention provides selective HNF-4 ⁇ receptor binding agents. In certain embodiments, the invention provides methods of making and methods of using selective HNF-4 ⁇ receptor modulators and/or selective HNF-4 ⁇ binding agents. In certain embodiments, selective HNF-4 ⁇ modulators are agonists, partial agonists, and/or antagonists for the HNF-4 receptor.
  • the invention provides compounds that are selective for an HNF-4 ⁇ receptor relative to a retinoic X receptor (RXR) (e.g., Compounds 104, 105, 110, 124, 125, 126, 158, 163, 171, 173, 177, 179, 190, 192, 201, 202, 212, 213, 214, 215, 217, and 218).
  • RXR retinoic X receptor
  • the invention provides compounds that are selective for an HNF-4 ⁇ receptor relative to an RXR by at least 8 times.
  • the intermediate 2 are usually obtained by a Friedel-Craft reaction between 1 and A in the presence of A1C1 3 in CH 2 C1 2 . Saponification of 2 affords the acids 3.
  • the nitro group present in 4 can be reduced to the corresponding amine 6 or hydroxylamine 7 using Zinc dust in MeOH/H 2 O/CH 2 Cl 2 at room temperature.
  • Derivatives 9 could be transformed into the chlorines 15 that can be used as alkylating agents with alcohols, amines or thiols. Saponification of these adducts afford the acids 16.
  • the hydrazones 17 and the oximes 18 and 19 are easily synthesized from the ketones 2.
  • the invention provides a salt corresponding to any of the compounds provided herein.
  • the invention provides a salt corresponding to a selective HNF-4 ⁇ modulator.
  • the mvention provides a salt corresponding to a selective HNF-4 ⁇ receptor binding agent.
  • a salt is obtained by reacting a compound with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • a salt is obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.
  • a salt such as an ammonium salt, an alkali metal salt, such as
  • compounds of the present invention comprising one or more silicon atoms possess certain desired properties, including, but not limited to, greater stability and/or longer half-life in a patient, when compared to the same compound in which none of the carbon atoms have been replaced with a silicon atom.
  • Protecting groups that may be used in the present invention include those that are commonly known to those skilled in the art, such groups include, but are not limited to TBDMS, TBS and Benzyl.
  • compounds of the present invention are capable of modulating activity of HNF-4 receptors in a "co-transfection” assay (also called a “cis-trans” assay), which has been discussed previously. See e.g., Evans et al, Science, 240:889-95 (1988); U.S. Patent Nos. 4,981,784 and 5,071,773; Pathirana et al., Mol. Pharm. 47:630-35 (1995)). Modulating activity in a co-transfection assay has been shown to correlate with in vivo modulating activity. Thus, in certain embodiments, such assays are predictive of in vivo activity. See, e.g., Berger et al, J.
  • co-transfection assays two different co-transfectiott plasmids are prepared.
  • cloned cDNA encoding an intracellular receptor e.g., HNF-4 ⁇ receptor
  • a constitutive promoter e.g., the SV40 promoter
  • cDNA encoding a reporter protein such as firefly luciferase (LUC)
  • LEC firefly luciferase
  • Both co-transfection plasmids are co-transfected into the same cells.
  • Expression of the first co-transfection plasmid results in production of the intracellular receptor protein.
  • Activation of that intracellular receptor protein results in production of a receptor- dependant activation factor for the promoter of the second co-transfection plasmid.
  • That receptor-dependant activation factor in turn results in expression of the reporter protein encoded on the second co-transfection plasmid.
  • reporter protein expression is linked to activation of the receptor.
  • that reporter activity can be conveniently measured (e.g., as increased luciferase production).
  • Certain co-transfection assays can be used to identify agonists, partial agonists, and/or antagonists of intracellular receptors.
  • to identify agonists co-transfected cells are exposed to a test compound. If the test compound is an agonist or partial agonist, reporter activity is expected to be higher compared to co-transfected cells in the absence of the test compound.
  • to identify antagonists the cells are exposed to a known agonist (e.g., the natural ligand for the receptor) in the presence and absence of a test compound. If the test compound is an antagonist, reporter activity is expected to be lower than that of cells exposed only to the known agonist.
  • compounds of the invention are used to detect the presence, quantity and/or state of receptors in a sample.
  • samples are obtained from a patient.
  • compounds are radio- or isotopically-labeled.
  • compounds of the present invention that selectively bind HNF-4 receptors may be used to determine the presence or amount of such receptors in a sample, such as cell homogenates and lysates.
  • the present invention provides for use of both CARLA and mammalian-2-hybrid assays, to characterize the in vitro profile of compounds of the invention on a HNF-4 ⁇ receptor.
  • the present invention provides for use of [H] 3 -[4- [(phenylhydrazino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)]benzoic acid] (Example 73) and/or [H] 3 -4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2- naphthalenyl]benzoyl benzoic acid (Example 3) as radioactive ligands for a binding assay.
  • At least one selective HNF-4 ⁇ receptor modulator, or pharmaceutically acceptable salt, ester, amide, and/or prodrug thereof, either alone or combined with one or more pharmaceutically acceptable carriers forms a pharmaceutical agent.
  • Techniques for formulation and admimstration of compounds of the present invention may be found for example, in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990.
  • a pharmaceutical agent comprising one or more compounds of the present invention is prepared using known techniques, including, but not limited to mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.
  • a pharmaceutical agent comprising one or more compounds of the present invention is a liquid (e.g., a suspension, elixir and/or solution).
  • a liquid pharmaceutical agent comprising one or more compounds of the present invention is prepared using ingredients known in the art, including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • a pharmaceutical agent comprising one or more compounds of the present mvention is a solid (e.g., a powder, tablet, and/or capsule).
  • a solid pharmaceutical agent comprising one or more compounds of the present invention is prepared using ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • a pharmaceutical agent comprising one or more compounds of the present invention is formulated as a depot preparation. Certain of such depot preparations are typically longer acting than non-depot preparations. In certain embodiments, such preparations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • depot preparations are prepared using suitable polymeric or hydrophobic materials (for example an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical agent comprising one or more compounds of the present invention comprises a delivery system.
  • delivery systems include, but are not limited to, liposomes and emulsions.
  • Certain delivery systems are useful for preparing certain pharmaceutical agents including those comprising hydrophobic compounds.
  • certain organic solvents such as dimethylsulfoxide are used.
  • a pharmaceutical agent comprising one or more compounds of the present invention comprises one or more tissue-specific delivery molecules designed to deliver the pharmaceutical agent to specific tissues or cell types.
  • pharmaceutical agents include liposomes coated with a tissue-specific antibody.
  • a pharmaceutical agent comprising one or more compounds of the present invention comprises a co-solvent system.
  • co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water- miscible organic polymer, and an aqueous phase.
  • co- solvent systems are used for hydrophobic compounds.
  • VPD co-solvent system is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM , and 65% w/v polyethylene glycol 300.
  • the proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics.
  • a pharmaceutical agent comprising one or more compounds of the present mvention comprises a sustained-release system.
  • a non- limiting example of such a sustained-release system is a semi-permeable matrix of solid hydrophobic polymers.
  • sustained-release systems may, depending on their chemical nature, release compounds over a period of hours, days, weeks or months.
  • compositions used in pharmaceutical agent of the present invention may be provided as pharmaceutically acceptable salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.
  • a pharmaceutical agent comprising one or more compounds of the present invention comprises an active ingredient in a therapeutically effective amount.
  • the therapeutically effective amount is sufficient to prevent, alleviate or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art.
  • a pharmaceutical agent comprising one or more compounds of the present invention is formulated as a prodrug.
  • prodrugs are useful because they are easier to administer than the corresponding active form.
  • a prodrug may be more bioavailable (e.g., through oral administration) than is the corresponding active form.
  • a prodrug may have improved solubility compared to the corresponding active form.
  • a prodrug is an ester.
  • such prodrugs are less water soluble than the corresponding active form.
  • such prodrugs possess superior transmittal across cell membranes, where water solubility is detrimental to mobility.
  • the ester in such prodrugs is metabolically hydrolyzed to carboxylic acid.
  • the carboxylic acid containing compound is the corresponding active fo ⁇ n.
  • a prodrug comprises a short peptide (polyaminoacid) bound to an acid group.
  • the peptide is metabolized to form the corresponding active form.
  • a pharmaceutical agent comprising one or more compounds of the present invention is useful for treating a conditions or disorder in a mammalian, and particularly in a human patient.
  • Suitable administration routes include, but are not limited to, oral, rectal, transmucosal, intestinal, enteral, topical, suppository, through inhalation, intrathecal, mtraventricular, intraperitoneal, intranasal, intraocular and parenteral (e.g., intravenous, intramuscular, intramedullary, and subcutaneous).
  • intrathecals are administered to achieve local rather than systemic exposures.
  • pharmaceutical agents may be injected directly in the area of desired effect (e.g., in the renal or cardiac area).
  • a pharmaceutical agent comprising one or more compounds of the present invention is administered in the form of a dosage unit (e.g., tablet, capsule, bolus, etc.).
  • dosage units comprise a selective a HNF-4 ⁇ receptor modulator in a dose from about 1 ⁇ g/kg of body weight to about 50 mg/kg of body weight.
  • dosage units comprise a selective a HNF-4 ⁇ receptor modulator in a dose from about 2 ⁇ g/kg of body weight to about 25 mg/kg of body weight.
  • such dosage units comprise a selective a HNF-4 ⁇ receptor modulator in a dose from about 10 ⁇ g/kg of body weight to about 5 mg/kg of body weight.
  • pharmaceutical agents are administered as needed, once per day, twice per day, three times per day, or four or more times per day. It is recognized by those skilled in the art that the particular dose, frequency, and duration of administration depends on a number of factors, including, without limitation, the biological activity desired, the condition of the patient, and tolerance for the pharmaceutical agent.
  • a pharmaceutical agent comprising a compound of the present invention is prepared for oral administration.
  • a pharmaceutical agent is formulated by combining one or more compounds of the present invention with one or more pharmaceutically acceptable carriers.
  • compositions of the invention enable compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient.
  • pharmaceutical agents for oral use are obtained by mixing one or more compounds of the present mvention and one or more solid excipient.
  • Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • such a mixture is optionally ground and auxiliaries are optionally added.
  • pharmaceutical agents are formed to obtain tablets or dragee cores.
  • disintegrating agents e.g., cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate
  • disintegrating agents e.g., cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate
  • dragee cores are provided with coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to tablets or dragee coatings.
  • pharmaceutical agents for oral administration are push-fit capsules made of gelatin.
  • Such push-fit capsules comprise one or more compounds of the present invention in admixture with one or more filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • pharmaceutical agents for oral administration are soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • one or more compounds of the present invention are be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • pharmaceutical agents are prepared for buccal administration.
  • a pharmaceutical agent is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.).
  • a pharmaceutical agent comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks 's solution, Ringer's solution, or physiological saline buffer.
  • other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives).
  • injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like.
  • Certain pharmaceutical agents for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers.
  • Certain pharmaceutical agents for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Certain solvents suitable for use in pharmaceutical agents for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.
  • Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • such suspensions may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • a pharmaceutical agent is prepared for transmucosal administration.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • a pharmaceutical agent is prepared for administration by inhalation. Certain of such pharmaceutical agents for inhalation are prepared in the form of an aerosol spray in a pressurized pack or a nebulizer.
  • Such pharmaceutical agents comprise a propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined with a valve that delivers a metered amount.
  • capsules and cartridges for use in an inhaler or insufflator may be formulated.
  • Certain of such formulations comprise a powder mixture of a compound of the mvention and a suitable powder base such as lactose or starch.
  • a pharmaceutical agent is prepared for rectal administration, such as a suppositories or retention enema.
  • a pharmaceutical agent comprises known ingredients, such as cocoa butter and/or other glycerides.
  • a pharmaceutical agent is prepared for topical admimstration.
  • Certain of such pharmaceutical agents comprise bland moisturizing bases, such as ointments or creams.
  • Exemplary suitable ointment bases include, but are not limited to, petrolatum, petrolatum plus volatile silicones, lanolin and water in oil emulsions such as EucerinTM, available from Beiersdorf (Cincinnati, Ohio).
  • Suitable cream bases include, but are not limited to, NiveaTM Cream, available from Beiersdorf (Cincinnati, Ohio), cold cream (USP), Purpose CreamTM, available from Johnson & Johnson (New Brunswick, New Jersey), hydrophilic ointment (USP) and LubridermTM, available from Pfizer (Morris Plains, New Jersey).
  • the formulation, route of administration and dosage for a pharmaceutical agent of the present invention can be chosen in view of a particular patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1).
  • a pharmaceutical agent is administered as a single dose.
  • a pharmaceutical agent is administered as a series of two or more doses administered over one or more days.
  • a pharmaceutical agent of the present mvention is administered to a patient between about 0.1% and 500%, more preferably between about 25% and 75% of an established human dosage. Where no human dosage is established, a suitable human dosage may be inferred from ED 50 or ID 50 values, or other appropriate values derived from in vitro or in vivo studies.
  • a daily dosage regimen for a patient comprises an oral dose of between 0.1 mg and 2000 mg of a compound of the present invention. In certain embodiments, a daily dosage regimen is administered as a single daily dose.
  • a daily dosage regimen is administered as two, three, four, or more than four doses.
  • a pharmaceutical agent of the present invention is administered by continuous intravenous infusion. In certain of such embodiments, from 0.1 mg to 500 mg of a composition of the present invention is administered per day.
  • a pharmaceutical agent of the invention is administered for a period of continuous therapy. For example, a pharmaceutical agent of the present mvention may be administered over a period of days, weeks, months, or years.
  • Dosage amount, interval between doses, and duration of treatment may be adjusted to achieve a desired effect. In certain embodiments, dosage amount and interval between doses are adjusted to maintain a desired concentration on compound in a patient.
  • dosage amount and interval between doses are adjusted to provide plasma concentration of a compound of the present invention at an amount sufficient to achieve a desired effect.
  • the plasma concentration is maintained above the minimal effective concentration (MEC).
  • pharmaceutical agents of the present invention are administered with a dosage regimen designed to maintain a concentration above the MEC for 10-90% of the time, between 30-90%) of the time, or between 50-90% of the time.
  • the dosage regimen is adjusted to achieve a desired local concentration of a compound of the present mvention.
  • a pharmaceutical agent may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • Such notice for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • a pharmaceutical agent is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • one or more pharmaceutical agents of the present mvention are co-administered with one or more other pharmaceutical agents.
  • such one or more other pharmaceutical agents are designed to treat the same disease or condition as the one or more pharmaceutical agents of the present invention.
  • such one or more other pharmaceutical agents are designed to treat a different disease or condition as the one or more pharmaceutical agents of the present invention.
  • such one or more other pharmaceutical agents are designed to treat an undesired effect of one or more pharmaceutical agents of the present invention.
  • one or more pharmaceutical agents of the present invention is co-administered with another pharmaceutical agent to treat an undesired effect of that other pharmaceutical agent.
  • one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are administered at the same time.
  • one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are administered at the different times.
  • one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are prepared together in a single formulation.
  • one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are prepared separately.
  • Examples of pharmaceutical agents that may be co-administered with a pharmaceutical agent of the present invention include, but are not limited to, analgesics (e.g., acetaminophen); anti-inflammatory agents, including, but not limited to non- steroidal anti-inflammatory drugs (e.g., ibuprofen, COX-1 inhibitors, and COX-2, inhibitors); salicylates; antibiotics; antivirals; antifungal agents; antidiabetic agents (e.g., biguanides, glucosidase inhibitors, insulins, sulfonylureas, and thiazolidenediones); adrenergic modifiers; diuretics; hormones (e.g., anabolic steroids, androgen, estrogen, calcitonin, progestin, somatostatin, and thyroid hormones); immunomodulators; muscle relaxants; antihistamines; osteoporosis agents (e.g., biphosphonates,
  • the invention provides methods of treating a patient comprising administering one or more compounds of the present invention.
  • Compounds of the present invention including, but not limited to, pharmaceutically acceptable salts, solvates and hydrates, are expected to be effective in treating diseases or conditions that are mediated by HNF-4 ⁇ . Therefore, in certain embodiments, compounds of the invention are effective in treating conditions that are mediated by HNF-4 ⁇ , including, but not limited to, syndrome X, non-insulin dependent diabetes mellitus, cancer, obesity, cardiovascular disease and dyslipidemia.
  • a patient is treated prophylactically to reduce or prevent the occurrence of a condition.
  • the present invention provides a method of lowering blood glucose levels in a mammal by administering to the patient a pharmaceutically effective amount of at least one compound of the present invention.
  • the patient is a mammal.
  • the patient is a human.
  • the present invention provides a method of lowering plasma triglycerides levels in a patient by administering to the mammal a pharmaceutically effective amount of at least one compound of the present invention.
  • the patient is a mammal.
  • the patient is a human.
  • the present mvention provides a method of increasing insulin levels in a patient by administering to the mammal a pharmaceutically effective amount of at least one compound of the present invention.
  • the patient is a mammal.
  • the patient is a human.
  • the ether extract was washed with water (2 x 100 mL) and brine (100 mL). The ether layer was dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude product was further purified by recrystallization from a 9/1 ratio of hexane/ether mixture to provided desired 0.6191 g (78%, theo. 0.7976 g) of product as a white solid. !
  • Compound 119 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3- ethoxy-2-naphthalenyl)methyl]benzoate according to the procedure described in Example 3 using iodoethane as alkylating reagent.
  • Compound 121 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-propoxy-2-naphthalenyl)methyl]benzoate according to the procedure described in Example 3 using 1-iodopropane as alkylating reagent. !
  • Compound 124 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3, 5,5,8,8- pentamethyl-4-amino-2-naphthalenyl)methyl]benzoate according to the procedure described in Example 3 using -toluenesulfonylchloride as reagent. !
  • Reagent and conditions a) ArB(OH) 2 , Pd(PPh 3 ) 4 , toluene, ethanol, aq.2N Na 2 CO 3 , reflux, b) LiOH, THF/MeOH,room temp, c) HNO 3 , H 2 SO 4 , AcOH, 0° C toroom temp, d) BINAP, Pd 2 dba 3 , amine, CsF, toluene, reflux.
  • Example 32 was synthesized from A according to the procedure described in Example 28 using 3-nitrophenyl boronic acid as coupling reagent.
  • Compound 136 was synthesized from Methyl-4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-(2-fluorobenzene)-2-naphthalenyl]benzoyl benzoate according to the nitration procedure used in the synthesis of Example 8 and the saponification procedure used in Example 3.
  • Compound 141 was synthesized from methyl-4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-hydroxy-6-fluoro-2-naphthalenyl]benzoyl benzoate according to the procedure described in Example 3 using iodoethane as alkylating reagent.
  • Compound 142 was sj ⁇ thesized frommethyl-4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-hydroxy-6-fluoro-2-naphthalenyl]benzoyl benzoate according to the nitration procedure described in Example 1 and the saponification procedure described in Example 3.
  • Compound 144 was synthesized from methyl 3-chloro-4-[5,6,7,8-tetrahydro-5, 5,8,8- tetramethyl-3-hydroxy-2-naphthalenyl]benzoyl benzoate according to the procedure described in Example 3 using iodoethane as alkylating reagent.
  • Example 45 was synthesized from methyl 3-chloro-4-[5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-3-hydroxy-2-naphthalenyl]benzoyl benzoate according to the procedure described in Example 3 using iodomethane as alkylating reagent.
  • a dispersion of sodium hydride in oil (200 mg, 60%>wt, 5 mmol) was added to a suspension of methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2- naphthalenyl)hydroxymethyl] benzoate in 10 mL of THF atroom temp. The mixture was stirred for 20 min before addition of 2-fluorobenzyl bromide (0.8 mL, 6.3 mmol). The mixture was stirred overnight and then 25 mL of IM aqueous HCI solution was slowly added.
  • Compound 150 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl)(2-fluorobenzyloxy)methyl] benzoate according to the procedure described in Example 49 using 4-fluorobenzyl bromide as alkylating reagent. !
  • Compound 151 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl)(2-fluorobenzyloxy)methyl] benzoate according to the procedure described in Example 47 using 2-trifluoromethoxybenzyl bromide as alkylating reagent. !
  • Compound 152 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl)(2-fluorobenzyloxy)methyl] benzoate according to the procedure described for Example 49 using 2,3-difluorobenzyl bromide as alkylating reagent.
  • Compound 153 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl)(2-fluorobenzyloxy)methyl] benzoate according to the procedure described for Example 49 using 4-trifluoromethylbenzyl bromide as alkylating reagent.
  • Compound 154 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5, 5,8,8- pentamethyl-2-naphthalenyl)(2-fluorobenzyloxy)methyl] benzoate according to the procedure described in Example 49 using 4-trifluoromethoxybenzyl bromide as alkylating reagent.
  • Compound 155 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl)(2-fluorobenzyloxy)methyl] benzoate according to the procedure described in Example 49 using 4-trifluorothiomethoxybenzyl bromide as alkylating reagent.
  • Compound 156 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-ethoxy-2-naphthalenyl)hydroxymethyl] benzoate according to the procedure described in Example 49 using 2,3-difluorobenzyl bromide as alkylating reagent. !
  • Compound 157 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-ethoxy-2-naphthalenyl)hydroxymethyl] benzoate according to the procedure described for Example 49 using 4-fiuorobenzyl bromide as alkylating reagent.
  • Compound 158 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-ethoxy-2-naphthalenyl)hydroxymethyl] benzoate according to the procedure described in Example 49 using 2-fluorobenzyl bromide as alkylating reagent.
  • Compound 160 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-ethoxy-2-naphthalenyl)hydroxymethyl] benzoate according to the procedure described in Example 49 using iodobutane as alkylating reagent. !
  • Compound 164 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl)(hydroxymethyl] benzoate according to the procedure described in Example 63 using 4-fluorobenzylamine.
  • Compound 167 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3, 5,5,8,8- pentamethyl-2-naphthaleny ⁇ ) (chloromethyl] benzoate according to the procedure described in Example 66 using 4-tert-butylbenzylmercaptan as alkylating reagent.
  • Compound 168 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl) (chloromethyl] benzoate according to the procedure described in Example 66 using 4-fluorophenol as alkylating reagent. !
  • Compound 169 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl) (chloromethyl)] benzoate according to the procedure described in Example 66 using 4-tert-butylphenol as alkylating reagent.
  • Compound 170 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl) (chloromethyl)] benzoate according to the procedure described in Example 66 using 4-phenylphenol as alkylating reagent.
  • Compound 171 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl) (chloromethyl)] benzoate according to the procedure described in Example 66 using phenol as alkylating reagent.
  • Compound 172 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-ethoxy-2-naphthalenyl) (chloromethyl)] benzoate according to the procedure described in Example 66 using 4-tert-butylbenzylmercaptan as alkylating reagent. !
  • methyl-4-[(oxyimino)(5,6,7,8- tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl)] benzoate (1.24 g, 3.02 mmol) was dissolved in 14 mL dry ethanol and cooled to 0°C. Sodium hydride (60% in mineral oil, 0.138 g, 3.43 mmol) was added in one portion and the mixture was allowed to stir for 30 min.
  • Compound 185 was synthesized from methyl-4-[(oxyimino)(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-3-ethoxy-2-naphthalenyl)] benzoate according to the procedure described in Example 76 using ethyl iodide as alkylating agent.
  • Compound 188 was synthesized from methyl-4-[(oxyimmo)(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-3-ethoxy-2-naphthalenyl)] benzoate according to the procedure described in Example 84 using pentyl iodide as alkylating agent.
  • Compound 190 was synthesized from methyl-4-[(oxyimino)(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-3-ethoxy-2-naphthalenyl)] benzoate according to the procedure described in Example 84 using l-iodo-3-methylbutane as alkylating agent.
  • Compound 192 was synthesized from methyl-4-[(oxyimino)(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-3-ethoxy-2-naphthalenyl)] benzoate according to the procedure described in Example 84 using 2,3-difluorobenzyl bromide as alkylating agent.
  • Example 93 was synthesized from Methyl-6-[(2,3-dihydro-4,4-dimethyl-7-hydroxy- benzopyranyl)]benzoyl benzoate according to the procedure described in Example 3 using ethyl iodide as alkylating agent.
  • Example 102 was synthesized from Methyl-6-[(2,3-dihydro-4,4-dimethyl-7-hydroxy- benzothiopyranyl)]benzoyl benzoate according to the procedure described in Example 3 using ethyl iodide as alkylating agent.
  • Example 103 was synthesized from 6-[(2,3-dihydro-4,4,7- trimethylbenzopyranyl)]benzoic acid according to the procedure described for the synthesis of compound 108.
  • 3-methoxy-2-methylaniline (3.87g, 28 mmol) was taken up in acetone and cooled to OC using a water/ice bath under nitrogen. Potassium carbonate (5.86g, 42 mmol) was added, followed by addition of 3,3-Dimethylacryloylchloride (3.78mls, 34mmol). The reaction was allowed to warm to room temperature and stir for 12 hrs. The mix was concentrated under reduced pressure to an off white solid.
  • the solid was purified using a silica packed plug (hexanes/EtoAc) affording a dull orange solid, which was recrystallized from hexanes and a minimal amount of ethylacetate to generate 2-methyl-3-(3-methyl-2- butenamido) anisole as crystals (2.6g, yield: 42%). !
  • the amide (2.5g, 11.5mmol) was taken up in dry methylene chloride (60ml) in a flame dried flask under nitrogen and aluminum chloride (15.2g, 115mmol) was added. The reaction was heated to reflux for 1.5 hrs at which time the reaction was poured over ice. The water ethylacetate mix was extracted three times with ethyl acetate (100mls/X3) from water, the organic layers were collected and washed with brine, dried over solid sodium sulfate, filtered, and concentrated under reduced pressure to a solid. The solid was recrystallized from 50%Etoac/Hexanes to afford the desired product as a crystal (1.65g, yield: 66%).
  • Example 113 was synthesized from methyl-6-(4,4,8-trimethyl-7-ethoxy-l,2,3,4- tetrahydroquinolino)benzoyl benzoate according to the procedure described for Example 112.
  • the reaction mixture was allowed to slowly warm to 23° C, meanwhile a stream of nifrogen was bubbled into the solution to remove excess ozone. The solvent was removed under reduced pressure. The residue was taken into 40 mL of THF and treated with 10 L of 1.0 M aqueous AgNO 3 solution. This mixture was stirred at 23° C for 24h. Filtered through a pad of celite and the celite cake was further rinsed with 200 mL of EtOAc. The filtrate was washed with H2O (3x100 mL) and brine (100 mL). The organic layer was dried over MgSO 4 , filtered and concentrated under reduced pressure.
  • Binding Assays Compounds of the invention were separately incubated with HNF-4 ⁇ at varying concentrations in the presence of varying concentrations of radiolabeled methyl 4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2-naphthalenyl]benzoyl benzoate (Compound 103; Example 3) to determine each compound's binding affinity for HNF- 4 ⁇ .
  • Compounds were also separately incubated with RXR ⁇ in the presence of varying concentrations of radiolabeled 9-cis-retinoic acid to determine each compound's binding affinity for RXR ⁇ . Data for 20 compounds is provided in Table 1.
  • Table 1 Binding affinity. l Ki determined using [ 3 H]-compound 103. 2 Ki determined using [ 3 H]-9-cis-RA.
  • CV-1 cells African green monkey kidney fibroblasts
  • DMEM Dulbecco's Modified Eagle Medium
  • CH-FBS charcoal resin- stripped fetal bovine serum
  • the CV-1 cells were transiently transfected by FuGENE 6 transfection reagent in 175 cm 2 flask with the following plasmids: pCMX- HNF-4 ⁇ DF (3 ⁇ g/flask), apoAl-LUC reporter (l ⁇ g/flask), and filler DNA (pcDNA; 3 ⁇ g/flask).
  • the receptor plasmid contains the rat HNF-4 ⁇ l under constitutive control of the CMV promoter, as more fully described in Fraser et al, "DNA binding and franscription activation specificity of hepatocyte nuclear factor 4" Nucl Acids Res., 16: 2702-2707 (1998).
  • the reporter plasmid, apoAl-LUC contains the cDNA for firefly luciferase (LUC) under control of a multimerized HNF-4 ⁇ response element (the A site from the apo Al promoter) linked to the TK minimal promoter. See e.g., Fraser et al. supra. Twenty hours four after transfection, the cells were harvested and plated in 96 well plates at 10,000 cells/well. Media containing reference compounds (compound
  • the modulator compounds of the present invention in concentrations ranging from 10- 10 to 10- 5 M were added to the cells. Three to four replicates were used for each sample. Transfections and subsequent procedures were performed on a Biomek 1000 automated laboratory work station. [0196] After 24 hours, the cells were washed with PBS, lysed with a Triton X- 100-based buffer and assayed for LUC activity using a NORTHSTAR HTS workstation. [0197] The mean and standard error of the mean (SEM) of the luciferase response were calculated. Data were plotted as the response of the compound compared to the reference compounds over the range of the dose-response curve.
  • SEM standard error of the mean
  • HNF-4 ⁇ receptor modulator compounds of present invention Agonist, partial agonist, antagonist and binding activity of HNF-4 ⁇ receptor modulator compounds of present invention and the reference agonist compound, (compound 103) and reference antagonist compounds (compound 173).
  • Efficacy (%) for HNF-4 ⁇ agonist is determined by comparing activity (e.g., luciferase production) of putative agonist to that LGO 100695.
  • Efficacy (%) for HNF ⁇ 4 ⁇ antagonist is determined by the percentage amount by which the luciferase production was reduced (maximum concentration of antagonist) from the luciferase production without compound.
  • na not active (i.e. efficacy of ⁇ 20 and potency of > 10,000 nM for the cotransfection assay and K; > 1000 nM for the binding assay)
  • nd not determined
  • the present invention includes any combination of the various species and subgeneric groupings falling within the generic disclosure. This invention therefore includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein. [0199] While in accordance with the patent statutes, description of the various embodiments and processing conditions have been provided, the scope of the invention is not to be limited thereto or thereby. Modifications and alterations of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention. [0200] Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims, rather than by the specific examples which have been presented merely to illustrate certain embodiments of the present invention.

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Abstract

The present invention is directed to hepatocyte nuclear factor 4α (HNF-4α) receptor modulator compounds. This invention is also directed to pharmaceutical compositions containing such compounds as well as methods of using such compounds and pharmaceutical compositions for modulating HNF-4α receptors as well as processes mediated by HNF-4α receptors. Also provided are methods of making such compounds and pharmaceutical compositions, as well as intermediates used in their synthesis.

Description

HEPATOCYTE NUCLEAR FACTOR 4α MODULATOR COMPOUNDS
RELATED APPLICATIONS
[001] This application claims the benefit of priority of U.S. Provisional Application Ser. No. 60/488,237 filed luly 16, 2003, the entire disclosure of which is incorporated herein by reference. TECHNICAL FIELD
[002] This invention relates to compounds that bind to and/or modulate hepatocyte nuclear factor 4α receptors and to methods for making and using such compounds. BACKGROUND
[003] Hepatocyte nuclear factor 4α (HNF-4 ) has been described as a member of the steroid/thyroid superfamily of transcription factors that is expressed in liver, kidney, intestine and pancreas. Sladeket al, (1990) Genes Dev. 4, 2353-2365; Miquerol et al, (1994) J. Biol Chem. 269:8944-8951. No ligand has been identified at present and therefore HNF-4α is referred to as an orphan member of the intracellular receptor family (3-5). Tsai & O'Malley (1994) Annu. Rev. Biochem. 63: 451-486; Mangelsdorf & Evans (1995) Cell 83:841-850; Kastner et al (1995) Cell 83:859-869. [004] HNF-4α has been described as being capable of activating transcription in tissue culture cells under certain conditions. Kou et al, (1992) Nature 355:457-461;
Ladias et al, (1992) J. Biol. Chem. 267:15849-15860; Mietus-Snyder et al, (1992) Mol.
Cell. Biol. 12:1708-1718; Metzger et al,. (1993) J. Biol. Chem. 268:16831-16838. It has been suggested that HNF-4α plays a role in one or more metabolic pathways, including glucose and lipid homeostasis. Ladias et al, (1992) J. Biol. Chem. 267:15849- 15860; Mietus-Snyder et al, (1992) Mol. Cell. Biol. 12:1708-1718; Metzger et al, (1993) J. Biol. Chem. 268:16831-16838; Yamagata et al, (1996) Nature 384, 458-460; Stoffel & Duncan (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 13209-13214. [005] Certain mutations of HNF-4 result in defective function of the endocrine pancreas and maturity-onset diabetes of the young (MODY1), suggesting that HNF-4 α plays a role in metabolic gene regulation. Yamagata et al, (1996) Nature 384;458-460. Liver-specific knockouts demonstrate that HNF-4 plays a role in liver development and function. Li et al, (2000) Genes & Dev. 14:464-474; Hayhurst et al, (2001) Mol. Cell. Biol. 21:1393-1403; Fraser (1998) Nuc. Acids Res. 26:2702-2707.
SUMMARY OF THE INVENTION
[006] In certain embodiments, the present invention provides a compound of formula I:
Figure imgf000003_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
R1 is selected from H, a halogen, SH, and OH; R2 is selected from H, a halogen, a NR12R13, a sulfonamide, a nitro, a formyl, an acyl, a C1-C3 alkyl optionally substituted with one or more fluorines, a C2-C3 alkenyl optionally substituted with one or more fluorines, a C2-C3 akynyl optionally substituted with one or more fluorines, a Cι-C2 alkoxy optionally substituted with one or more fluorines, a Cι-C2 thioalkyl optionally substituted with one or more fluorines, a C2 thioalkenyl optionally substituted with one or more fluorines, a C2 thioakynyl optionally substituted with one or more fluorines, and a hydroxylamine optionally substituted with a Cι-C2 alkyl, a C2 alkenyl, C2 akynyl, a C1-C2 fluoroalkyl, a C2 fluoroalkenyl, or a C2 fluoroakynyl;
R3 is selected from H, a halogen, a nitro, a -C10 alkyl optionally substituted with one or more halogens, a C2-Cιo alkenyl optionally substituted with one or more halogens, a C2-Cιo akynyl optionally substituted with one or more halogens, a C1-C10 alkoxy optionally substituted with one or more halogens, a Cj-Cio thioalkyl optionally substituted with one or more halogens, a C2-Cιo thioalkenyl optionally substituted with one or more halogens, a C2-Cιo thioakynyl optionally substituted with one or more fluorines, a NR14R15, and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with up to two R19 groups;
R4 is selected from H, a halogen, and OH;
R5 is selected from CH2OH, CHO, COOH, and a C(R5')( R5")(COOH);
R5' and R5 are each independently selected from H, O, S and F; or R5 and R5" together form an O or S; R6 and R7 are each independently selected from H, a halogen, a Cι-Cι2 alkyl optionally substituted with one or more R , a C2-Cι2 alkenyl optionally substituted with one or more R19, a C2-Cι2 akynyl optionally substituted with one or more R19, a Ci-C12 alkoxy optionally substituted with one or more R , a -C^ thioalkyl optionally substituted with one or more R19, a C2-Cι2 thioalkenyl optionally substituted with one or more R19, a C2-C12 thioakynyl optionally substituted with one or more R19, a NR16R17, a NHC(O)R18 and null; or R6 and R7 taken together form an O, S, NH or CH2;
R8 and R9 are each independently selected from H, a halogen, a methyl optionally substituted with one or more halogens, and null; or R8 and R9 taken together with Y form a tliree to five-membered optionally substituted carbocyclic ring; each R10 is independently selected from H, a halogen, and a methyl optionally substituted with one or more halogens;
R11 and R11' are each independently selected from H, a halogen and OH; or R11 and R11 taken together form an O;
R12 and R13 are each independently a Cι-C3 alkyl optionally substituted with one or more halogens, a C2-C3 alkenyl optionally substituted with one or more halogens, or a C2-C3 akynyl optionally substituted with one or more halogens; or R12 and R13 taken together with the nitrogen atom to which they are both bound form a five to six- membered heterocyclic ring;
R14 and R15 are each independently a Cι-C2 alkyl optionally substituted with one or more halogens, a C2 alkenyl optionally substituted with one or more halogens, or a C2 akynyl optionally substituted with one or more halogens; R16 and R17 are each independently selected from a -C^ alkyl optionally substituted with one or more R19, a C2-Cι2 alkenyl optionally substituted with one or more R19, a C2-Cι2 akynyl optionally substituted with one or more R19, and a five to six- membered carbocyclic or heterocyclic ring optionally substituted with one or more R19; or R16 and R17 taken together with the nitrogen atom to which they are both bound form a five to six-membered heterocyclic ring;
R18 is selected from a Ci- o alkyl optionally substituted with one or more halogens, a C2-Cιo alkenyl optionally substituted with one or more halogens, a C2-C10 akynyl optionally substituted with one or more halogens, and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with one or more R19;
R19 is selected from a halogen, a Cι-C4 alkyl optionally substituted with one or more fluorines, a C2-C4 alkenyl optionally substituted with one or more fluorines, a C2- C4 akynyl optionally substituted with one or more fluorines, a -C4 alkoxy optionally substituted with one or more halogens, a C1-C3 thioalkyl optionally substituted with one or more halogens, a C2-C3 thioalkenyl optionally substituted with one or more halogens, C2-C3 thioakynyl optionally substituted with one or more halogens, a formyl and a nitro;
X and Y are each independently selected from O, S, N and C; wherein: if X is O or S, then each of R6 and R7 is null; if X is N, then one of R6 and R7 is null; if Y is O or S, then each of R and R is null; and if Y is N, then one of Rs and R9 is null.
[007] In certain embodiments, the invention provides a compound of formula II:
Figure imgf000007_0001
π or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
R1 is selected from H, a halogen, SH, and OH;
R2 is selected from H, a halogen, a NR12R13, a sulfonamide, a nitro, a formyl, an acyl optionally substituted with one or more halogens, a Cι-C3 alkyl optionally substituted with one or more fluorines, a C2-C3 alkenyl optionally substituted with one or more fluorines, a C2-C3 akynyl optionally substituted with one or more fluorines, a Cι-C2 alkoxy optionally substituted with one or more fluorines, a d-C2 thioalkyl optionally substituted with one or more fluorines, a C2 thioalkenyl optionally substituted with one or more fluorines, a C2 thioakynyl optionally substituted with one or more fluorines, and a hydroxylamine optionally substituted with a d-C2 alkyl, a C2 alkenyl, a C2 akynyl, a Ci-C2 fluoroalkyl, a C2 fluoroalkenyl, or C2 fluoroakynyl;
R3 is selected from H, a halogen, a nitro, a Cj-Cio alkyl optionally substituted with one or more halogens, a C2-Cι0 alkenyl optionally substituted with one or more halogens, a C2-C10 akynyl optionally substituted with one or more halogens, a Ci-Cio alkoxy optionally substituted with one or more halogens, a d-Cio thioalkyl optionally substituted with one or more halogens, a C2-Cιo thioalkenyl optionally substituted with one or more halogens, a C2-Cιo thioakynyl optionally substituted with one or more halogens, a NR1 R15, and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with up to two R groups;
R4 is selected from H, a halogen, and OH;
R5 is selected from CH2OH, CHO, COOH, and a C(R5')( R5")(COOH);
R5' and R5" are each independently selected from H, O, S and F; or R5' and R5 together form an O or S;
R6 and R7 are each independently selected from H, a halogen, a Cι-C12 alkyl optionally substituted with one or more R19, a C2-C12 alkenyl optionally substituted with one or more R19, a C2-C12 akynyl optionally substituted with one or more R , a Cι-Cι2 alkoxy optionally substituted with one or more R19, a Ct-Cn thioalkyl optionally substituted with one or more R19, a C2-Cι2 thioalkenyl optionally substituted with one or more R19, a C2-C12 thioakynyl optionally substituted with one or more R19, a NR1 R17, a NHC(O)R18 and null; or R6 and R7 taken together form an O, S, NH or CH2;
R8 and R9 are each independently selected from H, halogen, a methyl optionally substituted with one or more halogens, and null; or R8 and R9 taken together with Y form a tliree to five-membered optionally substituted carbocyclic ring;
R12 and R13 are each independently a Cι-C3 alkyl optionally substituted with one or more halogens, a C2-C3 alkenyl optionally substituted with one or more halogens, or a C2-C3 akynyl optionally substituted with one or more halogens; or R12 and R13 taken together with the nitrogen atom to which they are both bound form a five to six- membered heterocyclic ring;
R14 and R15 are each independently a Cι-C2 alkyl optionally substituted with one or more halogens, a C2 alkenyl optionally substituted with one or more halogens, or a C2 akynyl optionally substituted with one or more halogens;
R16 and R17 are each independently selected from a Cι-C12 alkyl optionally substituted with one or more R19, a C2-Cι2 alkenyl optionally substituted with one or more R19, a C2-Cι2 akynyl optionally substituted with one or more R19, and a five to six- membered carbocyclic or heterocyclic ring optionally substituted with one or more R19; or R16 and R17 taken together with the nitrogen atom to which they are both bound form a five to six-membered heterocyclic ring;
R18 is selected from a C1-C10 alkyl optionally substituted with one or more halogens, a C2-Cιo alkenyl optionally substituted with one or more halogens, a C2-C10 akynyl optionally substituted with one or more halogens, and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with one or more R ;
R19 is selected from a halogen, a Cι-C4 optionally substituted with one or more fluorines, a C2-C4 alkenyl optionally substituted with one or more fluorines, a C2-C4 akynyl optionally substituted with one or more fluorines, a Q-C4 alkoxy optionally substituted with one or more halogens, a Cι-C3 thioalkyl optionally substituted with one or more halogens, a C2-C3 thioalkenyl optionally substituted with one or more halogens, a C2-C3 thioakynyl optionally substituted with one or more halogens, a formyl and a nitro; X and Y are each independently selected from O, S, N and C; wherein: if X is O or S, then each of R6 and R7 is null; if X is N, then one of R6 and R7 is null; if Y is O or S, then each of R and R is null; and if Y is N, then one of R and R is null.
[008] In certain embodiments, the invention provides a compound of formula III:
Figure imgf000010_0001
III
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein
R1 is selected from H, a halogen, SH, and OH;
R2 is selected from H, a halogen,a NR12R13, a sulfonamide, a nitro, a formyl, an acyl optionally substituted with one or more halogens, a d-d alkyl optionally substituted with one or more fluorines, a C2-C3 alkenyl optionally substituted with one or more fluorines, a C2-C3 akynyl optionally substituted with one or more fluorines, a d-C2 alkoxy optionally substituted with one or more fluorines, a d-C2 thioalkyl optionally substituted with one or more fluorines, a thioC2 alkenyl optionally substituted with one or more fluorines, a C2 thioakynyl optionally substituted with one or more fluorines, and a hydroxylamine optionally substituted with a Cι-C2 alkyl, a d- C2 alkenyl, a C2 akynyl, a Cι-C2 fluoroalkyl, a C2 fluoroalkenyl, or a C2 fluoroakynyl;
R3 is selected from H, a halogen, a nitro, a d-Cι0 alkyl optionally substituted with one or more halogens, a d-Cio alkenyl optionally substituted with one or more halogens, a C2-C10 akynyl optionally substituted with one or more halogens, a d-C10 alkoxy optionally substituted with one or more halogens, a Ci-do thioalkyl optionally substituted with one or more halogens, a C2-Cιo thioalkenyl optionally substituted with one or more halogens, C2-C10 thioakynyl optionally substituted with one or more halogens, a NR14R15, and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with up to two R19 groups;
R4 is selected from H, a halogen, and OH;
R5 is selected from CH2OH, CHO, COOH, and a C(R5')( R5")(COOH);
R5 and R5 are each independently selected from H, O, S and F; or R5 and R5 together form an O or S;
R8 and R9 are each independently selected from H, a halogen, a methyl optionally substituted with one or more halogens, and null; or R8 and R9 taken together with Y form a three to five-membered optionally substituted carbocyclic ring;
R12 and R13 are each independently a Cι-C3 alkyl optionally substituted with one or more halogens, a C2-C3 alkenyl optionally substituted with one or more halogens, or a C2-C6 akynyl optionally substituted with one or more halogens; or R12 and R13 taken together with the nitrogen atom to which they are both bound form a five to six- membered heterocyclic ring;
R14 and R15 are each independently a Cι-C2 alkyl optionally substituted with one or more halogens, a C2 alkenyl optionally substituted with one or more halogens, or a C2 akynyl optionally substituted with one or more halogens;
R19 is selected from a halogen, a Cι-C4 alkyl optionally substituted with one or more fluorines, a C2-C4 alkenyl optionally substituted with one or more fluorines, a C2- C4 akynyl optionally substituted with one or more fluorines, a C1-C4 alkoxy optionally substituted with one or more halogens, a C1-C3 thioalkyl optionally substituted with one or more halogens, a C2-C3 thioalkenyl optionally substituted with one or more halogens, a C2-C3 thioakynyl optionally substituted with one or more halogens, a formyl and a nitro;
Y is selected from O, S, N and C; wherein: if Y is O or S, then each of R8 and R9 is null; and if Y is N, then one of R8 and R9 is null.
[009] In certain embodiments, the invention provides a compound of formula IV:
Figure imgf000013_0001
rv
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
R1 is selected from H, a halogen, SH, and OH;
R2 is selected from H, a halogen, a NRI2R13, a sulfonamide, a nitro, a formyl, an acyl, a d-C3 alkyl optionally substituted with one or more fluorines, a C2-C3 alkenyl optionally substituted with one or more fluorines, a C2-C3 akynyl optionally substituted with one or more fluorines, a d-C2 alkoxy optionally substituted with one or more fluorines, a Cι-C2 thioalkyl optionally substituted with one or more fluorines, a C2 thioalkenyl optionally substituted with one or more fluorines, a C2 thioakynyl optionally substituted with one or more fluorines, and a hydroxylamine optionally substituted with a C]-C2 alkyl, a C2 alkenyl, a C2 akynyl, a d-C2 fluoroalkyl, a C2 fluoroalkenyl, or a C2-C6 fluoroakynyl;
R3 is selected from H, a halogen, a nitro, a d-Cio alkyl optionally substituted with one or more halogens, a C2-Cιo alkenyl optionally substituted with one or more halogens, a C2-Cιo akynyl optionally substituted with one or more halogens, a d-C10 alkoxy optionally substituted with one or more halogens, a Cι-C10 thioalkyl optionally substituted with one or more halogens, a C2-Cιo thioalkenyl optionally substituted with one or more halogens, C2-Cιo thioakynyl optionally substituted with one or more halogens, a NR R , and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with up to two R19 groups;
R4 is selected from H, a halogen, and OH;
R5 is selected from CH2OH, CHO, COOH, and a C(R5')( R5")(COOH);
R5 and R5' are each independently selected from H, O, S or F; and R5' and R5" together form an O or S;
R6 is selected from H, a halogen, a Cι-Cι2 alkyl optionally substituted with one or more R19, a C2-Cι2 alkenyl optionally substituted with one or more R19, a C2-Cι2 akynyl optionally substituted with one or more R19, a Cι-C12 alkoxy optionally substituted with one or more R19, a d-Cι2 thioalkyl optionally substituted with one or more R19, a C2-C12 thioalkenyl optionally substituted with one or more R , a C2-C12 thioakynyl optionally substituted with one or more R19,a NR16R17, a NHC(O)R18 and null;
R and R are each independently selected from H, a halogen, a methyl optionally substituted with one or more halogens, and null; or R8 and R9 taken together with Y form a three to five-membered optionally substituted carbocyclic ring;
R12 and R13 are each independently a d-C3 alkyl optionally substituted with one or more halogens, a C2-C3 alkenyl optionally substituted with one or more halogens, or C2-C3 akynyl optionally substituted with one or more halogens; or R12 and R13 taken together with the nitrogen atom to which they are both bound form a five to six- membered heterocyclic ring; R14 and R15 are each independently a Cι-C2 alkyl optionally substituted with one or more halogens, a C2 alkenyl optionally substituted with one or more halogens, or a C2 akynyl optionally substituted with one or more halogens;
R16 and R17 are each independently selected from a Cι-C12 alkyl optionally substituted with one or more R , a C2-Cι2 alkenyl optionally substituted with one or more R19, a C2-Cι2 akynyl optionally substituted with one or more R19, and a five to six- membered carbocyclic or heterocyclic ring optionally substituted with one or more R19; or R16 and R17 taken together with the nitrogen atom to which they are both bound form a five to six-membered heterocyclic ring;
R18 is selected from a Ci-do alkyl optionally substituted with one or more halogens, a C2-Cιo alkenyl optionally substituted with one or more halogens, a C2-C10 akynyl optionally substituted with one or more halogens, and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with one or more R19;
R19 is selected from a halogen, a d-C4 alkyl optionally substituted with one or more fluorines, a C2-C alkeny optionally substituted with one or more fluorines 1, a C2- C4 akynyl optionally substituted with one or more fluorines, a d-d alkoxy optionally substituted with one or more halogens, a Cj-C thioalkyl optionally substituted with one or more halogens, a C2-C3 thioalkenyl optionally substituted with one or more halogens, a C2-C3 thioakynyl optionally substituted with one or more halogens, a formyl and a nitro;
R20 is selected from a C4-C5 alkyl optionally substituted with one or more halogens, a C4-C5 alkenyl optionally substituted with one or more halogens, a C4-C5 akynyl optionally substituted with one or more halogens, a phenyl optionally substituted with one or more fluorines, a thienyl optionally substituted with one or more fluorines, and a benzyl optionally substituted with one or more R19;
X is selected from O and NH;
Y is selected from O, S, N, and C; and
Z is selected from CH2, NH, and phenylene; wherein: if Y is O or S, then each of R8 and R9 is null; and if Y is N, then one of R and R is null.
[010] In certain embodiments, the invention provides a compound of formula V:
Figure imgf000016_0001
v
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
R1 is selected from H, a halogen, SH, and OH;
R2 is selected from H, a halogen, a NR12R13, a sulfonamide, a nitro, a formyl, an acyl, a Cj-C3 alkyl optionally substituted with one or more fluorines, a C2-C3 alkenyl optionally substituted with one or more fluorines, a C2-C akynyl optionally substituted with one or more fluorines , a d-C2 alkoxy optionally substituted with one or more fluorines, a d-C2 thioalkyl optionally substituted with one or more fluorines, a C2 thioalkenyl optionally substituted with one or more fluorines, a C2- thioakynyl optionally substituted with one or more fluorines, and a hydroxylamine optionally substituted with a Cι-C2 alkyl, a C2 alkenyl, a C2 akynyl, a Cι-C2 fluoroalkyl, a C2 fluoroalkenyl, or a C2 fluoroakynyl;
R3 is selected from H, a halogen, a nitro, a Cj-Cio alkyl optionally substituted with one or more halogens C2-C10 alkenyl optionally substituted with one or more halogens, C2-do akynyl optionally substituted with one or more halogens, a Ci-Cio alkoxy optionally substituted with one or more halogens, a CI-CIQ thioalkyl optionally substituted with one or more halogens, a C2-Cιo thioalkenyl optionally substituted with one or more halogens, a C2-C10 thioakynyl optionally substituted with one or more halogens, a NR14R15, and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with up to two R19 groups;
R4 is selected from H, a halogen, and OH;
R5 is selected from CH2OH, CHO, COOH, and a C(R5')( R5")(COOH);
R5 and R5' are each independently selected from H, O, S and F; or R5 and R5 together form an O or S;
R8 and R9 are each independently selected from H, a halogen, a methyl optionally substituted with one or more halogens, and null; or R8 and R9 taken together with Y form a three to five-membered optionally substituted carbocyclic ring; R12 and R13 are each independently a C1-C3 alkyl optionally substituted with one or more halogens, a C2-C3alkenyl optionally substituted with one or more halogens, or a C2-C3 akynyl optionally substituted with one or more halogens; or R12 and R13 taken together with the nitrogen atom to which they are both bound form a five to six- membered heterocyclic ring;
R14 and R15 are each independently a Cι-C2 alkyl optionally substituted with one or more halogens, a C2 alkenyl optionally substituted with one or more halogens, or a C2 akynyl optionally substituted with one or more halogens;
R19 is selected from a halogen, a Cι-C4 alkyl optionally substituted with one or more fluorines, a C2-C4 alkenyl optionally substituted with one or more fluorines, a C2- C4 akynyl optionally substituted with one or more fluorines, a Cι-C4 alkoxy optionally substituted with one or more halogens, a Cι-C3 thioalkyl optionally substituted with one or more halogens, a C2-C3 thioalkenyl optionally substituted with one or more halogens, a C2-C3 thioakynyl optionally substituted with one or more halogens , a formyl and a nitro;
R20 is selected from a d-C5 alkyl optionally substituted with one or more halogens a C4-C5 alkenyl optionally substituted with one or more halogens, a C4-C5 akynyl optionally substituted with one or more halogens, a phenyl optionally substituted with one or more fluorines, a thienyl optionally substituted with one or more fluorines, and a benzyl optionally substituted with one or more R19;
Y is selected from O, S, N, and C; and
Z is selected from CH2, NH, and phenylene; wherein: if Y is O or S, then each of R and R is null; and if Y is N, then one of R and R is null.
[Oi l] In certain embodiments, the invention provides a compound of formula VI:
Figure imgf000019_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
R1 is selected from H, a halogen, SH, and OH;
R is selected from H, a halogen, a NR12R13, a sulfonamide, a nitro, a formyl, an acyl optionally substituted with one or more halogens, a d-C3 alkyl optionally substituted with one or more fluorines, a C2-C3 alkenyl optionally substituted with one or more fluorines, a C2-C akynyl optionally substituted with one or more fluorines, a Cι-C2 alkoxy optionally substituted with one or more fluorines, a Cι-C2 thioalkyl optionally substituted with one or more fluorines, a C2 thioalkenyl optionally substituted with one or more fluorines, a C2 thioakynyl optionally substituted with one or more fluorines, and a hydroxylamine optionally substituted with a Cι-C2 alkyl, a C2 alkenyl, a C2 akynyl, a Cι-C2 fluoroalkyl, a C2 fluoroalkenyl, or a C2 fluoroakynyl; R3 is selected from H, a halogen, a nitro, a d-do alkyl optionally substituted with one or more halogens, a C2-Cιo alkenyl optionally substituted with one or more halogens, a C2-C10 akynyl optionally substituted with one or more halogens, a d-do alkoxy optionally substituted with one or more halogens, a d-do thioalkyl optionally substituted with one or more halogens a C2-Cιo thioalkenyl optionally substituted with one or more halogens, a C2-C10 thioakynyl optionally substituted with one or more halogens, a NR14R15, and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with up to two R19 groups;
R4 is selected from H, a halogen, and OH;
R5 is selected from CH2OH, CHO, COOH, and a C(R5')( R5")(COOH);
R5' and R5" are each independently selected from H, O, S and F; or R5 and R5 together form an O or S;
R12 and R13 are each independently a d-C3 alkyl optionally substituted with one or more halogens; a C2-C alkenyl optionally substituted with one or more halogens, or a C2-C3 akynyl optionally substituted with one or more halogens; or R12 and R13 taken together with the nitrogen atom to which they are both bound form a five to six- membered heterocyclic ring;
R14 and R15 are each independently a d-C2 alkyl optionally substituted with one or more halogens, a C2 alkenyl optionally substituted with one or more halogens, or C akynyl optionally substituted with one or more halogens; R19 is selected from a halogen, a C1-C4 alkyl optionally substituted with one or more fluorines, a C2-C4 alkenyl optionally substituted with one or more fluorines, a C2- C4 akynyl optionally substituted with one or more fluorines, a d-d alkoxy optionally substituted with one or more halogens, a d-C thioalkyl optionally substituted with one or more halogens, a C2-C3 thioalkenyl optionally substituted with one or more halogens, a C2-C3 thioakynyl optionally substituted with one or more halogens, a formyl and a nitro; and
A is selected from O, CH2, CF2, and S.
[012] In certain embodiments, the invention provides a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, and/or Formula VI. [013] In certain embodiments, the invention provides a method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, and/or Foπnula VI. [014] In certain embodiments, the invention provides a selective HNF-4α modulator of Formula I, Formula II, Formula III, Formula IV, Formula V, and/or Formula VI. In certain embodiments, the invention provides an HNF-4α selective binding agent of Formula I, Formula II, Formula III, Formula IV, Formula V, and/or Formula VI. DETAILED DESCRIPTION OF THE INVENTION
[015] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, "or" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "includes," and "included," is not limiting. [016] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, but not limited to, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incoφorated by reference in their entirety for any purpose. Definitions
[017] Unless specific definitions are provided, the nomenclatures utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, medicinal chemistry and pharmaceutical chemistry described herein are those known in the art. Standard chemical symbols are used interchangeably with the full names represented by such symbols. Thus, for example, the terms "hydrogen" and "H" are understood to have identical meaning. Standard techniques may be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, delivery, and treatment of patients.' Standard techniques may be used for recombinant DNA methodology, oligonucleotide synthesis, tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques may be performed e.g., using kits according to manufacturer's specifications, as commonly accomplished in the art or as described herein. The foregoing techniques and procedures may be generally performed according to conventional methods well known in the art and as described in various general or more specific references that are cited and discussed throughout the present specification. See e.g., Sambrook et al. Molecular- Cloning: A Laboratoiγ Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)), which is incorporated herein by reference for any purpose. [018] As used herein, the following terms are defined with the following meanings: [019] The term "selective binding compound" refers to a compound that selectively binds to any portion of one or more target receptors. [020] The term "selective HNF-4α receptor binding compound" refers to a compound that selectively binds to any portion of an HNF-4α receptor. [021] The term "selectively binds" refers to the ability of a selective binding compound to bind to a target receptor with greater affinity than it binds to a non-target receptor. In certain embodiments, selective binding refers to binding to a target with an affinity that is at least 10, 50, 100, 250, 500, or 1000 times greater than the affinity for a non-target. [022] The term "target receptor" refers to a receptor or a portion of a receptor capable of being bound by a selective binding compound. In certain embodiments, a target receptor is an HNF-4 receptor. [023] The term "modulator" refers to a compound that alters or elicits an activity of a molecule. For example, a modulator may cause an increase or decrease in the magnitude of a certain activity of a molecule compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor, which decreases the magnitude of one or more activities of a molecule. In certain embodiments, an inhibitor completely prevents one or more activities of a molecule. In certain embodiments, a modulator is an activator, which increases the magnitude of at least one activity of a molecule. In certain embodiments the presence of a modulator results in an activity that does not occur in the absence of the modulator. [024] The term "selective modulator" refers to a compound that selectively modulates a target activity. [025] The term "selective HNF-4 α receptor modulator" refers to a compound that selectively modulates at least one activity associated with an HNF-4a receptor. [026] The term "selectively modulates" refers to the ability of a selective modulator to modulate a target activity to a greater extent than it modulates a non-target activity. [027] The term "target activity" refers to a biological activity capable of being modulated by a selective modulator. Certain exemplary target activities include, but are not limited to, changes in binding affinity, signal transduction, enzymatic activity, transcription of one or more genes, tumor growth, changes in blood glucose concentration, and inflammation or inflammation-related processes. [028] The term "receptor-mediated activity" refers to any biological activity that results, either directly or indirectly, from binding of a ligand to a receptor. [029] The term "agonist" refers to a compound, the presence of which results in a biological activity of a receptor that is the same as the biological activity resulting from the presence of a naturally occurring ligand for the receptor. [030] The term "partial agonist" refers to a compound the presence of which results in a biological activity of a receptor that is of the same type as that resulting from the presence of a naturally occurring ligand for the receptor, but of a lower magnitude. [031] The term "antagonist" refers to a compound, the presence of which results in a decrease in the magnitude of a biological activity of a receptor. In certain embodiments, the presence of an antagonist results in complete inhibition of a biological activity of a receptor. The term "alkyl," alone or in combination, refers to an optionally substituted straight-chain or branched-chain alkyl radical having from 1 to about 12 carbon atoms. The term also includes substituted straight-chain or branched-chain alkyl radicals having from 1 to about 6 carbon atoms as well as those having from 1 to about 4 carbon atoms. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the like. [032] The term "alkenyl," alone or in combination, refers to an optionally substituted straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon double-bonds and having from 2 to about 18 carbon atoms. The term also includes substituted straight-chain or branched-chain alkyl radicals having one or more carbon-carbon double bonds and having from 2 to about 6 carbon atoms as well as those having from 2 to about 4 carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, 1,4-butadienyl and the like. [033] The term "alkynyl," alone or in combination, refers to an optionally substituted straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon triple-bonds and having from 2 to about 12 carbon atoms. The term also includes substituted straight-chain or branched-chain alkyl radicals having one or more carbon-carbon tyriple bonds and having from 2 to about 6 carbon atoms as well as those having from 2 to about 4 carbon atoms. Examples of alkynyl radicals include ethynyl, propynyl, butynyl and the like. [034] In certain embodiments, an alkyl comprises 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; e.g., "1 to 20 carbon atoms" means that an alkyl group may comprise only 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the term "alkyl" also includes instances where no numerical range of carbon atoms is designated). [035] The term "lower alkyl" refers to an alkyl comprising 1 to 6 carbon atoms. The term "medium alkyl" refers to an alkyl comprising 7 to 12 carbon atoms. An alkyl may be designated as "C1-C4 alkyl" or similar designations. By way of example only, "d-d alkyl", " -d alkenyl" and"d-d alkynyl" indicate a radical having one, two, three, or four carbon atoms (e.g., methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, and butynyl). [036] The term "haloalkyl" refers to an alkyl in which at least one hydrogen atom is replaced with a halogen atom. In certain of the embodiments in which two or more hydrogen atom are replaced with halogen atoms, the halogen atoms are all the same as each other. In certain of such embodiments, the halogen atoms are not all the same as each other. [037] The term "heteroalkyl" refers to a group comprising an alkyl and one or more heteroatoms. Certain heteroalkyls are acylalkyls, in which the one or more heteroatoms are within an alkyl chain. Examples of heteroalkyls, heteroalkenyl, and heteroalkynyls include, but are not limited to, CH3C(=O)CH2-, CH3C(=O)CH2CH2-, CH3CH2C(=O)CH2CH2-, CH3C(=O)CH2CH2CH2-, CH3OCH2CH2-, CH3NHCH2-, and the like. [038] The term "heterohaloalkyl" refers to a heteroalkyl in which at least one hydrogen atom is replaced with a halogen atom. [039] The term "carbocycle" refers to a group comprising a covalently closed ring, wherein each of the atoms forming the ring is a carbon atom. Carbocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Carbocycles may be optionally substituted. [040] The term "heterocycle" refers to a group comprising a covalently closed ring wherein at least one atom forming the ring is a heteroatom. Heterocyclic rings may be formed by tliree, four, five, six, seven, eight, nine, or more than nine atoms. Any number of those atoms may be heteroatoms (i.e., a heterocyclic ring may comprise one, two, three, four, five, six, seven, eight, nine, or more than nine heteroatoms). In heterocyclic rings comprising two or more heteroatoms, those two or more heteroatoms may be the same as or different from each other. Heterocycles may be optionally substituted. Binding to a heterocycle can be at a heteroatom or via a carbon atom. For example, binding for benzo-fused derivatives, may be via a carbon of the benzenoid ring. Examples of heterocycles include, but are not limited to the following:
Figure imgf000028_0001
Figure imgf000029_0001
wherein D, E, F, and G each independently represent a heteroatom. Each of D, E, F, and G may be the same as or different from each other.
[041] The term "heteroatom" refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from oxygen, sulfur, nitrogen, and phosphorus, but are not limited to those atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms may all be the same, or some or all of the two or more heteroatoms may each be different from the others. [042] The term "aromatic" refers to a group comprising a covalently closed ring having a delocalized π-electron system. Aromatic rings may be formed by five, six, seven, eight, nine, or more than nine atoms. Aromatics may be optionally substituted. Examples of aromatic groups include, but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl. The term aromatic includes, for example, benzenoid groups, connected via one of the ring-forming carbon atoms, and optionally carrying one or more substituents selected from an aryl, a heteroaryl, a cycloalkyl, a non-aromatic heterocycle, a halo, a hydroxy, an amino, a cyano, a nitro, an alkylamido, an acyl, a Cι-6 alkoxy, a d-6 alkyl, a C]-6 hydroxyalkyl, a d-6 aminoalkyl, a d-6 alkylamino, an alkylsulfenyl, an alkylsulfinyl, an alkylsulfonyl, an sulfamoyl, and a trifluoromethyl. In certain embodiments, an aromatic group is substituted at one or more of the para, meta, and or ortho positions. Examples of aromatic groups comprising substitutions include, but are not limited to, phenyl, 3- halophenyl, 4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl, 4- aminophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4- trifluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl, (trifluoromethyl)phenyl, alkoxyphenyl, 4- morpholin-4-ylphenyl, 4-pyrcolidin-l-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl, and 4-(2-oxopyrrolidin- 1 -yl)phenyl. [043] The term "aryl" refers to an aromatic group wherein each of the atoms forming the ring is a carbon atom. Aryl rings may be formed by five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups may be optionally substituted. [044] The term "heteroaryl" refers to an aromatic group wherein at least one atom forming the aromatic ring is a heteroatom. Heteroaryl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Heteroaryl groups may be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C3-8 heterocyclic groups comprising one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and their substituted as well as benzo- and pyrido-fused derivatives, for example, connected via one of the ring-forming carbon atoms. In certain embodiments, heteroaryl groups are optionally substituted with one or more substituents, independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, C1-6 alkoxy, d_6 alkyl, C1-6 hydroxyalkyl, d-6 aminoalkyl, Cι-6 alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, and trifluoromethyl. Examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidme, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, O-Cι-6 alkyl, Cι-6 alkyl, hydroxy-Cι-6 alkyl, or ammo-Cι-6 alkyl. [045] The term "non-aromatic ring" refers to a group comprising a covalently closed ring that does not have a delocalized π-electron system. [046] The term "cycloalkyl", alone or in combination, refers to a monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety has from 3 to about 8 carbon atoms. Examples of cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Cycloalkyl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Cycloalkyls may be optionally substituted. [047] The term "non-aromatic heterocycle" refers to a group comprising a non- aromatic ring wherein one or more atoms forming the ring is a heteroatom. Non- aromatic heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Non-aromatic heterocycles may be optionally substituted. In certain embodiments, non-aromatic heterocycles comprise one or more carbonyl or thiocarbonyl groups such as, for example, oxo- and thio-containing groups. Examples of non-aromatic heterocycles include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane, tetrahydro- 1,4-thiazme, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-l,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3- dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3-oxathiolane. [048] The term "arylalkyl" refers to a group comprising an aryl group bound to an alkyl group. [049] The term "carbocycloalkyl" refers to a group comprising a carbocyclic cycloalkyl ring. Carbocycloalkyl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Carbocycloalkyl groups may be optionally substituted. [050] The term "ring" refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non-aromatic heterocycles), aromatics (e.g., aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and non-aromatic heterocycles). Rings may be optionally substituted. Rings may form part of a ring system. [051] The term "ring system" refers to two or more rings, wherein two or more of the rings are fused. The term "fused" refers to structures in which two or more rings share one or more bonds. [052] The substituent "R" appearing by itself and without a number designation refers to a substituent selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon). [053] The term "null" refers to a group being absent from a structure. For R' R" example, in the structure ^- ^ , if X is C, then both R' and R" exist, but if X is N, then one of those R groups is null, meaning that only tliree groups are bound to the N. [054 The term "O-carboxy" refers to a group of formula RC(=O)O-. [055 The term "C-carboxy" refers to a group of formula -C(=O)OR. [056 The term "acetyl" refers to a group of formula -C(=O)CH3. [057 The term "trihalomethanesulfonyl" refers to a group of formula X3CS(=O)2- where X is a halogen. [058 The term "cyano" refers to a group of formula -CN. [059 The term "isocyanato" refers to a group of formula -NCO. [060 The term "thiocyanato" refers to a group of formula -CNS. [061 The term "isothiocyanato" refers to a group of formula -NCS. [062 The term "sulfonyl" refers to a group of formula -S(=O)-R. [063 The term "S-sulfonamido" refers to a group of formula -S(=O)2NR. [064 The term "N-sulfonamido" refers to a group of formula RS(=O)2NH- [065] The term "trihalomethanesulfonamido" refers to a group of formula X3CS(=O)2NR-. [066] The term "O-carbamyl" refers to a group of formula -OC(=O)-NR. [067] The term "N-carbamyl" refers to a group of formula ROC(=O)NH-. [068] The term "O-thiocarbamyl" refers to a group of formula -OC(=S)-NR. [069] The term "N-thiocarbamyl" refers to a group of formula ROC(=S)NH-. [070] The term "C-amido" refers to a group of formula -C(=O)-NR2. [071] The term "N-amido" refers to a group of formula RC(=O)NH-. [072] The term "ester" refers to a chemical moiety with formula -(R)n-COOR', where R and R' are independently selected from alkenyl, alkynyl,, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl (bonded through a ring carbon) and non- aromatic heterocycle (bonded through a ring carbon), where n is 0 or 1. [073] The term "amide" refers to a chemical moiety with formula -(R)n-C(O)NHR' or -(R)n-NHC(O)R, where R and R' are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), where n is 0 or 1. In certain embodiments, an amide may be an amino acid or a peptide. [074] The term "alkoxy," refers to an alkyl ether radical. Examples of alkoxy radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like. [075] The term "formyl" includes aldehydes attached to a compound via an alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl group (e.g., -alkyl-CHO, -aryl-CHO, • arylalkyl-CHO or -heteroarylalkyl-CHO, etc.). [076] The term "oxime" refers to a group of formula:
Figure imgf000035_0001
[077] The term "hydrazone" refers to a group of formula:
Figure imgf000035_0002
[078] The term "hydroxylamine" refers to a group of formula:
RVR" w
[079] The term sulfonamide refers to a group of formula:
Figure imgf000035_0003
[080] The term "halogen" includes F, CI, Br and I [081] The terms "amine," "hydroxy," and "carboxyl" include such groups that have been esterified or amidified. Procedures and specific groups used to achieve esterification and amidification are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, which is incoφorated by reference herein in its entirety. [082] Unless otherwise indicated, the term "optionally substituted," refers to a group in which none, one, or more than one of the hydrogen atoms has been replaced with one or more group(s) individually and independently selected from: alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, haloalkenyl, haloalkynyl, heterohaloalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkyl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, alkenylthio, alkynylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono- and di-substituted amino groups, and the protected derivatives of amino groups. Such protective derivatives (and protecting groups that may form such protective derivatives) are known to those of skill in the art and may be found in references such as Greene and Wuts, supra. In embodiments in which two or more hydrogen atoms have been substituted, the substituent groups may together form a ring. [083] The term "carrier" refers to a compound that facilitates the incoφoration of another compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier for improving incoφoration of certain organic compounds into cells or tissues. [084] The term "pharmaceutical agent" refers to a chemical compound or composition capable of inducing a desired therapeutic effect in a patient. In certain embodiments, a pharmaceutical agent comprises an active agent, which is the agent that induces the desired therapeutic effect. In certain embodiments, a pharmaceutical agent comprises a prodrug. In certain embodiments, a pharmaceutical agent comprises inactive ingredients such as carriers, excipients, and the like. [085] The term "therapeutically effective amount" refers to an amount of a pharmaceutical agent sufficient to achieve a desired therapeutic effect. [086] The term "prodrug" refers to a pharmaceutical agent that is converted from a less active form into a corresponding more active form in vivo. [087] The term "phannaceutically acceptable" refers to a formulation of a compound that does not significantly abrogate a biological activity, a pharmacological activity and/or other properties of the compound when the formulated compound is administered to a patient. In certain embodiments, a pharmaceutically acceptable formulation does not cause significant irritation to a patient. [088] The term "co-administer" refers to administering more than one pharmaceutical agent to a patient. In certain embodiments, co-administered pharmaceutical agents are administered together in a single dosage unit. In certain embodiments, co-administered pharmaceutical agents are administered separately. In certain embodiments, co-administered pharmaceutical agents are administered at the same time. In certain embodiments, co-administered pharmaceutical agents are administered at different times. [089] The term "patient" includes human and animal subjects. [090] The term "substantially pure" means an object species (e.g., compound) is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition). In certain embodiments, a substantially pure composition is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all species present. In certain embodiments, a substantially pure composition is a composition wherein the object species comprises more than about 80%, 85%, 90%), 95%o, or 99%> of all species present in the composition. In certain embodiments, a substantially pure object species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of the single object species. [091] The term "tissue-selective" refers to the ability of a compound to modulate a biological activity in one tissue to a greater or lesser degree than it modulates a biological activity in another tissue. The biological activities modulated in the different tissues may be the same or they may be different. The biological activities modulated in the different tissues may be mediated by the same type of target receptor. For example, in certain embodiments, a tissue-selective compound may modulate an HNF-4α receptor-mediated biological activity in one tissue and fail to modulate, or modulate to a lesser degree, an HNF-4α receptor-mediated biological activity in another tissue type. [092] The term "monitoring" refers to observing an effect or absence of any effect. In certain embodiments, cells are monitored after contacting those cells with a compound of the present invention. Examples of effects that may be monitored include, but are not limited to, changes in cell phenotype, cell proliferation, an HNF-4α receptor activity, or the interaction between an HNF-4α receptor and a natural binding partner. [093] The term "cell phenotype" refers to physical or biological characteristics. Examples of characteristics that constitute phenotype included, but are not limited to, cell size, cell proliferation, cell differentiation, cell survival, apoptosis (cell death), or the utilization of a metabolic nutrient (e.g., glucose uptake). Certain changes or the absence of changes in cell phenotype are readily monitored using techniques known in the art. [094] The term "cell proliferation" refers to the rate at which cells divide. The number of cells growing in a vessel can be quantified by a person skilled in the art (e.g., by counting cells in a defined area using a light microscope, or by using laboratory apparatus that measure the density of cells in an appropriate medium). One skilled in that art can calculate cell proliferation by determining the number of cells in a sample at two or more times. [095] The term "contacting" refers to bringing two or more materials into close enough proximity that they may interact. In certain embodiments, contacting can be accomplished in a vessel such as a test tube, a petri dish, or the like. In certain embodiments, contacting may be performed in the presence of additional materials. In certain embodiments, contacting may be performed in the presence of cells. In certain of such embodiments, one or more of the materials that are being contacted may be inside a cell. Cells may be alive or may dead. Cells may or may not be intact. Certain compounds
[096] Certain compounds that bind to HNF-4α receptors and/or certain compounds that modulate an activity of such receptors play a role in health (e.g., normal growth, development, and/or absence of disease). In certain embodiments, compounds of the present invention are useful for treating any of a variety of diseases or conditions. [097] Certain compounds have been previously described as receptor modulators. See e.g., U. S. Patent Nos. 6,462,038, 5,693,646; 6,380,207; 6,506,766;
5,688,810; 5,696,133; 6,569,896, 6,673,799; 4,636,505; 4,097,578; 3,847,988; U.S.
Patent Application No. 10/209,461 (Pub. No. US 2003/0055094); International Patent Application Nos. WO 01/27086 and WO 02/22585; Zhi, et al. Bioorganic & Med. Chem. Lett. 2000, 10:415-418; Pooley, et al, J. Med. Chem. 1998, 41:3461; Hamann, etal J. Med. Chem. 1998, 41:623; and Yin, et al, Molec. Pharmacol, 2003, 63:211-223 the entire disclosures of which are incoφorated by reference herein in their entirety. Certain cyclothiocarbamate analogues have been described as progesterone receptor modulators (e.g., U.S. Pat. Nos. 6,436,929 and 6,509,334). Certain cyclocarbamate analogues have been described as progesterone receptor antagonists (e.g., U.S. Pat. Nos. 6,306,851, 6,380,178, 6,441,019, 6,444,668, 6,509,334, and 6,566,358; Zhang, et al. J. Med. Chem. 45:4379 (2002)). [098] In certain embodiments, the invention provides a compound of formula I, II, III, IV, V, or VI:
Figure imgf000040_0001
Figure imgf000040_0002
II
Figure imgf000041_0001
m rv
Figure imgf000041_0002
or a pharmaceutically acceptable sale, ester, amide, or prodrug thereof.
[099] In certain embodiments, R1 is selected from H, a halogen, SH, and OH. [0100] In certain embodiments, R2 is selected from H, a halogen, an optionally substituted d-d alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 akynyl, an optionally substituted d-d heteroalkyl, an optionally substituted C2- heteroalkenyl, an optionally substituted C2-C6 heteroakynyl, an optionally substituted Cι-C6 haloalkyl, an optionally substituted C2-C6 haloalkenyl, an optionally substituted C2-C6 haloakynyl, an optionally substituted Cι-C6 heterohaloalkyl, an optionally substituted C2-C6 heterohaloalkenyl, an optionally substituted C2-C6 heterohaloakynyl, an optionally substituted C3-C8 cycloalkyl, an optionally substituted C3-C8 cycloalkenyl, an optionally substituted C3-C8 cycloakynyl, an optionally substituted C3-C8 heterocycle, an optionally substituted C3-C8 aryl, an optionally substituted C -C8 heteroaryl, an optionally substituted Cι-C2 alkoxy, a NR12R13, an optionally substituted sulfonamide, an optionally substituted Cι-C2 thioalkyl, an optionally substituted C2 thioalkenyl, an optionally substituted C2 thioakynyl, an optionally substituted nitro, an optionally substituted formyl, an optionally substituted acyl, and an optionally substituted hydroxylamine. In certain embodiments, R2 is an optionally substituted d-C8 alkyl, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 akynyl, an optionally substituted C2-C8 thioalkyl, an optionally substituted C2-C8 thioalkenyl, an optionally substituted C2-C8 thioakynyl, or an optionally substituted C3-C8 cycloalkyl. In certain embodiments, R2 is an optionally substituted Cι-C8 alkyl, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 akynyl, an optionally substituted C2-C8 thioalkyl, an optionally substituted C2-C8 thioalkenyl, an optionally substituted C2-C8 thioakynyl, an optionally substituted C3-C8 cycloalkyl, an optionally substituted C3-C8 cycloalkenyl, or an optionally substituted C3-C8 cycloakynyl. In certain of such embodiments, R2 is selected from an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an optionally substituted C2-C3 thioalkenyl, an optionally substituted C2-C3 thioalkynyl, an optionally substituted C3-C8 cycloalkenyl, and an optionally substituted C3-C8 cycloalkynyl. In certain embodiments, R2 is selected from an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert- butyl. In certain of the embodiments where R2 is a halogen, R2 is F or CI. In certain embodiments where R2 is selected from an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, thioalkenyl, thioalkynyl, aldehyde and ketone, those groups are optionally substituted with one or more fluorines. In certain embodiments where R2 is selected from an optionally substituted hydroxylamine, that group is optionally substituted with a Cι-C2 alkyl, a C2 alkenyl, a C2 akynyl, a d-C2 fluoroalkyl, a C2 a fluoroalkenyl, or a C2 fluoroakynyl,. [0101] In certain embodiments, R3 is selected from H, a halogen, a nitro, an optionally substituted d-do alkyl, an optionally substituted C2-Cιo alkenyl, an optionally substituted C2-Cιo akynyl, an optionally substituted d-Cio alkoxy, an optionally substituted d-do thioalkyl, an optionally substituted C2-do thioalkenyl, an optionally substituted C2-Cιo thioakynyl, a NR14R15, and an optionally substituted five to six-membered carbocyclic or heterocyclic ring. In certain embodiments, R3 is an optionally substituted d-C8 alkyl, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 akynyl, an optionally substituted C2-C8 thioalkyl, an optionally substituted C2-C8 thioalkenyl, an optionally substituted C2-C8 thioakynyl, or an optionally substituted C3-C8 cycloalkyl. In certain embodiments, R is an optionally substituted Cι-C8 alkyl, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 akynyl, an optionally substituted C2-C8 thioalkyl, an optionally substituted C2-C8 thioalkenyl, an optionally substituted C2-C8 thioakynyl, an optionally substituted C3-C8 cycloalkyl, an optionally substituted C3-C8 cycloalkenyl, or an optionally substituted C3- C8 cycloakynyl. In certain of suchembodiments, R3 is selected from an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an optionally substituted C2-C3 thioalkenyl, an optionally substituted C2-C3 thioalkynyl, an optionally substituted C3-C8 cycloalkenyl, and an optionally substituted C3-C8 cycloalkynyl. In certain embodiments, R3 is selected from an optionally substituted methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. In certain of the embodiments where R is a halogen, R3 is F or CI. In certain embodiments where R3 is selected from an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, thioalkenyl, thioalkynyl, aldehyde and ketone, those groups are optionally substituted with one or more halogens. In certain embodiments where R3 is selected from an optionally substituted carboxylic or heterocyclic ring, that ring is optionally substituted with a one or two R19 groups. [0102] In certain embodiments, R4 is selected from H, a halogen, and OH. [0103] In certain embodiments, R5 is selected from CH2OH, CHO, COOH, and a C(R5')(R5")(COOH). [0104] In certain embodiments, R5' and R5 are each independently selected from H, O, S and F. In certain embodiments, R5 and R5 together are O or S. [0105] In certain embodiments, R6 and R7 are each independently selected from H, a halogen, a NHC(O)R18, an optionally substituted d-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 akynyl, an optionally substituted C2-C6 alkenyl, Cι-C6 heteroalkyl, an optionally substituted C2-C6 heteroalkenyl, an optionally substituted C2-C6 heteroakynyl, an optionally substituted d- d haloalkyl, an optionally substituted C2-C6 haloalkenyl, an optionally substituted C2-C6 haloakynyl, an optionally substituted Cι-C6 heterohaloalkyl, an optionally substituted C2- heterohaloalkenyl, an optionally substituted C2-C6 heterohaloakynyl, an optionally substituted C3-C8 cycloalkyl, an optionally substituted C3-C8 cycloalkenyl, an optionally substituted C3-C8 cycloakynyl, an optionally substituted C3-C8 heterocycle, an optionally substituted C3-C8 aryl, an optionally substituted C3-C8 heteroaryl, an optionally substituted d-C2 alkoxy, a NR12R 3, an optionally substituted sulfonamide, an optionally substituted d-C2 thioalkyl, an optionally substituted C2 thioalkenyl, an optionally substituted C2 thioakynyl, an optionally substituted nitro, an optionally substituted formyl, an optionally substituted acyl, an optionally substituted hydroxylamine, and null. In certain embodiments, R6 and/or R7 is an optionally substituted d-C8 alkyl, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 akynyl, an optionally substituted C2-C8 thioalkyl, an optionally substituted C2-C8 thioalkenyl, an optionally substituted C2-C8 thioakynyl, or an optionally substituted C3-C8 cycloalkyl. In certain embodiments, R6 and/or R7 is an optionally substituted d-C8 alkyl, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 akynyl, an optionally substituted C2-C8 thioalkyl, an optionally substituted C2-C8 thioalkenyl, an optionally substituted C2-C8 thioakynyl, or an optionally substituted C3-C8 cycloalkyl, an optionally substituted C3-C8 cycloalkenyl,or an optionally substituted C3-C8 cycloakynyl . In certain of such embodiments, R6 and/or R7 is selected from an optionally substituted d-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an optionally substituted C2-C3 thioalkenyl, an optionally substituted C2-C3 thioalkynyl, an optionally substituted C3-C8 cycloalkenyl, and an optionally substituted C3-C8 cycloalkynyl. In certain embodiments, R6 and/or R7 is selected from an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl. In certain of the embodiments where R6 and/or R7 is a halogen, R6 and or R7 is F or CI. In certain embodiments where R6 and/or R7 is selected from an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, thioalkenyl, thioalkynyl, aldehyde and ketone, those groups are optionally substituted with one or more fluorines. In certain embodiments where R and/or R is selected from an optionally substituted hydroxylamine, that hydroxylamine is optionally substituted with a Cι-C2 alkyl, a C2 alkenyl, a C2 akynyl, a Cι-C2 fluoroalkyl, a C2 fluoroalkenyl, or a C2 fluoroakynyl,. [0106] In certain embodiments, R6 and R7 taken together form a group selected from O, S, NH and CH2. [0107] In certain embodiments, R8 and R9 are each independently selected from H, a halogen, an optionally substituted Cι-C2 alkyl, an optionally substituted C2 alkenyl, an optionally substituted C2 akynyl, and null. In certain embodiments, R8 and/or R9 is methyl optionally substituted with one or more halogens. In certain embodiments, R and R9 taken together with Y form a three to five-membered optionally substituted carbocyclic ring. [0108] In certain embodiments, R10 is selected from H, a halogen, an optionally substituted d-C2 alkyl, an optionally substituted C2 alkenyl, and an optionally substituted C2 akynyl. In certain embodiments, R10 is a methyl optionally substituted with one or more halogens. [0109] In certain embodiments, R11 and Rn are each independently selected from H, a halogen and OH. In certain embodiments, Rn and R11' taken together form an O. In certain embodiments, if R11 is OH, then R11 is H. [0110] In certain embodiments, R and R are each independently selected from a C1-C3 alkyl optionally substituted with one or more halogens, C2-C3 alkenyl optionally substituted with one or more halogens, and a C2-C3 akynyl optionally substituted with one or more halogens. In certain embodiments, R12 and R13 taken together with the nitrogen atom to which they are both bound form a five to six-membered optionally substituted heterocyclic ring. [0111] In certain embodiments, R14 and R15 are each independently selected from a Cι-C2 alkyl optionally substituted with one or more halogens, an C2-C6 alkenyl optionally substituted with one or more halogens, and a C2-C6 akynyl optionally substituted with one or more halogens. [0112] In certain embodiments, R16 and R17 are each independently selected from an optionally substituted Cι-Cι2 alkyl, optionally substituted C2-Cι2 alkenyl, optionally substituted C2-C12 akynyl, an optionally substituted Cj-Cn heteroalkyl, an optionally substituted C2-C12 heteroalkenyl, an optionally substituted C2-C12 akynyl, an optionally substituted d-C12 haloalkyl, an optionally substituted C2-Cι2 haloalkenyl, an optionally substituted C2-Cι2 haloakynyl, an optionally substituted Cι-C12 heterohaloalkyl, an optionally substituted C2-Cι2 heterohaloalkenyl, an optionally substituted C2-C12 heterohaloakynyl, an optionally substituted C3-C12 cycloalkyl, an optionally substituted C3-Cι2 alkenyl, an optionally substituted C3-Cι2 akynyl, an optionally substituted C3-Cι2 heterocycle, an optionally substituted C3-Cι2 aryl, and an optionally substituted C3-Cj2 heteroaryl. In certain embodiments, R16 and/or R17 is an optionally substituted Cι-Cι2 alkyl, optionally substituted C2-Cι2 alkenyl, optionally substituted C2-Cι2 akynyl, an optionally substituted C3-C12 cycloalkyl, an optionally substituted C3-Cι2 cycloalkenyl, or an optionally substituted C3-Cι2 cycloakynyl. In certain embodiments, R16 and/or R17 is an optionally substituted Cι-C12 alkyl optionally substituted C2-C12 alkenyl, optionally substituted C2-Cι2 akynyl, an optionally substituted C3-C12 cycloalkyl, an optionally substituted C3-C12 cycloalkenyl, or an optionally substituted C -Cι2 cycloakynyl. In certain of such embodiments, R16 and or R17 is selected from an optionally substituted C2-Cι2 alkenyl, an optionally substituted C2-Cι2 alkynyl, an optionally substituted C3-C12 cycloalkenyl, and an optionally substituted C3-Cι2 cycloalkynyl. In certain embodiments, R16 and/or R17 is selected from an optionally substituted methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments where R16 and/or R17 is optionally substituted with one or more R19. [0113] In certain embodiments, R16 and R17 taken together with the nitrogen atom to which they are both bound form a five to six-membered optionally substituted heterocyclic ring. [0114] In certain embodiments, R18 is selected from an optionally substituted Cv- C12 alkyl, optionally substituted C2-Cι2 alkenyl, optionally substituted C2-C12 akynyl, an optionally substituted Cι-Cι2 heteroalkyl, an optionally substituted C2-C12 heteroalkenyl, an optionally substituted C2-Cι2 heteroakynyl, an optionally substituted Cι-C12 haloalkyl, an optionally substituted C2-C12 haloalkenyl, an optionally substituted C2-Cι2 haloakynyl, an optionally substituted d-Cι2 heterohaloalkyl, an optionally substituted C2-C12 heterohaloalkenyl, an optionally substituted C2-Cι2 heterohaloakynyl, an optionally substituted C3-C12 cycloalkyl, an optionally substituted C3-C8 cycloalkenyl, an optionally substituted C3-C8 cycloakynyl, an optionally substituted C3-C12 heterocycle, an optionally substituted C3-C12 aryl, and an optionally substituted C -Cj2 heteroaryl. In certain embodiments, R18 is an optionally substituted Cι-C12 alkyl, an optionally substituted C2-Cι2 alkenyl, an optionally substituted C2-C12 akynyl, or an optionally substituted C3-Cι2 cycloalkyl . In certain embodiments, R18 is an optionally substituted Cι-Cι2 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2- Cι akynyl, an optionally substituted C3-C12 cycloalkyl, an optionally substituted C3-Cι2 cycloalkenyl, or an optionally substituted C3-Cι2 cycloakynyl . In certain of such embodiments, R18 is selected from an optionally substituted C2-C12 alkenyl, an optionally substituted C2-Cι2 alkynyl, an optionally substituted C -Cι2 cycloalkenyl, and an optionally substituted C3-Cj2 cycloalkynyl. In certain embodiments, R18 is selected from an optionally substituted methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments R 8 is optionally substituted with one or more R1 . [0115] In certain embodiments, R19 is selected from a halogen, an optionally substituted C1-C4 alkyl, optionally substituted C2-d alkenyl, optionally substituted C2-d akynyl, an optionally substituted C1-C4 alkoxy, an optionally substituted d-C3 thioalkyl, optionally substituted C2-C3 thioalkenyl, optionally substituted C2-C3 thioakynyl, an optionally substituted formyl, and an optionally substituted nitro. In certain embodiments, Ri9 is a -d alkyl optionally substituted with one or more fluorines, a C2-d alkenyl optionally substituted with one or more fluorines, or a C2-d akynyl optionally substituted with one or more fluorines. In certain embodiments, R19 is a - alkoxy optionally substituted with one or more halogens. In certain embodiments, R19 is a Cι-C3 thioalkyl optionally substituted with one or more halogens, a C2-C3 thioalkenyl optionally substituted with one or more halogens, or a C2-C3 thioakynyl optionally substituted with one or more halogens. [0116] In certain embodiments, R20 is selected from a C4-C5 alkyl optionally substituted with one or more halogens, a C4-d alkenyl optionally substituted with one or more halogens, a C4-C5 akynyl optionally substituted with one or more halogens, a phenyl optionally substituted with one or more fluorines, a thienyl optionally substituted 91 with one or more fluorines, and a benzyl optionally substituted with one or more R . [0117] In certain embodiments, R21 is selected from a halogen, a methyl optionally substituted with one or more fluorines, and a thiomethyl optionally substituted with one or more halogens. [0118] In certain embodiments, X and Y are each independently selected from O, S, N and C. [0119] In certain embodiments, A is selected from O, CH2, CF2 and S. [0120] In certain embodiments, Z is selected from C, N and phenylene. [0121] In certain embodiments, if X is O or S, then each of R6 and R7 is null; if X is N, then one of R6 and R7 is null; if Y is O or S, then each of the R8 and R9 is null; and if Y is N, then one of R8 and R9 is null. [0122] In certain embodiments, if R6 is selected from a halogen, a Cι-C12 alkyl a C2-Cι2 alkenyl, a C2-C12 alkynyl or a C2-Cι2 alkoxy any of which is optionally substituted with one or more R19, or a Cι-C12 thioalkyl Cι-C12 thioalkenyl or d-Cι2 thioalkynyl any of which is optionally substituted with one or more R19, NR16R17 or HNC(O)R18, then R7 is H or F. [0123] In certain embodiments, if Y is N then neither R nor R is a halogen. [0124] In certain embodiments, if R19 is selected from a - alkyl substituted with one or more halogens, a C2-C4 alkenyl substituted with one or more halogens, a C2- d akynyl substituted with one or more halogens, a - alkoxy group substituted with one or more halogens, a d-C3 thioalkyl substituted with one or more halogens, a C2-C3 thioalkenyl substituted with one or more halogens, and C2-C3 akynyl substituted with one or more halogens, group substituted with one or more halogens, then each of R3, R and R17 is substituted with no more than two R19 groups. [0125] In certain embodiments, if R3 is a methyl substituted with one or more fluorines, then neither R1 nor R2 is either hydrogen or a halogen. [0126] In certain embodiments, if R4 is a halogen, then R3 is an ethoxy optionally substituted with one or more fluorines. [0127] In certain embodiments, if Y is nitrogen then neither R8 nor R9 is a halogen. In certain embodiments, if Y is either oxygen or sulfur, then R is null and R is null. [0128] In embodiments in which two or more of a particular group are present, the identities of those two or more particular groups are selected independently and, thus, may be the same or different from one another. For example, certain compounds of the invention comprise two or more R19 groups. The identities of those two or more R19 groups are each selected independently. Thus, in certain embodiments, those R19 groups are all the same aseach other; in certain embodiments, those R19 groups are all different fromeach other; and in certain embodiments, some of those R19 groups are the same as each other and some are different from the others. This independent selection applies to any group that is present in a compound more than once. [0129] Certain compounds of the present inventions may exist as stereoisomers including, but not limited to, optical isomers. The present disclosure is intended to include all stereoisomers and both the racemic mixtures of such stereoisomers as well as the individual enantiomers that may be separated according to methods that are known in the art or that may be excluded by synthesis schemes known in the art designed to yield predominantly one enantiomer relative to another. [0130] As used herein, the term "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term "enantiomer" refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another. The term "chiral center" refers to a carbon atom to which four different groups are attached. As used herein, the term "diastereomers" refers to stereoisomers which are not enantiomers. In addition, two diastereomers which have a different configuration at only one chiral center are referred to herein as "epimers." The terms "racemate," "racemic mixture" or "racemic modification" refer to a mixture of equal parts of enantiomers. [0131] The compounds of the present invention may be chiral, and it is intended that any enantiomers, as separated, pure or partially purified enantiomers or racemic mixtures thereof are included within the scope of the invention. Furthermore, when a double bond or a fully or partially saturated ring system or more than one center of asymmetry or a bond with restricted rotatability is present in the molecule diastereomers may be formed. It is intended that any diastereomers, as separated, pure or partially purified diastereomers or mixtures thereof are included within the scope of the invention. Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms, which the compounds are able to form, are included within the scope of the present invention. Thus, as one skilled in the art knows, certain aryls may exist in tautomeric forms. The mvention also includes tautomers, enantiomers and other stereoisomers of the compounds of Formula I. Such variations are contemplated to be within the scope of the invention. [0132] The terms "R" and "S" are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term "R" (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term "S" (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in "Nomenclature of Organic Compounds: Principles and Practice", (J.H. Fletcher, et al., eds., 1974) at pages 103-120. [0133] The designation " "— ■ " refers to a bond that protrudes forward out of the plane of the page. [0134] The designation " " refers to a bond that protrudes backward out of the plane of the page. [0135] The designation " ~ ^ " refers to a bond wherein the stereochemistry is not defined. [0136] The compounds of Formula I, when existing as a diastereomeric mixture, may be separated into diastereomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof. The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent. Alternatively, any enantiomer of a compound of Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration or through enantioselective synthesis. [0137] The term "enantiomeric enrichment" as used herein refers to the increase in the amount of one enantiomer as compared to the other. A convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or "ee," which is found using the following equation: ee = E1 - E2 X 100 E! + E2 [0138] wherein E1 is the amount of the first enantiomer and E2 is the amount of the second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 70:30 is achieved, the ee with respect to the first enantiomer is 40%>.
However, if the final ratio is 90:10, the ee with respect to the first enantiomer is 80%>.
An ee of greater than 90%> is preferred, an ee of greater than 95%. is most preferred and an ee of greater than 99% is most especially preferred. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art. In addition, the specific stereoisomers and enantiomers of compounds of Formula I can be prepared by one of ordinary skill in the art utilizing well known techniques and processes, such as those disclosed by J. Jacques, et al., "Enantiomers. Racemates. and Resolutions." John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen," Stereochemistry of Organic Compounds." (Wiley-Interscience 1994), and European Patent Application No. EP-A-838448, published April 29, 1998. Examples of resolutions include recrystallization techniques or chiral chromatography.
[0139] The following table provides examples of certain variables from various Markush groups in this application. One of ordinary skill in the art will recognize that the variables may selected in any combination.
Table A. Table of Markush Groups by Variable
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
[0140] In certain embodiments, the invention provides compounds selected from: 4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl]benzoyl benzoic acid (Compound 103); 4-[5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-l-hydroxy-2-naphthalenyl]benzoyl benzoic acid (Compound 104);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(l , 1 , 1 -trifluoroethoxy)-2- naphthalenyl]benzoyl benzoic acid (Compound 105);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-propoxy-2-naphthalenyl]benzoyl benzoic acid (Compound 106); 4-[5,6,7,8-tetrahydro-3,5,5,8,8-ρentamethyl-4-nitro-2-naphthalenyl]benzoyl benzoic acid (Compound 108);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-4-nitro-2- naphthalenyl]benzoyl benzoic acid (Compound 109);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(2,2-difluoroethoxy)-4-nitro-2- naphthalenyl]benzoyl benzoic acid (Compound 110);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methoxy-2- naphthalenyl)methyl]benzoic acid (Compound 117);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-w6>-propoxy-2- naphthalenyl)methyl]benzoic acid (Compound 118);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2- naphthalenyl)methyl]benzoic acid (Compound 119);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(l,l,l-trifuoroethoxy)-2- naphthalenyl)methyl]benzoic acid (Compound 120);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-propoxy-2- naphthalenyl)methyl]benzoic acid (Compound 121);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-butoxy-2- naphthalenyl)methyl]benzoic acid (Compound 122);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-heptoxy-2- naphthalenyl)methyl]benzoic acid (Compound 123); 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetτamethyl-3-methyl-4- >-tolenesulfonamido-2- naphthalenyl) methyl]benzoic acid (Compound 124);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methyl-4-ethylamino-2- naphthalenyl)methyl]benzoic acid (Compound 125);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methyl-4-propylamino-2- naphthalenyl)methyl] benzoic acid (Compound 126);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(2-fluorophenyl)-2- naphthalenyljbenzoyl benzoic acid (Compound 128);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-phenyl-2-naphthalenyl]benzoyl benzoic acid (Compound 129);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(3-thienyl)-2-naphthalenyl]benzoyl benzoic acid (Compound 130);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(4-fluorophenyl)-2- naphthalenyljbenzoyl benzoic acid (Compound 131);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(3-nitrophenyl)-2- naphthalenyl]benzoyl benzoic acid (Compound 132);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(N-methyl-N-ethylamino)-2- naphthalenyl]benzoyl benzoic acid (Compound 134);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(2-fluorophenyl)-4-nitro-2- naphthalenyl]benzoyl benzoic acid (Compound 136); 4-[(5,6,7,8-tetrahydro-3,8,8-trimethyl-4-nitro-2-naphthalenyl)benzoyl] benzoic acid (Compound 137);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-l-fluoro-3-ethoxy-2- naphthalenyl]benzoyl benzoic acid (Compound 141);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-l-fluoro-3-ethoxy-4-nitro-2- naphthalenyl] benzoyl benzoic acid (Compound 142);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl]benzoyl-3- chloro-benzoic acid (Compound 144);
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-tetramethyl-2-naphthalenyl)(2-fluorobenzyloxy) methyl] benzoic acid (Compound 149);
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4-fluorobenzyloxy) methyl]benzoic acid (Compound 150);
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(2-thifluoromethoxy benzyloxy) methyl]benzoic acid (Compound 151);
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-tetramethyl-2-naphthalenyl)(2,3- difluorobenzyloxy) methyl] benzoic acid (Compound 152);
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-tetramethyl-2-naphthalenyl)(4-trifluoromethyl benzyloxy) methyl] benzoic acid (Compound 153);
4-[(5,6,7,8-tetrahydro-3, 5,5,8, 8-pentamethyl-2-naphthalenyl)(4-trifluoromethoxy benzyloxy) methyl] benzoic acid (Compound 154); 4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4- trifluorothiomethoxy benzyloxy) methyl] benzoic acid (Compound 155);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl)(2,3-difluoro benzyloxy) methyl]benzoic acid (Compound 156);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl)(4-fluoro benzyloxy)methyl] benzoic acid (Compound 157);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl)(2- fluorobenzyloxy)methyl] benzoic acid (Compound 158);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl) (benzyloxy)methyl]benzoic acid (Compound 159);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl) (butyloxy)methyl]benzoic acid (Compound 160);
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(phenylacetamido) methyl] benzoic acid (Compound 162);
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(3- fluorobenzylamino) methyl] benzoic acid (Compound 163);
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4- fluorobenzylamino) methyl] benzoic acid (Compound 164);
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)( benzylamino) methyl] benzoic acid (Compound 165); 4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4-trifluoromethyl phenoxy)methyl]benzoic acid (Compound 166);
4-[(5,6,7,8-tetrahydro-3, 5,5,8, 8-pentamethyl-2-naphthalenyl)(4-tert- buιylbenzylthio)methyl] benzoic acid (Compound 167);
4-[(5,6,7,8-tetrahydro-3, 5,5,8, 8-pentamethyl-2-naphthalenyl)(4- fluorophenyloxy)methyl]benzoic acid (Compound 168);
4-[(5,6,7,8-tetrahydro-3, 5,5,8, 8-pentamethyl-2-naphthalenyl)(4-tert- butylphenyloxy) methyl]benzoic acid (Compound 169);
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4- phenylphenyloxy) methyl]benzoic acid (Compound 170);
4-[(5,6,7,8-tetrahydro-3, 5,5,8, 8-pentamethyl-2-naphthalenyl)(4-phenoxy) methyl]benzoic acid (Compound 171);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl)(4-tert- butylbenzylthio) methyl]benzoic acid (Compound 172);
4-[(phenylhydrazino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)]benzoic acid (Compound 173);
4-[(phenylhydrazino)(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)] benzoic acid (Compound 174);
4-[(phenylhydrazino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4-ethoxy-2- naphthalenyl)]benzoic acid (Compound 175); 4-[(Pyridine-2-hydrazonyl)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)]benzoyl benzoic acid (Compound 176);
4-[(2,4-difluorophenylhydrazino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4- ethoxy-2-naphthalenyl)]benzoic acid (Compound 177);
4-[(2,5-difluorophenylhydrazino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4- ethoxy-2-naphthalenyl)]benzoic acid (Compound 178);
4-[(2,5-dimethylphenylhydrazino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4- ethoxy-2-naphthalenyl)]benzoic acid (Compound 179);
4-[(2-fluorophenylhydrazino)(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2- naphthalenyl)]benzoic acid (Compound 180);
4-[(phenylimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4-ethoxy-2- naphthalenyl)] benzoic acid (Compound 183);
4-[(4,4,4-trifluorobutoximino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy- 2-naphthalenyl)]benzoic acid (Compound 184);
4-[(ethoxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)] benzoic acid (Compound 185);
4-[(propoxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetτamethyl-3-ethyloxy -2- naphthalenyl)]benzoic acid (Compound 186);
4-[(butoxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)]benzoic acid (Compound 187); 4-[(pentoxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)]benzoic acid (Compound 188);
4-[(hexyloxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)]benzoic acid (Compound 189);
4-[(3-methyl-butoxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)] benzoic acid (Compound 190);
4-[(decyloxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)]benzoic acid (Compound 191);
4-[(2,3-difluorobenzyloxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3- ethyloxy-2-naphthalenyl)] benzoic acid (Compound 192);
6-(2,3-dihydro-4,4-dimethyl-7-ethoxybenzopyranyl)benzoyl benzoic acid (Compound 201);
6-[(2,3 -dihydro-4,4-dimethyl-7-ethoxy-benzothiopyranyl)]benzoyl benzoic acid (Compound 202);
6-(2,3 -dihydro-4,4,7-trimethyl-8nitro-benzopyranyl)benzoyl benzoic acid (Compound 203);
7-[ 1 ,4,4-trimethyl-5-methyl-6-methoxy 1 ,2,3 ,4-tetrahydroquinoline]benzoyl benzoic acid (Compound 212);
7-[l,4,4-trimethyl-5-methyl-6-ethoxyl,2,3,4-tetrahydroquinoline]benzoyl benzoic acid (Compound 213); 4-[(5,6,7,8-tetrahydro-3,8,8-trimethyl-2-naphthalenyl)ethenyl] benzoic acid (Compound 214);
2-Oxo-2-[4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl]phenyl] acetic acid (compound 217); and
2-Oxo-2-[4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methyl-2- naphthalenyl]phenyl]acetic acid (compound 218); and pharmaceutically acceptable salts, esters, amides, and/or prodrugs of any of those compounds.
[0141] In certain embodiments, a compound of Formula I, II, III, IV, V, or VI is a selective HNF-4α receptor modulator. In certain embodiments, a compound of Formula I, II, III, IV, V, or VI is a selective HNF-4α receptor agonist. In certain embodiments, a compound of Formula I, II, III, IV, V, or VI is a selective HNF-4α receptor antagonist. In certain embodiments, a compound of Formula I, II, III, IV, V, or VI is a selective HNF-4α receptor partial agonist. In certain embodiments, a compound of Formula I, II, III, IV, V, or VI is a tissue-specific selective HNF-4α receptor modulator. In certain embodiments, a compound of Formula I, II, III, IV, V, or VI is a gene-specific selective HNF-4α receptor modulator. In certain embodiments, a compound of Formula I, II, III, IV, V, or VI is a selective HNF-4α receptor binding compound. [0142] In certain embodiments, the present invention provides selective HNF-4α receptor modulators. In certain embodiments, the invention provides selective HNF-4α receptor binding agents. In certain embodiments, the invention provides methods of making and methods of using selective HNF-4α receptor modulators and/or selective HNF-4α binding agents. In certain embodiments, selective HNF-4α modulators are agonists, partial agonists, and/or antagonists for the HNF-4 receptor. In certain embodiments, the invention provides compounds that are selective for an HNF-4α receptor relative to a retinoic X receptor (RXR) (e.g., Compounds 104, 105, 110, 124, 125, 126, 158, 163, 171, 173, 177, 179, 190, 192, 201, 202, 212, 213, 214, 215, 217, and 218). In certain embodiments, the invention provides compounds that are selective for an HNF-4α receptor relative to an RXR by at least 8 times. Certain Synthesis Methods [0143] Certain synthesis schemes are now provided. The synthesis schemes are provide only to illustrate possible ways to make certain compounds of the invention and do not limit the invention in any way. One of skill in the art will recognize that compounds of the present mvention may be synthesized through any of a variety of schemes using a variety of different starting materials. Scheme 1
Figure imgf000072_0001
The intermediate 2 are usually obtained by a Friedel-Craft reaction between 1 and A in the presence of A1C13 in CH2C12. Saponification of 2 affords the acids 3. In the case of R2 = H, 2 can be nitrated using a mixture of HNO /H2SO4 in acetic acid at room temperature to give 4. The derivatives 5 may be obtained by saponification of 4 or by selective nitration of 3 (R2 = H in 3). The nitro group present in 4 can be reduced to the corresponding amine 6 or hydroxylamine 7 using Zinc dust in MeOH/H2O/CH2Cl2 at room temperature. 7 can be O-alkylated with various alkyl iodide or bromide (X-Rz) in the presence of K2CO3 in DMF at room temperature. Reduction with NaBEU of the benzophenone 4 affords the alcohol 9. Removal of the hydroxyl by catalytic hydrogenation (H2/Pd/C) yields the methylene-bridged derivatives 10. Reduction of the nitro group on 10 releases the amino derivatives 11. The amino group of 11 may be alkylated and saponificated to afford the acids 12. Diazotation followed by nucleophilic displacement of 10 affords the phenols 13. These are then alkylated and saponified to give the derivatives 14.
Scheme 2
Figure imgf000074_0002
Figure imgf000074_0001
R Reduction
Figure imgf000074_0003
11 Derivatives 9 could be transformed into the chlorines 15 that can be used as alkylating agents with alcohols, amines or thiols. Saponification of these adducts afford the acids 16. The hydrazones 17 and the oximes 18 and 19 are easily synthesized from the ketones 2.
Scheme 3
Figure imgf000075_0001
1/ Alkylation 2/ Saponification
Figure imgf000075_0002
Figure imgf000075_0003
Alternatively, the following scheme using a Suzuki coupling between the boronic acids 20 and methyl 4-bromomethyl benzoate followed by saponification may be used to synthesize the derivatives 22.
Scheme 4
Saponification
Figure imgf000075_0004
Figure imgf000075_0005
Suzuki coupling
Figure imgf000075_0007
Figure imgf000075_0006
20
[0144] In certain embodiments, the invention provides a salt corresponding to any of the compounds provided herein. In certain embodiments, the invention provides a salt corresponding to a selective HNF-4α modulator. In certain embodiments, the mvention provides a salt corresponding to a selective HNF-4α receptor binding agent. In certain embodiments, a salt is obtained by reacting a compound with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In certain embodiments, a salt is obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like. [0145] In certain embodiments, one or more carbon atoms of a compound of the present invention is replaced with silicon. See e.g., WO 03/037905A1; Tacke & Zilch, Endeavour, New Series, 10:191-197 (1986); Bains & Tacke, Curr. Opin. Drug Discov Devel 6:526-43 (2003). In certain embodiments, compounds of the present invention comprising one or more silicon atoms possess certain desired properties, including, but not limited to, greater stability and/or longer half-life in a patient, when compared to the same compound in which none of the carbon atoms have been replaced with a silicon atom. [0146] Protecting groups that may be used in the present invention include those that are commonly known to those skilled in the art, such groups include, but are not limited to TBDMS, TBS and Benzyl. Certain Assays
[0147] In certain embodiments, compounds of the present invention are capable of modulating activity of HNF-4 receptors in a "co-transfection" assay (also called a "cis-trans" assay), which has been discussed previously. See e.g., Evans et al, Science, 240:889-95 (1988); U.S. Patent Nos. 4,981,784 and 5,071,773; Pathirana et al., Mol. Pharm. 47:630-35 (1995)). Modulating activity in a co-transfection assay has been shown to correlate with in vivo modulating activity. Thus, in certain embodiments, such assays are predictive of in vivo activity. See, e.g., Berger et al, J. Steroid Biochem. Molec. Biol. 41:773 (1992). [0148] In certain co-transfection assays, two different co-transfectiott plasmids are prepared. In the first co-transfection plasmid, cloned cDNA encoding an intracellular receptor (e.g., HNF-4α receptor) is operatively linked to a constitutive promoter (e.g., the SV40 promoter). In the second co-transfection plasmid, cDNA encoding a reporter protein, such as firefly luciferase (LUC), is operatively linked to a promoter that is activated by a receptor-dependant activation factor. Both co-transfection plasmids are co-transfected into the same cells. Expression of the first co-transfection plasmid results in production of the intracellular receptor protein. Activation of that intracellular receptor protein (e.g., by binding of an agonist) results in production of a receptor- dependant activation factor for the promoter of the second co-transfection plasmid. That receptor-dependant activation factor in turn results in expression of the reporter protein encoded on the second co-transfection plasmid. Thus, reporter protein expression is linked to activation of the receptor. Typically, that reporter activity can be conveniently measured (e.g., as increased luciferase production). [0149] Certain co-transfection assays can be used to identify agonists, partial agonists, and/or antagonists of intracellular receptors. In certain embodiments, to identify agonists, co-transfected cells are exposed to a test compound. If the test compound is an agonist or partial agonist, reporter activity is expected to be higher compared to co-transfected cells in the absence of the test compound. In certain embodiments, to identify antagonists, the cells are exposed to a known agonist (e.g., the natural ligand for the receptor) in the presence and absence of a test compound. If the test compound is an antagonist, reporter activity is expected to be lower than that of cells exposed only to the known agonist. [0150] In certain embodiments, compounds of the invention are used to detect the presence, quantity and/or state of receptors in a sample. In certain of such embodiments, samples are obtained from a patient. In certain embodiments, compounds are radio- or isotopically-labeled. For example, compounds of the present invention that selectively bind HNF-4 receptors may be used to determine the presence or amount of such receptors in a sample, such as cell homogenates and lysates. [0151] In certain embodiments, the present invention provides for use of both CARLA and mammalian-2-hybrid assays, to characterize the in vitro profile of compounds of the invention on a HNF-4α receptor. [0152] In certain embodiments, the present invention provides for use of [H]3-[4- [(phenylhydrazino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)]benzoic acid] (Example 73) and/or [H]3-4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2- naphthalenyl]benzoyl benzoic acid (Example 3) as radioactive ligands for a binding assay. Certain Pharmaceutical Agents [0153] In certain embodiments, at least one selective HNF-4α receptor modulator, or pharmaceutically acceptable salt, ester, amide, and/or prodrug thereof, either alone or combined with one or more pharmaceutically acceptable carriers, forms a pharmaceutical agent. Techniques for formulation and admimstration of compounds of the present invention may be found for example, in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990. [0154] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention is prepared using known techniques, including, but not limited to mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes. [0155] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention is a liquid (e.g., a suspension, elixir and/or solution). In certain of such embodiments, a liquid pharmaceutical agent comprising one or more compounds of the present invention is prepared using ingredients known in the art, including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. [0156] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present mvention is a solid (e.g., a powder, tablet, and/or capsule). In certain of such embodiments, a solid pharmaceutical agent comprising one or more compounds of the present invention is prepared using ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents. [0157] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention is formulated as a depot preparation. Certain of such depot preparations are typically longer acting than non-depot preparations. In certain embodiments, such preparations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. In certain embodiments, depot preparations are prepared using suitable polymeric or hydrophobic materials (for example an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. [0158] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention comprises a delivery system. Examples of delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical agents including those comprising hydrophobic compounds. In certain embodiments, certain organic solvents such as dimethylsulfoxide are used. [0159] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention comprises one or more tissue-specific delivery molecules designed to deliver the pharmaceutical agent to specific tissues or cell types. For example, in certain embodiments, pharmaceutical agents include liposomes coated with a tissue-specific antibody. [0160] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention comprises a co-solvent system. Certain of such co- solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water- miscible organic polymer, and an aqueous phase. In certain embodiments, such co- solvent systems are used for hydrophobic compounds. A non-limiting example of such a co-solvent system is the VPD co-solvent system, which is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™ , and 65% w/v polyethylene glycol 300. The proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics. Furthermore, the identity of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose. [0161] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present mvention comprises a sustained-release system. A non- limiting example of such a sustained-release system is a semi-permeable matrix of solid hydrophobic polymers. In certain embodiments, sustained-release systems may, depending on their chemical nature, release compounds over a period of hours, days, weeks or months. [0162] Certain compounds used in pharmaceutical agent of the present invention may be provided as pharmaceutically acceptable salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. [0163] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention comprises an active ingredient in a therapeutically effective amount. In certain embodiments, the therapeutically effective amount is sufficient to prevent, alleviate or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art. [0164] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention is formulated as a prodrug. In certain embodiments, prodrugs are useful because they are easier to administer than the corresponding active form. For example, in certain instances, a prodrug may be more bioavailable (e.g., through oral administration) than is the corresponding active form. In certain instances, a prodrug may have improved solubility compared to the corresponding active form. In certain embodiments, a prodrug is an ester. In certain embodiments, such prodrugs are less water soluble than the corresponding active form. In certain instances, such prodrugs possess superior transmittal across cell membranes, where water solubility is detrimental to mobility. In certain embodiments, the ester in such prodrugs is metabolically hydrolyzed to carboxylic acid. In certain instances the carboxylic acid containing compound is the corresponding active foπn. In certain embodiments, a prodrug comprises a short peptide (polyaminoacid) bound to an acid group. In certain of such embodiments, the peptide is metabolized to form the corresponding active form. [0165] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention is useful for treating a conditions or disorder in a mammalian, and particularly in a human patient. Suitable administration routes include, but are not limited to, oral, rectal, transmucosal, intestinal, enteral, topical, suppository, through inhalation, intrathecal, mtraventricular, intraperitoneal, intranasal, intraocular and parenteral (e.g., intravenous, intramuscular, intramedullary, and subcutaneous). In certain embodiments, pharmaceutical intrathecals are administered to achieve local rather than systemic exposures. For example, pharmaceutical agents may be injected directly in the area of desired effect (e.g., in the renal or cardiac area). [0166] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention is administered in the form of a dosage unit (e.g., tablet, capsule, bolus, etc.). In certain embodiments, such dosage units comprise a selective a HNF-4α receptor modulator in a dose from about 1 μg/kg of body weight to about 50 mg/kg of body weight. In certain embodiments, such dosage units comprise a selective a HNF-4α receptor modulator in a dose from about 2 μg/kg of body weight to about 25 mg/kg of body weight. In certain embodiments, such dosage units comprise a selective a HNF-4α receptor modulator in a dose from about 10 μg/kg of body weight to about 5 mg/kg of body weight. In certain embodiments, pharmaceutical agents are administered as needed, once per day, twice per day, three times per day, or four or more times per day. It is recognized by those skilled in the art that the particular dose, frequency, and duration of administration depends on a number of factors, including, without limitation, the biological activity desired, the condition of the patient, and tolerance for the pharmaceutical agent. [0167] In certain embodiments, a pharmaceutical agent comprising a compound of the present invention is prepared for oral administration. In certain of sμch embodiments, a pharmaceutical agent is formulated by combining one or more compounds of the present invention with one or more pharmaceutically acceptable carriers. Certain of such carriers enable compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient. In certain embodiments, pharmaceutical agents for oral use are obtained by mixing one or more compounds of the present mvention and one or more solid excipient. Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). In certain embodiments, such a mixture is optionally ground and auxiliaries are optionally added. In certain embodiments, pharmaceutical agents are formed to obtain tablets or dragee cores. In certain embodiments, disintegrating agents (e.g., cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate) are added. [0168] In certain embodiments, dragee cores are provided with coatings. In certain of such embodiments, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to tablets or dragee coatings. [0169] In certain embodiments, pharmaceutical agents for oral administration are push-fit capsules made of gelatin. Certain of such push-fit capsules comprise one or more compounds of the present invention in admixture with one or more filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In certain embodiments, pharmaceutical agents for oral administration are soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In certain soft capsules, one or more compounds of the present invention are be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. [0170] In certain embodiments, pharmaceutical agents are prepared for buccal administration. Certain of such pharmaceutical agents are tablets or lozenges formulated in conventional manner. [0171] In certain embodiments, a pharmaceutical agent is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.). In certain of such embodiments, a pharmaceutical agent comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks 's solution, Ringer's solution, or physiological saline buffer. In certain embodiments, other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives). In certain embodiments, injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like. Certain pharmaceutical agents for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers. Certain pharmaceutical agents for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Certain solvents suitable for use in pharmaceutical agents for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, such suspensions may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. [0172] In certain embodiments, a pharmaceutical agent is prepared for transmucosal administration. In certain of such embodiments penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. [0173] In certain embodiments, a pharmaceutical agent is prepared for administration by inhalation. Certain of such pharmaceutical agents for inhalation are prepared in the form of an aerosol spray in a pressurized pack or a nebulizer. Certain of such pharmaceutical agents comprise a propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In certain embodiments using a pressurized aerosol, the dosage unit may be determined with a valve that delivers a metered amount. In certain embodiments, capsules and cartridges for use in an inhaler or insufflator may be formulated. Certain of such formulations comprise a powder mixture of a compound of the mvention and a suitable powder base such as lactose or starch. [0174] In certain embodiments, a pharmaceutical agent is prepared for rectal administration, such as a suppositories or retention enema. Certain of such pharmaceutical agents comprise known ingredients, such as cocoa butter and/or other glycerides. [0175] In certain embodiments, a pharmaceutical agent is prepared for topical admimstration. Certain of such pharmaceutical agents comprise bland moisturizing bases, such as ointments or creams. Exemplary suitable ointment bases include, but are not limited to, petrolatum, petrolatum plus volatile silicones, lanolin and water in oil emulsions such as Eucerin™, available from Beiersdorf (Cincinnati, Ohio). Exemplary suitable cream bases include, but are not limited to, Nivea™ Cream, available from Beiersdorf (Cincinnati, Ohio), cold cream (USP), Purpose Cream™, available from Johnson & Johnson (New Brunswick, New Jersey), hydrophilic ointment (USP) and Lubriderm™, available from Pfizer (Morris Plains, New Jersey). [0176] In certain embodiments, the formulation, route of administration and dosage for a pharmaceutical agent of the present invention can be chosen in view of a particular patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1). In certain embodiments, a pharmaceutical agent is administered as a single dose. In certain embodiments, a pharmaceutical agent is administered as a series of two or more doses administered over one or more days. [0177] In certain embodiments, a pharmaceutical agent of the present mvention is administered to a patient between about 0.1% and 500%, more preferably between about 25% and 75% of an established human dosage. Where no human dosage is established, a suitable human dosage may be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies. [0178] In certain embodiments, a daily dosage regimen for a patient comprises an oral dose of between 0.1 mg and 2000 mg of a compound of the present invention. In certain embodiments, a daily dosage regimen is administered as a single daily dose. In certain embodiments, a daily dosage regimen is administered as two, three, four, or more than four doses. [0179] In certain embodiments, a pharmaceutical agent of the present invention is administered by continuous intravenous infusion. In certain of such embodiments, from 0.1 mg to 500 mg of a composition of the present invention is administered per day. [0180] In certain embodiments, a pharmaceutical agent of the invention is administered for a period of continuous therapy. For example, a pharmaceutical agent of the present mvention may be administered over a period of days, weeks, months, or years. [0181] Dosage amount, interval between doses, and duration of treatment may be adjusted to achieve a desired effect. In certain embodiments, dosage amount and interval between doses are adjusted to maintain a desired concentration on compound in a patient. For example, in certain embodiments, dosage amount and interval between doses are adjusted to provide plasma concentration of a compound of the present invention at an amount sufficient to achieve a desired effect. In certain of such embodiments the plasma concentration is maintained above the minimal effective concentration (MEC). In certain embodiments, pharmaceutical agents of the present invention are administered with a dosage regimen designed to maintain a concentration above the MEC for 10-90% of the time, between 30-90%) of the time, or between 50-90% of the time. [0182] In certain embodiments in which a pharmaceutical agent is administered locally, the dosage regimen is adjusted to achieve a desired local concentration of a compound of the present mvention. [0183] In certain embodiments, a pharmaceutical agent may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. [0184] In certain embodiments, a pharmaceutical agent is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Certain Combination Therapies [0185] In certain embodiments, one or more pharmaceutical agents of the present mvention are co-administered with one or more other pharmaceutical agents. In certain embodiments, such one or more other pharmaceutical agents are designed to treat the same disease or condition as the one or more pharmaceutical agents of the present invention. In certain embodiments, such one or more other pharmaceutical agents are designed to treat a different disease or condition as the one or more pharmaceutical agents of the present invention. In certain embodiments, such one or more other pharmaceutical agents are designed to treat an undesired effect of one or more pharmaceutical agents of the present invention. In certain embodiments, one or more pharmaceutical agents of the present invention is co-administered with another pharmaceutical agent to treat an undesired effect of that other pharmaceutical agent. In certain embodiments, one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are administered at the same time. In certain embodiments, one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are administered at the different times. In certain embodiments, one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are prepared together in a single formulation. In certain embodiments, one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are prepared separately. [0186] Examples of pharmaceutical agents that may be co-administered with a pharmaceutical agent of the present invention include, but are not limited to, analgesics (e.g., acetaminophen); anti-inflammatory agents, including, but not limited to non- steroidal anti-inflammatory drugs (e.g., ibuprofen, COX-1 inhibitors, and COX-2, inhibitors); salicylates; antibiotics; antivirals; antifungal agents; antidiabetic agents (e.g., biguanides, glucosidase inhibitors, insulins, sulfonylureas, and thiazolidenediones); adrenergic modifiers; diuretics; hormones (e.g., anabolic steroids, androgen, estrogen, calcitonin, progestin, somatostatin, and thyroid hormones); immunomodulators; muscle relaxants; antihistamines; osteoporosis agents (e.g., biphosphonates, calcitonin, and estrogens); prostaglandins, antmeoplastic agents; psychotherapeutic agents; sedatives; poison oak or poison sumac products; antibodies; and vaccines. Certain Indications [0187] In certain embodiments, the invention provides methods of treating a patient comprising administering one or more compounds of the present invention. Compounds of the present invention, including, but not limited to, pharmaceutically acceptable salts, solvates and hydrates, are expected to be effective in treating diseases or conditions that are mediated by HNF-4α. Therefore, in certain embodiments, compounds of the invention are effective in treating conditions that are mediated by HNF-4α, including, but not limited to, syndrome X, non-insulin dependent diabetes mellitus, cancer, obesity, cardiovascular disease and dyslipidemia. In certain embodiments, a patient is treated prophylactically to reduce or prevent the occurrence of a condition. [0188] In certain embodiments, the present invention provides a method of lowering blood glucose levels in a mammal by administering to the patient a pharmaceutically effective amount of at least one compound of the present invention. In certain embodiments, the patient is a mammal. In certain embodiments, the patient is a human. [0189] In certain embodiments, the present invention provides a method of lowering plasma triglycerides levels in a patient by administering to the mammal a pharmaceutically effective amount of at least one compound of the present invention. In certain embodiments, the patient is a mammal. In certain embodiments, the patient is a human. [0190] In certain embodiments, the present mvention provides a method of increasing insulin levels in a patient by administering to the mammal a pharmaceutically effective amount of at least one compound of the present invention. In certain embodiments, the patient is a mammal. In certain embodiments, the patient is a human. EXAMPLES [0191] The following examples, including experiments and results achieved, are provided for illustrative purposes only and are not to be construed as limiting the present invention.
Example 1
Methyl 4-[5,6,7,8-tetτahydro-5,5,8,8-tetramethyl-3-hydroxy-2-naphthalenyl]benzoyl benzoate (Compound 101)
Figure imgf000092_0001
To a solution of 10.0 g (45.8 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3- methoxy-2-naphthalene and 11.0 g (54.2 mmol) of 4-methoxycarbonyl benzoyl chloride in 100 ml of dry 1,2-dichloroethane in a round-bottomed flask was added portionwise 22.0 g (165.0 mmol) of A1C13 at 0° C. The mixture is warmed-up to room temperature and heated to reflux for 4 hours. After cooling down to room temperature, the deep reddish mixture was carefully poured on ice. The organic layer was separated and the aqueous layer extracted twice with CH2C12. The organic layers were combined, dried over MgSO4, filtered and evaporated under reduced pressure. The crude adduct was recrystallized from EtOAc/Hexane (1/9) to afford 8.6 g (25.9 mmol, yield: 55%) of Methyl 4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-hydroxy-2-naphthalenyl]benzoyl benzoate as a bright yellow solid. *H NMR (500 MHz, CDC13) 11.5 (s, IH), 8.19 (d, J=8.5 Hz, 2H), 7.82 (d, J=8.5 Hz, 2H), 7.43 (s, IH), 7.01 (s, IH), 3.99 (s, 3H), 1.67 (m, 4H), 1.31 (s, 6H), 1.16 (s, 6H).
Example 2
Methyl 4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl]benzoyl benzoate (Compound 102)
Figure imgf000092_0002
To a solution of methyl 4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-hydroxy-2- naphthalenyl]benzoyl benzoate (0.9164 g, 2.5 mmol) in 20 mL of anhydrous DMF was sequentially treated withNaH (0.2 g, 5.0 mmol) and iodoethane (3.9 g, 25.0 mmol). The resulting mixture was heated to 60° C and stirred for 16 h. The reaction mixture was then quenched with 20 mL of water and extracted with ethyl acetate (150 mL). The ethyl acetate extract was washed with water (2 x 80 mL) and brine (80 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 3 x 20 cm, 10% ethyl acetate in hexane as eluant) to give 0.8270 g (84%, theo. 0.9865 g) of product as a white solid. !H NMR (500 MHz, CDC13) 8.08 (d, J=8.2 Hz, 2H), 7.82 (d, J=8.2 Hz, 2H), 7.43 (s, IH), 6.83 (s, IH), 3.95 (s, 3H), 3.89 (q, J=7.0 Hz, 2H), 1.71 (m, 4H), 1.32 (s, 6H), 1.27 (s, 6H), 0.98 (t, J=7.0 Hz, 3H).
Example 3
4-[5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2-naphthalenyl]benzoyl benzoic acid (Compound 103)
Figure imgf000093_0001
To a solution of methyl 4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl]benzoyl benzoate (0.8270 g, 2.1 mmol) in 30 mL of a 3/1/1 ratio mixture of THF/MeOH/H2O was treated with lithium hydroxide monohydrate (0.8796 g, 21.0 mmol). The resulting mixture was heated to reflux for 3 h. After TLC analysis indicating the completion of reaction. The mixture was acidified to pH=l with 3.0 M aqueous HCI solution and extracted with ether (150 mL). The ether extract was washed with water (2 x 100 mL) and brine (100 mL). The ether layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was further purified by recrystallization from a 9/1 ratio of hexane/ether mixture to provided desired 0.6191 g (78%, theo. 0.7976 g) of product as a white solid. !H NMR (500 MHz, DMSO-d6) 13.23(s, IH), 8.02(d, J=8.2 Hz, 2H), 7.72(d,J=8.2 Hz, 2H), 7.34(s, IH), 7.00(s, IH), 3.92(q, J=7.0 Hz, 2H), 1.65(m, 4H), 1.29(s, 6H), 1.22(s, 6H), 0.84(t, J=7.0 Hz, 3H).
Example 4
4-[5,6,7,8-tetrahydro-3, 5,5,8, 8-pentamethyl-l-hydroxy-2-naphthalenyl]benzoyl benzoic acid (Compound 104)
Figure imgf000094_0001
Compound 104 was synthesized from methyl-4-[5,6,7,8-tetrahydro-3, 5,5,8,8- pentamethyl-l-hydroxy-2-naphthalenyl]benzoyl benzoate according to the procedure described in Example 3 using 3-methylphenol as starting material. !H NMR (400 MHz, CDC13) δ: 11.5 (broad s, IH), 8.20 (d, J= 8.5 Hz, 2H), 7.89 (d, J= 8.5 Hz, IH), 6.81 (s, IH), 2.20 (s, 3H), 1.68 (m, 4H), 1.35 (s, 6H), 1.30 (s, 6H).
Example 5
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(l , 1 , 1 -trifluoroethoxy)-2- naphthalenyl]benzoyl benzoic acid (Compound 105)
Figure imgf000094_0002
Compound 105 was synthesized using the same synthetic procedure described in Example 3 with l-bromo-2,2,2-trifluoroethane as alkylating reagent. 1H NMR (500 MHz, DMSO-d6) 13.20(br. s, IH), 8.02(d, J=8.2 Hz, 2H), 7.73(d, J=8.2 Hz, 2H), 7.38(s, IH), 7.16(s, IH), 4.68(q, J=8.8 Hz, 2H), 1.66(m, 4H), 1.31(s, 6H), 1.22(s, 6H).
Example 6
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-propoxy-2-naphthalenyl]benzoyl benzoic acid (Compound 106)
Figure imgf000095_0001
Compound 106 was synthesized using the same synthetic procedure described in Example 3 with propyl iodide as alkylating reagent. 1H NMR (500 MHz, CHC13) 8.05 (d, J=8.3 Hz, 2H), 7.73 (d, J=8.3 Hz, 2H), 7.35 (s, IH), 7.03 (s, IH), 3.95 (q, J=7.0 Hz, 2H), 2.05 (m, 2H), 1.72 (m, 4H), 1.27 (s, 6H), 1.21 (s, 6H), 0.85 (t, J=7.0 Hz, 3H).
Example 7
Methyl 4-[5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-4-nitro-2-naphthalenyl]benzoyl benzoate (Compound 107)
Figure imgf000095_0002
To a solution of methyl 4-[5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2- naphthalenyl]benzoyl benzoate (17.42 g, 47.8 mmol) in 250 mL of glacial acetic acid and 20 mL of concentrated H2SO4 was added slowly through an additional funnel of 140 mL of 90% fuming HNO3. The resulting mixture was stirred at 23° C for 3 h. The reaction mixture was then poured onto 500 g of ice-water mixture. The product crushed out of ice- water solution was collected by filtration. The crude product was taken into 500 mL of EtOAc and washed with water (3 x 300 mL) and brine (300 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 10 x 25 cm, 10% ethyl acetate in hexane as eluant) to give 15.66 g (80%, theo. 19.57 g) of product as a white solid. 1H NMR (500 MHz, CDC13) 8.15 (d, J=8.5 Hz, 2H), 7.87 (d, J=8.5 Hz, 2H), 7.37 (s, IH), 3.97 (s, 3H), 2.12 (s, 3H), 1.75 (m, 4H), 1.38 (s, 6H), 1.25 (s, 6H).
Example 8
4-[5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-4-nitro-2-naphthalenyl]benzoyl benzoic acid (Compound 108)
Figure imgf000096_0001
Compound 108 was synthesized by saponification of methyl-4-[5,6,7,8-tetrahydro- 3,5,5,8,8-pentamethyl-4-nitro-2-naphthalenyl]benzoyl benzoate as described in Example 3. !H NMR (400 MHz, DMSO-d6) 10.10 (s, IH), 8.1 l(d, J=8.2 Hz, 2H), 7.83(d, J=8.2 Hz, 2H), 7.60(s, IH), 1.98(s, 3H), 1.65(m, 4H), 1.31(s, 6H), 1.24(s, 6H).
Example 9
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-4-nitro-2-naphthalenyl]benzoyl benzoic acid (Compound 109)
Figure imgf000096_0002
Compound 109 was synthesized according to the synthetic scheme described in Example 3. !H NMR (500 MHz, CDC13) 8.11 (d, J= 8.55, 2H), 7.86 (d, J= 8.85, 2H), 7.68 (s, IH), 3.67 (q, J= 6.7, 13.7, 2H), 1.71 (m, 4H), 1.31 (s, 6H), 1.27 (s, 6H), 0.85 (t, J= 7.0, 3H). Example 10
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(2,2-difluoroethoxy)-4-nitro-2- naphthalenyljbenzoyl benzoic acid (Compound 110)
Figure imgf000097_0001
Compound 110 was synthesized according to the synthetic scheme described in Example 3. Η NMR (500 MHz, CDC13) 8.11 (d, J= 8.2, 2H), 7.87 (d, J= 8.2, 2H), 7.69 (s, IH), 5.95 (m, IH), 4.00 (m, 2H), 1.71 (m, 4H), 1.31 (s, 6H), 1.26 (s, 6H).
Example 11
Methyl 4-[5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-4-amino-2- naphthalenyl]hydroxymethyl benzoate (Compound 111)
Figure imgf000097_0002
To a solution of methyl 4-[5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-4-amino-2- naphthalenyljbenzoyl benzoate (0.3016 g, 0.8 mmol) in 20 mL of a 1:1 ratio mixture of CH2Cl2/MeOH was treated with NaBILt (90.2 mg, 2.38 mmol) in one portion. The resulting mixture was stirred at 0° C for 30 min. The reaction mixture was quenched with 40 mL of water and extracted with EtOAc (100 mL). The extract was washed with water (3 x 50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 3 x 20 cm, 25%o ethyl acetate in hexane as eluant) to give product 0.25 g (82%, theo. 0.3031 g) as a white solid. 1H NMR (500 MHz, CDC13) 8.01 (d, J=8.5 Hz, 2H), 7.44 (d, J=8.5 Hz, 2H), 6.76 (s, IH), 6.02 (d, J=4.0 Hz, IH), 3.91 (s, 3H), 3.86 (s, 2H), 2.16 (d, J=4.0 Hz, IH), 2.03 (s, 3H), 1.72 (m, 2H), 1.61 (m, 2H), 1.45 (s, 3H), 1.44 (s, 3H), 1.24 (s, 3H), 1.17 (s, 3H).
Example 12
Methyl 4-[5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-4-amino-2-naphthalenyl]methyl benzoate (Compound 112)
Figure imgf000098_0001
To a solution of methyl 4-[5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-4-amino-2- naphthalenyl]hydroxymethyl benzoate (0.2496 g, 0.65 mmol) in 20 mL of a 9:1 ratio mixture of EtOH/AcOH was treated with 10%> palladium on carbon (50 mg). The resulting black suspension was stirred under hydrogen atmosphere (balloon pressure) at 23° C for 24 h. The catalyst was removed by filtering through a pad of celite and the celite cake was further rinsed with MeOH (80 mL) and CH2C12 (80 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 3 x 20 cm, 20% ethyl acetate in hexane as eluant) to give 0.1913 g (80%, theo. 0.2391 g) of product as a white solid. !H NMR (500 MHz, CDC13) 7.94 (d, J=8.5 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 6.61 (s, IH), 4.00 (s, 2H), 3.90 (s, 3H), 3.82 (s, 2H), 1.96 (s, 3H), 1.72 (m, 2H), 1.62 (m, 2H), 1.46 (s, 6H), 1.24 (s, 6H).
Example 13
Methyl 4-[5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-4-ethylamino-2-naphthalenyl]methyl benzoate (Compound 113)
Figure imgf000099_0001
To a solution of methyl 4-[5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-4-amino-2- naphthalenyl]methyl benzoate (0.2170 g, 0.6 mmol) in 15 mL of CH2C12 was sequentially treated with acetaldehyde (0.33 mL, 5.9 mmol), 10 drops of AcOH and NaCNBH3 (0.3709 g, 5.9 mmol). The resulting mixture was stirred at 0° C and allowed to slowly warm to 23° C and stirred for additional 16 h. The reaction mixture was quenched with 20 mL of water and extracted with EtOAc (100 mL). The extract was washed with water (3 x 50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 3 x 20 cm, 10% ethyl acetate in hexane as eluant) to give 0.2175 g (93%, theo. 0.2337 g) of product as a white solid. 1H NMR (500 MHz, CDC13) 7.95 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 6.76 (s, IH), 3.98 (s, 2H), 3.91 (s, 3H), 3.30 (s, IH), 2.85 (q, J=7.3 Hz, 2H), 2.11 (s, 3H), 1.71 (m, 2H), 1.62 (m, 2H), 1.44 (s, 6H), 1.23 (t, J=7.3 Hz, 3H), 1.22 (s, 6H). Example 14
Methyl 4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-hydroxy-2- naphthalenyl]hydroxymethyl benzoate (Compound 114)
Figure imgf000100_0001
To a solution of methyl 4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-hydroxy-2- naphthalenyl]benzoyl benzoate (2.4424 g, 6.7 mmol) in 100 mL of a 1:1 ratio mixture of CH2Cl2/MeOH was treated with NaBH4 (1.0086 g, 26.7 mmol) in one portion. The resulting mixture was stirred at 0° C for 30 min. The reaction mixture was quenched with 150 mL of saturated aqueous ammonium chloride solution and extracted with EtOAc (300 mL). The extract was washed with water (2 x 150 mL) and brine (150 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 5 x 20 cm, 25% ethyl acetate in hexane as eluant) to give 2.46 g (100%, theo. 2.4558 g) of product as a white solid. lΗ. NMR (500 MHz, CDC13) 8.03 (d, J=8.2 Hz, 2H), 7.48 (d, J=8.2 Hz, 2H), 7.09 (s, IH), 6.83 (s, IH), 6.81 (s, IH), 6.00 (d, J=3.7 Hz, IH), 3.91 (s, 3H), 3.03 (d, J=3.7 Hz, IH), 1.64 (m, 4H), 1.25 (s, 3H), 1.24 (s, 3H), 1.18 (s, 3H), 1.15 (s, 3H).
Example 15
Methyl 4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-hydroxy-2-naphthalenyl]methyl benzoate (Compound 115)
Figure imgf000100_0002
To a solution of methyl 4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-hydroxy-2- naphthalenyl]hydroxymethyl benzoate (2.46 g, 6.7 mmol) in 150 mL of a 9:1 ratio mixture of EtOH/AcOH was treated with 10% palladium on carbon (500 mg). The resulting black suspension was stirred under hydrogen atmosphere (balloon pressure) at 23° C for 16 h. The catalyst was removed by filtering through a pad of celite and the celite cake was further rinsed with MeOH (100 mL) and CH2C12 (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 5 x 20 cm, 10% ethyl acetate in hexane as eluant) to give 2.2259 g (95%, theo. 2.3492 g) of product as a white solid. !H NMR (500 MHz, CDC13) 7.96 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.2 Hz, 2H), 7.01 (s, IH), 6.69 (s, IH), 4.61 (s, IH), 3.99 (s, 2H), 3.90 (s, 3H), 1.65 (m, 4H), 1.24 (s, 6H), 1.21 (s, 6H).
Example 16
Methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methoxy-2- naρhthalenyl)methyl]benzoate (Compound 116)
Figure imgf000101_0001
To a solution of methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-hydroxy-2- naphthalenyl)methyl] benzoate (0.1987 g, 0.56 mmol) in 10 mL of anhydrous DMF was sequentially treated withNaH (45 mg, 1.1 mmol) and iodomethane (0.24 g, 1.7 mmol).
The resulting mixture was stirred at 23° C for 2 h. The reaction mixture was then quenched with 30 mL of water and extracted with ethyl acetate (150 mL). The ethyl acetate extract was washed with water (2 x 80 mL) and brine (80 mL). The organic layer was dried over MgSO , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 3 x 20 cm, 2 to 5% ethyl acetate in hexane as gradient eluant) to give 0.1805 g (87%, theo. 0.2066 g) of product as a white solid. *H NMR (500 MHz, CDC13) 7.94 (d, J=8.24 Hz, 2H), 7.29 (d, J=8.2 Hz, 2H), 6.98 (s, IH), 6.75 (s, IH), 3.96 (s, 2H), 3.90 (s, 3H), 3.77 (s, 3H), 1.66 (m, 4H), 1.29 (s, 6H), 1.20 (s, 6H).
Example 17
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methoxy-2-naphthalenyl)methyl]benzoic acid (Compound 117)
Figure imgf000102_0001
Compound 117 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-methoxy-2-naphthalenyl)methyl]benzoate according to the procedure described for Example 3 using iodomethane as alkylating reagent. !H NMR (500 MHz, DMSO-d6) 12.74(s, IH), 7.81(d, J=8.24 Hz, 2H), 7.29(d, J=8.2 Hz, 2H), 7.08(s, IH), 6.79(s, IH), 3.87(s, 2H), 3.71(s, 3H), 1.58(m, 4H), 1.22(s, 6H), 1.15(s, 6H).
Example 18
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3- >SO-propoxy-2-naphthalenyl)methyl]benzoic acid (Compound 118)
Figure imgf000102_0002
Compound 116 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-
3- iso-propoxy -2-naphthalenyl)methyl]benzoate according to the procedure described in
Example 3 using 2-iodopropane as alkylating reagent. !H NMR (500 MHz, DMSO-d6)
12.74(s, IH), 7.81(d, J=8.2 Hz, 2H), 7.31(d, J=8.2 Hz, 2H), 7.12(s, IH), 6.75(s, IH), 4.54(heptet, J=6.1 Hz, 2H), 3.84(s, 2H), 1.58(m, 4H), 1.19(s, 6H), 1.17(s, 6H), 1.15(d, J=6.1 Hz, 6H).
Example 19
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl)methyl]benzoic acid (Compound 119)
Figure imgf000103_0001
Compound 119 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3- ethoxy-2-naphthalenyl)methyl]benzoate according to the procedure described in Example 3 using iodoethane as alkylating reagent. 1H NMR (500 MHz, DMSO-d6) 12.74(s, IH), 7.81(d, J=8.2 Hz, 2H), 7.31(d, J=8.2 Hz, 2H), 7.11(s, IH), 6.75(s, IH), 3.94(q, J=7.0 Hz, 2H), 3.86(s, 2H), 1.58(m, 4H), 1.25(t, J=7.0 Hz, 3H), 1.20(s, 6H), 1.16(s, 6H).
Example 20
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(l ,1,1 -trifuoroethoxy)-2- naphthalenyl)methyl]benzoic acid (Compound 120)
Figure imgf000103_0002
Compound 120 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-
3-(l,l,l-trifluoroethoxy)-2-naphthalenyl)methyl]benzoate according to the procedure described in Example 3 using l-bromo-2,2,2-trifluoroethane as alkylating reagent. !H
NMR (500 MHz, DMSO-d6) 12.75(s, IH), 7.80(d, J=8.2 Hz, 2H), 7.30(d, J=8.2 Hz, 2H), 7.20(s, IH), 6.90(s, IH), 4.68(q, J=8.8 Hz, 2H), 3.89(s, 2H), 1.58(m, 4H), 1.22(s, 6H), 1.17(s, 6H).
Example 21
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-propoxy-2-naphthalenyl)methyl]benzoic acid (Compound 121)
Figure imgf000104_0001
Compound 121 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-propoxy-2-naphthalenyl)methyl]benzoate according to the procedure described in Example 3 using 1-iodopropane as alkylating reagent. !H NMR (500 MHz, DMSO-d6) 12.74(s, IH), 7.81(d, J=8.2 Hz, 2H), 7.30(d, J=8.2 Hz, 2H), 7.12(s, IH), 6.75(s, IH), 3.87(s, 2H), 3.84(t, J=6.2 Hz, 2H), 1.66(m, 2H), 1.58(m, 4H), 1.20(s, 6H), 1.16(s, 6H), 0.90(t, J=7.3 Hz, 3H).
Example 22
4-[(5,6,7,8-tetrahydro-5,5,8,8-texramethyl-3-butoxy-2-naphthalenyl)methyl]benzoic acid (Compound 122)
Figure imgf000104_0002
Compound 122 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-butoxy-2-naphthalenyl)methyl]benzoate according to the procedure described in Example 3. H NMR (500 MHz, DMSO-d6) 12.74(s, IH), 7.81(d, J=8.2 Hz, 2H), 7.29(d, J=8.2 Hz, 2H), 7.12(s, IH), 6.75(s, IH), 3.87(t, J=6.2 Hz, 2H), 3.86(s, 2H), 1.64- 1.56(m, 6H), 1.33(m, 2H), 1.20(s, 6H), 1.16(s, 6H), 0.87(t, J=7.3 Hz, 3H).
Example 23
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-heptoxy-2-naphthalenyl)methyl]benzoic acid (Compound 123)
Figure imgf000105_0001
Compound 123 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-heptyloxy-2-naphthalenyl)methyl]benzoate according to the procedure described in Example 3. *HNMR (500 MHz, DMSO-d6) 12.73(br. s, IH), 7.80(d, J=8.2 Hz, 2H), 7.27(d, J=8.2 Hz, 2H), 7.13(s, IH), 6.74(s, IH), 3.86(m, 4H), 1.62-1.56(m, 6H), 1.26- 1.13(m, 8H), 1.20(s, 6H), 1.17(s, 6H), 0.84(t, J=7.0 Hz, 3H).
Example 24
4-[(5,6,7,8-tetrahydro-3, 5,5,8, 8-pentamethyl-4- -toluenesulfonylamido-2- naphthalenyl)methyl]benzoic acid (Compound 124)
Figure imgf000105_0002
Compound 124 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3, 5,5,8,8- pentamethyl-4-amino-2-naphthalenyl)methyl]benzoate according to the procedure described in Example 3 using -toluenesulfonylchloride as reagent. !H NMR (500 MHz, DMSO-d6) 12.82(s, IH), 9.09(s, IH), 7.85(d, J=8.2 Hz, 2H), 7.52(d, J=8.2 Hz, 2H), 7.19(d, J=8.2 Hz, 2H), 7.17(s, 1H), 7.14(d, J=8.2 Hz, 2H), 3.87(s, 2H), 2.30(s, 3H), 1.59- 1.48(m, 4H), 1.42(s, 3H), 1.33(s, 6H), 1.20(s, 6H).
Example 25
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methyl-4-ethylamino-2- naphthalenyl)methyl]benzoic acid (Compound 125)
Figure imgf000106_0001
Compound 123 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-4-amino-2-naphthalenyl)methyl]benzoate according to the procedure described in Example 3 using iodoethane as alkylating reagent. H NMR (500 MHz, DMSO-de) 12.78(br. s, IH), 7.84(d, J=8.2 Hz, 2H), 7.23(d, J=8.2 Hz, 2H), 6.82(s, IH), 3.93(s, 2H), 2.69(q, J=7.0 Hz, 2H), 2.02(s, 3H), 1.63-1.51(m, 4H), 1.35(s, 6H), 1.16(s, 6H), 1.13(t, J=7.0 Hz, 3H).
Example 26
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methyl-4-propylamino-2- naphthalenyl)methyl]benzoic acid (Compound 126)
Figure imgf000106_0002
Compound 126 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-4-amino-2-naphthalenyl)methyl]benzoate according to the procedure described in Example 3 using iodopropane as alkylating reagent. *H NMR (500 MHz, DMSO-d6) 12.76(br. s, IH), 7.84(d, J=8.2 Hz, 2H), 7.23(d, J=8.2 Hz, 2H), 6.82(s, IH), 3.93(s, 2H), 2.64(t,J=7.3 Hz, 2H), 2.02(s, 3H), 1.63-1.52(m, 6H), 1.35(s, 6H), 1.17(s, 6H), 0.93(t, J=7.3 Hz, 3H).
Derivatives with an aromatic group an amine functionality in the 3-position may be synthesized using the following procedures:
Scheme 5
Figure imgf000107_0001
Reagent and conditions: a) ArB(OH)2, Pd(PPh3)4, toluene, ethanol, aq.2N Na2CO3, reflux, b) LiOH, THF/MeOH,room temp, c) HNO3, H2SO4, AcOH, 0° C toroom temp, d) BINAP, Pd2dba3, amine, CsF, toluene, reflux.
Example 27
Ethyl 4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(2-fluorobenzene)-2- naphthalenyfjbenzoyl benzoate (Compound 127)
Figure imgf000108_0001
In a two neck round bottomed flask containing a magnetic stir bar and equipped with a reflux condenser was introduced 429 mg (1.00 mmol) of ester A (Boehm and Al, J. Med. Chem., 1994, 37, 2930-2941), 208 mg (1.5 mmol, 1.5 equivalent) of 2-fluorobenzene boronic acid, 116 mg (0.10 mmol, 10 %/substrate) of tetrakistriphenylphosphine palladium (Pd(PPh3)4) followed by 5 ml of toluene, 5 ml of absolute EtOH and 1.0 ml of 2N aqueous Na2CO3 solution. The mixture was flushed with nitrogen and stirred at reflux overnight and then cooled to room temperature. Water was added and the solution was extracted with EtOAc (3 times). The organic layers were collected, washed with brine and dried over MgSO4. After filtration and removal of the solvents, the crude ester was purified over silica gel column chromatography (eluent: 90/10 hexane/EtOAc) to afford 275 mg (0.6 mmol, yield: 60%) of the desired ethyl ester (compound 127). !H NMR (400 MHz, CDC13) δ 8.00 (d, J= 8.5 Hz, 2H), 7.78 (d, J= 8.5 Hz, 2H), 7.47 (s, IH), 7.38 (s, IH), 7.27 (td, J= 6.5, 2.0 Hz, IH), 7.17 (m, IH), 7.07 (td, J= 7.5, 1.0 Hz, IH), 6.88 (t, J= 9.5 Hz, IH), 4.39 (dd, J= 14.3, 7.2 Hz, 2H), 1.75 (s, 4H), 1.41 (t, J= 7.0 Hz, 3H), 1.36 (s, 6H), 1.30 (s, 6H). Example 28
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(2-fluorobenzene)-2-naphthalenyl]benzoyl benzoic acid (Compound 128)
Figure imgf000109_0001
In a round-bottomed flask was added 270 mg (0.588 mmol) of ethyl 4-[5,6,7,8- tetrahydro-5,5,8,8-tetramethyl-3-(2-fluorobenzene)-2-naphthalenyl]benzoyl benzoate followed by 5 ml of THF, % ml of MeOH and 2 ml of 2N aqueous LiOH. The solution was stirred at room temperature until complexion and the solvents were removed under reduced pressure. The crude pasty mixture was acidified with 2N aqueous HCI (5 ml) and extracted twice with EtOAc. The organic layer was dried over MgSO4, filtrated and concentrated. The crude acid was recrystallized from CH3CN, to afford 190 mg (0.441 mmol, yield: 75%>) of 4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(2-fluorobenzene)-2- naphthalenyfjbenzoyl benzoic acid (Compound 128) as a white solid. 1H NMR (400 MHz, CDC13) δ 8.03 (d, J= 8.0 Hz, 2H), 7.80 (d, J= 8.0 Hz, 2H), 7.49 (s, IH), 7.38 (s, IH), 7.23 (m, IH), 7.187 (m, IH), 7.07 (td, J= 7.5, 1.0 Hz, IH), 6.88 (t, J= 8.5 Hz, IH), 1.76 (s, 4H), 1.36 (s, 6H), 1.31 (s, 6H).
Example 29
4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-benzene-2-naphthalenyl)benzoyl benzoic acid (Compound 129)
Figure imgf000110_0001
Compound 129 was synthesized from A according to the procedure described in Example 28 using phenyl boronic acid as coupling reagent. H NMR (400 MHz, CDC13) δ: 7.95 (d, J= 8.0 Hz, 2H), 7.71 (d, J= 8.0 Hz, 2H), 7.50 (s, IH), 7.39 (s, IH), 7.09 (m, 4H), 7.05 (m, IH), 5.87 (s, IH), 1.77 (m, 4H), 1.37 (s, 6H), 1.34 (s, 3H).
Example 30
4-[5 ,6,7, 8-tetrahydro-5, 5 ,8,8 -tetramethyl-3 -(3 -thienyl)-2-naphthalenyl]benzoyl benzoic acid (Compound 130)
Figure imgf000110_0002
Compound 130 was synthesized from A according to the procedure described in Example 28 using 2-thiophen boronic acid as coupling reagent. lR NMR (400 MHz, CDC13) δ: 7.98 (d, J= 8.5 Hz, 2H), 7.72 (d, J= 8.5 Hz, 2H), 7.46 (s, IH), 7.42 (s, IH), 7.11 (dd, J= 5.0, 3.0 Hz, IH), 7.03 (dd, J= 3.0, 1.5 Hz, IH), 6.94 (dd, J= 5.0, 1.5 Hz, IH), 1.76 (m, 4H), 1.37 (s, 6H), 1.33 (s, 3H). /017185
Example 31
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(4-fluorobenzene)-2-naphthalenyl]benzoyl benzoic acid (Compound 131)
Figure imgf000111_0001
Compound 131 was synthesized from A according to the procedure described in Example 28 using 4-fluorophenyl boronic acid as coupling reagent. !H NMR (400 MHz, CDC13) δ: 7.98 (d, J= 8.4 Hz, 2H), 7.71 (d, J= 8.4 Hz, 2H), 7.48 (s, IH), 7.34 (s, IH), 7.16 (d, J= 8.5 Hz, IH), 7.15 (d, J= 8.5 Hz, IH), 6.88 (d, J= 8.5 Hz, IH), 6.86 (d, J= 8.5 Hz, IH), 1.76 (m, 4H), 1.37 (s, 6H), 1.32 (s, 3H).
Example 32 4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(3-nitrobenzene)-2-naphthalenyl]benzoyl benzoic acid (Compound 132)
Figure imgf000111_0002
Example 32 was synthesized from A according to the procedure described in Example 28 using 3-nitrophenyl boronic acid as coupling reagent. ]H NMR (400 MHz, CDC13) δ: 8.11 (t, J= 2.0 Hz, IH), 8.03 (d, J= 8.0 Hz, 2H), 8.02 (m, IH), 7.77 (d, J= 8.0 Hz, 2H), 7.53 (s, IH), 7.51 (m, IH), 7.39 (d, J= 8.0 Hz, IH), 7.37 (d, J= 8.0 Hz, IH), 1.78 (m, 4H), 1.39 (s, 6H), 1.33 (s, 6H).
Example 33
Methyl 4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(NN-methyl ethyl)-2-naphthalenyl] benzoyl benzoate (Compound 133)
Figure imgf000112_0001
In a pressure tube equipped with a magnetic bar was introduced successively 107 mg (0.249 mmol) of A, 25 mg (0.027 mmol) of Pd2dba3, 36 mg (0.058 mmol) of BIΝAP, 2.5 ml of dry toluene and 243 mg (0.746 mmol) of Cs2CO3. The tube was flushed with nitrogen, sealed and heated to 100° C overnight. After cooling to room temperature, water was added and the mixture was extracted with EtOAc. The organic layers were collected, washed with water and brine, dried over MgSO4 and filtrated. After removal of the solvents, the crude oil was purified over silica gel column chromatography top afford 65 mg (0.159 mmol, yield: 64 %) of methyl 4-[5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-3-(ΝΝ-methyl ethyl)-2-naphthalenyl] benzoyl benzoate as a pale yellow oil. Η NMR (400 MHz, CDC13) δ: 8.05 (d, J= 8.3 Hz, 2H), 7.83 (d, J= 8.3 Hz, 2H), 7.31 (s, IH), 6.93 (s, IH), 3.94 (s, 3H), 2.86 (dd, J= 14.1, 7.0 Hz, 2H), 2.51 (s, 3H), 1.69 (m 4H), 1.32 (s, 6H), 1.24 (s, 6H), 0.81 (t, J= 6.9 Hz, 3H).
I l l Example 34
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(NN-methyl ethyl)-2-naphthalenyl] benzoyl benzoic acid (Compound 134)
Figure imgf000113_0001
Saponification of 50 mg (0.123 mmol) of the ester x in the presence of 2 ml of THF, 2 ml of MeOH and 1 ml of 2Ν aqueous LiOH followed by acidic work-up and recrystallization from CH3CN afford 25 mg (0.065 mmol, yield: 51 %) of the desired acid as a pale yellow solid. !H NMR (400 MHz, CDC13) δ: 8.21 (s, IH), 8.09 (d, J= 7.8 Hz, 2H), 7.85 (d, J= 7.8 Hz, 2H), 7.39 (s, IH), 3.82 (m, 23H), 3.34 (s, 3H), 1.72 (m 4H), 1.38 (s, 6H), 1.32 (m, 3H), 1.20 (s, 6H).
Example 35
Methyl-4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(2-fluorobenzene)-2- naphthalenyl]benzoyl benzoate (Compound 135)
Figure imgf000113_0002
Compound 135 was synthesized according to the procedure used in the synthesis of
Example 8. !H NMR (400 MHz, CDC13) δ: 8.04 (d, J= 8.1Hz, 2H), 7.70 (d, J= 8.1 Hz, 2H), 7.55 (s, IH), 7.24 (m, IH), 7.14 (t, J= 7.4 Hz, IH), 7.02 (t, J= 7.4 Hz, IH), 6.86 (t, J= 7.4 Hz, IH), 4.39 (dd/= 14.4, 7.2 Hz, 2H), 1.72 (m 4H), 1.42 (s, 6H), 1.34 (s, 6H), 1.31 (t, J= 7.2 Hz, 3H).
Example 36
Methyl-4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(2-fluorobenzene)-2- naphthalenyljbenzoyl benzoic acid (Compound 136)
Figure imgf000114_0001
Compound 136 was synthesized from Methyl-4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-(2-fluorobenzene)-2-naphthalenyl]benzoyl benzoate according to the nitration procedure used in the synthesis of Example 8 and the saponification procedure used in Example 3. JH NMR (400 MHz, CDC13) δ: 8.08 (d, J= 8.5 Hz, 2H), 7.72 (d, J= 8.5 Hz, 2H), 7.58 (s, IH), 7.23 (m, IH), 7.14 (t, J= 9.5 Hz, IH), 7.03 (t, J= 8.0 Hz, IH), 6.86 (t, J= 9.5 Hz, IH), 1.82 (m 4H), 1.43 (s, 3H), 1.40 (s, 3H), 1.36 (s, 3H), 1.34 (s, 3H).
Example 37
4-[5,6,7,8-tetrahydro-3, 8, 8-tetramethyl-4-nitro-2-naphthalenyl]benzoyl benzoic acid (Compound 137)
Figure imgf000114_0002
Compound 137 was synthesized from Methyl-4-[5,6,7,8-tetrahydro-3,5,5-tetramethyl-2- naphthalenyl]benzoyl benzoate according to the nitration procedure used in the synthesis in Example 8 and the saponification procedure used in Example 3. !H NMR (400 MHz, CDC13) δ: 8.22 (d, J= 8.2 Hz, 2H), 7.89 (d, J= 8.2 Hz, IH), 7.39 (s, IH), 2.69 (t, J= 6.7 Hz, 2H), 2.19 (s, 3H), 1.83 (m, 2H), 1.75 (m, 2H), 1.26 (s, 6H).
Introduction of substitutions in position 6 of structure 1 may be used using the following scheme:
Scheme 6
Figure imgf000115_0001
Figure imgf000115_0002
R = Et, example:
Example 38
(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-hydroxy-6-fluoro)-naphthalene (Compound 138)
Figure imgf000116_0001
To a mixture of 2.7 g (2.2 ml, 24 mmol) of 3-fluorophenol and 5.29 g (29 mmol) of 2,5- dichloro-2,5-dimethylhexane in 100 ml of dry CH2C12 was added carefully 3.8 g (28.8 mmol) of A1C13 portionwise at 0° C. The mixture was stirred until complexion (TLC monitored) and poured into ice. After extraction with CH C12, the organic layers were collected and washed with water and brine, then dried over MgSO . After filtration, the precipitate was purified over silica gel column chromatography top afford 2.9 g (13.0 mmol, yield: 54 %) of [5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-hydroxy-6- fluoro]naphthalene as a white solid. 1H NMR (500 MHz, CDC13) δ: 6.58 (dd, J= 2.7, 0.9 Hz, IH), 6.35 (dd, J= 13.4, 2.7 Hz, IH), 4.58 (broad s, IH), 1.66 (m, 4H), 1.34 (s, 3H), 1.33 (s, 3H), 1.25 (s, 6H).
Example 39
(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methoxy-l-fluoro)-naphthalene (Compound 139)
Figure imgf000116_0002
A mixture of 2.88 g (12.9 mmol) of (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-hydroxy-6- fluoro)-naρhthalene, 1.1 ml (2.2 g, 15.5 mmol) of CH3I and 6.3 g (19.0 mmol) of Cs2CO3 in 10 ml of dry DMF was stirred overnight at room temperature. 50 ml of a 95/5 mixture of hexane/EtOAc was added and the suspension was filtrated over a silica gel plug. The plug was washed 2 times and the solvent were removed under reduced pressure to afford the desired (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methoxy-6-fluoro)-naphthalene directly used in the next step. 1H NMR (500 MHz, CDC13) δ: 6.68 (dd, J= 2.6, 0.9 Hz, IH), 6.41 (dd, J= 13.2, 2.6 Hz, IH), 3.76 (s, 3H), 1.67 (m, 4H), 1.35 (s, 3H), 1.34 (s, 3H), 1.27 (s, 6H).
Example 40
Methyl-4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-hydroxy-6-fluoro-2- naphthalenyfjbenzoyl benzoate (Compound 140)
Figure imgf000117_0001
To a mixture of 700 mg (2.9 mmol) of (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3- methoxy-6-fluoro)-naphthalene, 600 mg (2.9 mmol) of methyl-4-chlorocarbonylbenzoate in 10 ml of dry 1,2-dichloroethane was added slowly 1.5 g (11.6 mmol) of A1C13. The mixture was stirred at reflux until complexion (TLC monitored) and poured into ice.
After work-up the organic layers were dried over MgSO4, filtrated and concentrated under reduced pressure. The crude oil was purified over silica gel column chromatography (eluent: 90/10 hexane/EtOAc) to afford 330 mg (0.86 mmol, yield: 30
%) ofmethyl-4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-hydroxy-6-fluoro-2- naphthalenyTJbenzoyl benzoate as a yellow pasty oil. ]H NMR (500 MHz, CDC13) δ: 10.75 (s, IH), 8.13 (d, J= 8.5 Hz, 2H), 7.72 (d, J= 8.5 Hz, 2H), 6.86 (d, J= 1.2 Hz, IH), 3.96 (s, 3H), 1.66 (m, 4H), 1.31 (s, 6H), 1.27 (s, 3H), 1.26 (s, 3H).
Example 41
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-6-fluoro-2-naphthalenyl]benzoyl benzoic acid (Compound 141)
Figure imgf000118_0001
Compound 141 was synthesized from methyl-4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-hydroxy-6-fluoro-2-naphthalenyl]benzoyl benzoate according to the procedure described in Example 3 using iodoethane as alkylating reagent. ]H NMR (400 MHz, CDC13) δ: 8.18 (d, J= 8.3 Hz, 2H), 7.94 (d, J= 8.3 Hz, IH), 6.69 (s, IH), 3.96 (dd, J= 13.9, 7.0 Hz, 2H), 1.67 (m, 4H), 1.33 (s, 6H), 1.31 (s, 6H), 1.13 (t, J= 7.0 Hz, 3H).
Example 42
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-4-nitro-6-fluoro-2- naphthalenyl]benzoyl benzoic acid (Compound 142)
Figure imgf000118_0002
Compound 142 was sjτιthesized frommethyl-4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-hydroxy-6-fluoro-2-naphthalenyl]benzoyl benzoate according to the nitration procedure described in Example 1 and the saponification procedure described in Example 3. 1H NMR (400 MHz, CDC13) δ: 8.23 (d, J= 8.4 Hz, 2H), 7.95 (d, J= 8.4 Hz, IH), 3.87 (dd, J= 14.0, 7.0 Hz, 2H), 1.75 (m, 2H), 1.69 (m, 2H), 1.38 (s, 6H), 1.36 (s, 3H), 1.35 (s, 3H), 1.08 (t, J= 7.1 Hz, 3H).
Introduction of substituents in the R position of compounds of structure I may be used according to the following scheme:
Scheme 7
SOCI2
Figure imgf000119_0001
Figure imgf000119_0002
Figure imgf000119_0003
R = Me, Example R = Et, Example methyl-3-chloro-4-chlorocarbonylbenzoate B.
Figure imgf000119_0004
To a solution of 5.1 g (23.7 mmol) 3-chloro-4-methylcarbonylbenzoic acid in 20 ml of toluene, was added 10 ml of thionyl chloride and 0.5 ml of DMF. The mixture was stirred at reflux for 3 hours and cooled down to room temperature. The solvents and excess of thionyl chloride were removed under reduced pressure and the crude acyl chloride recrystallized from hexane to afford 5.1 g (21.8 mmol, yield: 92 %) of methyl-3- chloro-4-chlorocarbonylbenzoate B as a white crystal.
Example 43
Methyl 3-chloro-4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-hydroxy-2- naphthalenyfjbenzoyl benzoate (Compound 143)
Figure imgf000120_0001
To a solution of 1.90 g (25.8 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3- methoxy-2-naphthalene and 1.93 g (54.2 mmol) of 3-chloro-4-methoxycarbonyl benzoyl chloride in 50 ml of dry 1,2-dichloroethane in a round-bottomed flask was added portionwise 3.4 g (25.8 mmol) of A1C13 at 0° C. The mixture is warmed-up to room temperature and heated to reflux for 4 hours. After cooling down to room temperature, the deep reddish mixture was carefully poured on ice. The organic layer was separated and the aqueous layer extracted twice with CH2C12. The organic layers were combined, dried over MgSO4, filtered and evaporated under reduced pressure. The crude adduct was purified over silica gel column chromatography (eluent: EtOAc/Hexane, 1/9) to afford 2.6 g (7.2.9 mmol, yield: 925%) of methyl 3-chloro-4-[5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-3-hydroxy-2-naphthalenyl]benzoyl benzoate as a white solid. Η NMR (400 MHz, CDC13) δ: 11.42 (s, IH), 8.18 (s, IH), 8.06 (d, J= 7.9 Hz, 2H), 7.43 (d, J= 7.9 Hz, 2H), 7.09 (s, IH), 6.99 (s, IH), 3.98 (s, 3H), 1.78 (m 4H), 1.29 (s, 6H), 1.07 (s, 6H). Example 44
3-chloro-4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl]benzoyl benzoic acid (Compound 144)
Figure imgf000121_0001
Compound 144 was synthesized from methyl 3-chloro-4-[5,6,7,8-tetrahydro-5, 5,8,8- tetramethyl-3-hydroxy-2-naphthalenyl]benzoyl benzoate according to the procedure described in Example 3 using iodoethane as alkylating reagent. H NMR (400 MHz, CDC13) δ: 8.12 (broad s, IH), 8.00 (broad d, J= 8.0 Hz, IH), 7.91 (s, IH), 7.39 (d, J= 8.0 Hz, IH), 6.74 (s, IH), 7.11 (s, IH), 3.79 (dd, J= 14.0, 7.0 Hz, IH), 1.70 (m, 4H), 1.31 (s, 6H), 1.29 (s, 6H), 0.82 (t, J= 7.0 Hz, 3H).
Example 45
3-chloro-4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methoxy-2-naphthalenyl]benzoyl benzoic acid (Compound 145)
Figure imgf000121_0002
Example 45 was synthesized from methyl 3-chloro-4-[5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-3-hydroxy-2-naphthalenyl]benzoyl benzoate according to the procedure described in Example 3 using iodomethane as alkylating reagent. 1H NMR (400 MHz, CDC13) δ: 8.13 (d,J= 1.5 H, IH), 8.02 (dd, J= 8.0, 1.5 Hz, IH), 7.81 (s, IH), 7.41 (d, J = 8.0 Hz, IH), 6.80 (s, IH), 3.56 (s, 3H), 1.71 (m, 4H), 1.31 (s, 6H), 1.29 (s, 6H).
Compounds of the generic formula 16 may be synthesized according to the following scheme:
Figure imgf000122_0001
Example 46
Methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)hydroxymethyl] benzoate (Compound 146)
Figure imgf000122_0002
To a solution of 2 g (5.5 mmol) of methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl- 3-methyl-2naphthalenyl)]benzoyl benzoate in 10 ml of methanol, was added 415 mg (11.0 mmol) of NaBEL; portionwise at 0° C. The mixture was stirred at this temperature until complexion, the mixture was worked-up and the residual oil was purified by crystallization from hexanes to afford 1.97 g (5.4 mmol, yield: 98 %>) of methyl 4- [(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)hydroxymethyl] benzoate as a white solid. 1H NMR (400 MHz, CDC13) δ: 8.03 (d, J= 8.0 Hz, 2H), 7.45 (d, J= 8.0 Hz, 2H), 7.13 (s, IH), 6.67 (s, IH), 5.88 (broad s, IH), 3.85 (s, 3H), 2.2 (s, 3H), 1.71 (m, 4H), 1.31 (s, 6H), 1.29 (s, 6H).
Example 47
Methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2- naphthalenyl)hydroxymethyl] benzoate (Compound 147)
Figure imgf000123_0001
To a solution of 3 g (7.6 mmol) of methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3- ethoxy-2naphthalenyl)]benzoyl benzoate in 15 ml of methanol, was added 575 mg (15.2 mmol) of NaBH4 portionwise at 0° C. The mixture was stirred at this temperature until complexion, the mixture was worked-up and the residual oil was purified by crystallization from hexanes to afford 2.86 g (7.2 mmol, yield: 95 %) of methyl 4- [(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl)hydroxymethyl] benzoate as a white solid. H NMR (400 MHz, CDC13) δ: 8.05 (d, J= 8.0 Hz, 2H), 7.46 (d, J= 8.0 Hz, 2H), 7.15 (s, IH), 6.62 (s, IH), 5.92 (broad s, IH), 3.92 (m, IH), 3.88 (m, IH), 3.83 (s, 3H), 2.19 (s, 3H), 1.70 (m, 4H), 1.32 (t, J= 7.0 Hz, 3H), 1.25 (s, 3H), 1.24 (s, 3H), 1.18 (s, 3H), 1.12 (s, 3H).
Example 48
Methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(2- fluorobenzyloxy)methyl] benzoate (Compound 148)
Figure imgf000124_0001
A dispersion of sodium hydride in oil (200 mg, 60%>wt, 5 mmol) was added to a suspension of methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2- naphthalenyl)hydroxymethyl] benzoate in 10 mL of THF atroom temp. The mixture was stirred for 20 min before addition of 2-fluorobenzyl bromide (0.8 mL, 6.3 mmol). The mixture was stirred overnight and then 25 mL of IM aqueous HCI solution was slowly added. The mixture was extracted with 75 mL of EtOAc, and the organic layer was dried and concentrated to leave a residue that was purified by silica gel chromatography (10%> followed by 25% EtOAc/hexane) to afford 580 mg (39%) of methyl 4-[(5,6,7,8- tetrahydro-3,5,5,8,8-pentamethyl-3-methyl-2-naphthalenyl)(2-fluorobenzyloxy )methyl] benzoate as a colorless oil. JH NMR (500 MHz, CDC13) δ: 8.05 (d, J= 8.3 Hz, 2H), 7.44 (m, IH), 7.43 (d, J= 8.3 Hz, 2H), 7.22 (m, IH), 7.21 (s, IH), 7.15 (ddd,J= 1, 8.5, 8.5 Hz, IH), 7.02 (s, IH), 7.01 (dd, J= 8.5, 8.5 Hz, IH), 5.67 (s, IH), 4.60 (ABq, JAB = 11.7 Hz, 2H), 2.18 (s, 3H), 1.67 (s, 4H), 1.29 (s, 6H), 1.25 (s, 3H), 1.13 (s, 3H).
Example 49
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(2- fluorobenzyloxy)methyl]benzoic acid (Compound 149)
To a solution of methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(2- fluorobenzyloxy)methyl] benzoate (580 mg, 1.2 mmol) in 2 mL of THF was added 2 mL of MeOH, 1 mL of water, and lithium hydroxide monohydrate (150 mg, 3.6 mmol). The mixture was stirred overnight at room temperature before treatment with 10 mL of IM aqueous HCI solution and extraction with 25 mL of EtOAc. The organic layer was dried and concentrated to leave a crude solid product that was recrystallized from CH3CN to yield 348 mg (62%) of 4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(2- fluorobenzyloxy)methyl]benzoic acid as a white solid. !H NMR (500 MHz, CDC13) δ: 8.07 (d, J= 8.3 Hz, 2H), 7.47 (m, IH), 7.46 (d, J= 8.3 Hz, 2H), 7.28 (m, IH), 7.26 (s, IH), 7.14 (ddd, J= 1, 8.5, 8.5 Hz, IH), 7.05 (s, IH), 7.04 (dd, J= 8.5, 8.5 Hz, IH), 5.64 (s, IH), 4.63/4.57 (ABq, JAB = 11.7 Hz, 2H), 2.20 (s, 3H), 1.66 (s, 4H), 1.27 (s, 6H), 1.24 (s, 3H), 1.19 (s, 3H).
Example 50
4-[(5,6,7,8-tetrahydro-3, 5,5,8, 8-pentamethyl-2-naphthalenyl)(4- fluorobenzyloxy)methyl]benzoic acid (Compound 150)
Figure imgf000125_0001
Compound 150 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl)(2-fluorobenzyloxy)methyl] benzoate according to the procedure described in Example 49 using 4-fluorobenzyl bromide as alkylating reagent. !H NMR (500 MHz, CDC13) δ: 8.06 (d, J= 8.5 Hz, 2H), 7.44 (d, J= 8.5 Hz, 2H), 7.33 (d, J= 8.6 Hz, IH), 7.32 (d, J= 8.9 Hz, IH), 7.27 (s, IH), 7.05 (s, IH), 7.04 (d, J= 8.5, IH), 7.03 (d, J= 8.9, IH), 5.58 (s IH), 4.54/4.45 (ABq, JAB = 11.6 Hz, 2H), 2.16 (s, 3H), 1.67 (s, 4H), 1.27 (s, 3H), 1.26 (s, 3H), 1.25 (s, 3H), 1.20 (s, 3H).
Example 51
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(2- trifluoromethoxybenzyloxy) methyl] benzoic acid (Compound 151)
Figure imgf000126_0001
Compound 151 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl)(2-fluorobenzyloxy)methyl] benzoate according to the procedure described in Example 47 using 2-trifluoromethoxybenzyl bromide as alkylating reagent. !H NMR (500 MHz, CDC13) δ: 8.09 (d, J= 8.3 Hz, 2H), 7.61 (dd, J = 2.0, 7.4 Hz), 7.48 (d, J= 8.3 Hz, 2H), 7.33 (m, 2H), 7.28 (s, IH), 7.26 (m, IH), 7.07 (s, IH), 5.65 (s, IH), 4.64/4.61 (ABq, JAB = 12.2 Hz, 2H), 2.20 (s, 3H), 1.67 (s, 4H), 1.27 (s, 6H), 1.25 (s, 3H), 1.20 (s, 3H).
Example 52
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(2,3- difluorobenzyloxy)methyl]benzoic acid (Compound 152)
Figure imgf000126_0002
Compound 152 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl)(2-fluorobenzyloxy)methyl] benzoate according to the procedure described for Example 49 using 2,3-difluorobenzyl bromide as alkylating reagent. 1H NMR (500 MHz, CDC13) δ: 8.08 (d, J= 8.2 Hz, 2H), 7.46 (d, J= 8.5 Hz, 2H), 7.26 (s, IH), 7.23 (m, IH), 7.08 (m, 2H), 7.06 (s, IH), 5.65 (s, IH), 4.65/4.59 (ABq, JAB = 12 Hz, 2H), 2.20 (s, 3H), 1.67 (s, 4H), 1.27 (s, 6H), 1.25 (s, 3H), 1.20 (s, 3H).
Example 53
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4- trifluoromethylbenzyloxy) methyl]benzoic acid (Compound 153)
Figure imgf000127_0001
Compound 153 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl)(2-fluorobenzyloxy)methyl] benzoate according to the procedure described for Example 49 using 4-trifluoromethylbenzyl bromide as alkylating reagent. 1H NMR (500 MHz, CDC13) δ: 8.08 (d, J= 8.2 Hz, 2H), 7.61 (d, J= 8.2 Hz, 2H), 7.48 (d, J= 8.5 Hz, 2H), 7.46 (d, J= 8.2 Hz, 2H), 7.31 (s, IH), 7.05 (s, IH), 5.61 (s, IH), 4.64/4.55 (ABq, JAB = 12.5 Hz, 2H), 2.17 (s, 3H), 1.67 (s, 4H), 1.27 (s, 3H), 1.27 (s, 3H), 1.26 (s, 3H), 1.21 (s, 3H).
Example 54
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4- trifluoromethoxybenzyloxy)methyl] benzoic acid (Compound 154)
Figure imgf000127_0002
Compound 154 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5, 5,8,8- pentamethyl-2-naphthalenyl)(2-fluorobenzyloxy)methyl] benzoate according to the procedure described in Example 49 using 4-trifluoromethoxybenzyl bromide as alkylating reagent. 1H NMR (500 MHz, CDC13) δ: 8.07 (d, J= 8.2 Hz, 2H), 7.45 (d, J= 8.5 Hz, 2H), 7.38 (d, J= 8.5 Hz, 2H), 7.28 (s, IH), 7.20 (d, J= 8.2 Hz, 2H), 7.05 (s, IH), 5.60 (s, IH), 4.57/4.49 (ABq, JAB = 12 Hz, 2H), 2.17 (s, 3H), 1.67 (s, 4H), 1.27 (s, 3H), 1.26 (s, 3H), 1.25 (s, 3H), 1.20 (s, 3H).
Example 55
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4- trifluorothiomethoxybenzyloxy)methyl] benzoic acid (Compound 155)
Figure imgf000128_0001
Compound 155 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl)(2-fluorobenzyloxy)methyl] benzoate according to the procedure described in Example 49 using 4-trifluorothiomethoxybenzyl bromide as alkylating reagent. 1H NMR (500 MHz, CDCI3) δ: 8.06 (d, J= 8.1 Hz, 2H), 7.46 (d, J= 8.2 Hz, 2H), 7.39 (d, J= 8.2 Hz, 2H), 7.29 (s, IH), 7.22 (d, J= 8.1 Hz, 2H), 7.03 (s, IH), 5.62 (s, IH), 4.58/4.45 (ABq, JAB = 12 Hz, 2H), 2.16 (s, 3H), 1.68 (s, 4H), 1.25 (s, 3H), 1.24 (s, 3H), 1.23 (s, 3H), 1.20 (s, 3H).
Example 56
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl)(2,3- difluorobenzyloxy)methyl]benzoic acid (Compound 156)
Figure imgf000129_0001
Compound 156 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-ethoxy-2-naphthalenyl)hydroxymethyl] benzoate according to the procedure described in Example 49 using 2,3-difluorobenzyl bromide as alkylating reagent. !H NMR (500 MHz, CDC13) δ: 8.03 (d, J= 8.2 Hz, 2H), 7.54 (d, J= 8.2 Hz, 2H), 7.36 (s, IH), 7.25 (m, IH), 7.07 (m, 2H), 6.71 (s, IH), 5.92 (s, IH), 4.66/4.59 (ABq, JAB = 12 Hz, 2H), 4.00 (m, 2H), 1.65 (s, 4H), 1.37 (t, J= 7 Hz, 3H), 1.26 (s, 3H), 1.24 (s, 3H), 1.24 (s, 3H), 1.17 (s, 3H).
Example 57
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl)(4- fluorobenzyloxy)methyl]benzoic acid (Compound 157)
Figure imgf000129_0002
Compound 157 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-ethoxy-2-naphthalenyl)hydroxymethyl] benzoate according to the procedure described for Example 49 using 4-fiuorobenzyl bromide as alkylating reagent. H NMR (500 MHz, CDCI3) δ: 8.04 (d, J= 8.3 Hz, 2H), 7.55 (d, J= 8.8 Hz, 2H), 7.41 (s,lH), 7.34 (dd, J= 5.4, 8.3 Hz, 2H), 7.04 (dd, J= 8.8, 8.8 Hz, 2H), 6.72 (s, IH), 5.88 (s, IH), 4.55/4.49 (ABq, JAB = 11.5 Hz, 2H), 4.00 (m, 2H), 1.66 (s, 4H), 1.38 (t, J= 7 Hz, 3H), 1.28 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H), 1.19 (s, 3H). Example 58
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl)(2- fluorobenzyloxy)methyl]benzoic acid (Compound 158)
Figure imgf000130_0001
Compound 158 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-ethoxy-2-naphthalenyl)hydroxymethyl] benzoate according to the procedure described in Example 49 using 2-fluorobenzyl bromide as alkylating reagent. 1H NMR (500 MHz, CDC13) δ: 8.05 (d, J= 8.3 Hz, 2H), 7.57 (d, J= 8.8 Hz, 2H), 7.52 (ddd, J= 2.0, 7.4, 7.4, IH), 7.42 (s, IH), 7.28 (m, IH), 7.15 (ddd, J= 1.0, 7.3, 7.3 Hz, IH), 7.04 (ddd, J= 1.0, 8.3, 9.3 Hz, IH), 6.73 (s, IH), 5.94 (s, IH), 4.67/4.59 (ABq, JAB = 12.2 Hz, 2H), 4.01 (m, 2H), 1.66 (s, 4H), 1.38 (t, J= 7 Hz, 3H), 1.28 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H), 1.20 (s, 3H).
Example 59
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl)(benzyloxy) methyl]benzoic acid (Compound 159)
Figure imgf000130_0002
Compound 159 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-
3-ethoxy-2-naphthalenyl)hydroxymethyl] benzoate according to the procedure described in Example 49 using benzyl bromide as alkylating reagent. !H NMR (500 MHz, CDC13) δ: 8.05 (d, J= 8.3 Hz, 2H), 7.57 (d, J= 8.3 Hz, 2H), 7.45 (s, IH), 7.3-7.4 (m, 5H), 6.73 (s, IH), 5.91 (s, IH), 4.60/4.53 (ABq, JAB = 11.7 Hz, 2H), 4.00 (m, 2H), 1.67 (s, 4H), 1.37 (t, J= 1 Hz, 3H), 1.28 (s, 3H), 1.28 (s, 3H), 1.26 (s, 3H), 1.20 (s, 3H).
Example 60
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2- naphthalenyl)(butyloxy)methyl]benzoic acid (Compound 160)
Figure imgf000131_0001
Compound 160 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-ethoxy-2-naphthalenyl)hydroxymethyl] benzoate according to the procedure described in Example 49 using iodobutane as alkylating reagent. !H NMR (500 MHz, CDC13) δ: 8.01 (d, /= 8.2 Hz, 2H), 7.51 (d, J= 8.2 Hz, 2H), 7.35 (s, IH), 6.69 (s, IH), 5.73 (s, IH), 3.98 (m, 2H), 3.46 (m, 2H), 1.61 (m, 2H), 1.43 (m, 2H), 1.39 (t, J= 6.1 Hz, 3H), 1.26 (s, 3H), 1.26 (s, 3H), 1.25 (s, 3H), 1.23 (s, 3H), 1.18 (s, 3H), 0.92 (t, J= 7.3 Hz, 3H).
Compounds possessing an amide or an amine between both aromatic rings (Rg = H, R7 = amide or amine) may be synthesized via the following scheme.
Figure imgf000132_0001
1/ Cone HCI X = 0, S, NH 2/ K2C03, Rz-XH 3/ LiOH then HCI
Figure imgf000132_0002
Example 61
Methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methyl-2-naphthalenyl)(benzamido) methyl]benzoate (Compound 161)
Figure imgf000132_0003
To a suspension of methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2- naphthalenyl)(hydroxymethyl] benzoate (50 mg, 0.14 mmol) in 1.5 mL of glacial acetic acid was added benzamide (290 mg, 2.3 mmol), followed by 5 drops of cone, H2SO4. The mixture was stirred and heated at 50° C overnight. After cooling to room temp., the mixture was diluted with water and extracted with Et2O. The ether layer was dried and concentrated to leave a residue that was purified by silica gel chromatography (25% followed by 50% EtOAc/hexane) to afford 32 mg (48%) of methyl 4-[(5,6,7,8- tetrahydro-5,5,8,8-tetramethyl-3-methyl-2-naphthalenyl)(benzamido)methyl]benzoate (compound 161) as a colorless oil. Example 62
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methyl-2-naphthalenyl)(benzamido) methyl]benzoic acid (Compound 162)
Figure imgf000133_0001
To a solution of methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methyl-2- naphthalenyl) (benzamido)methyl]benzoate (8 mg, 0.017 mmol) in 1 mL of THF was added 0.5 mL of 0.5M aqueous LiOH solution. The mixture was stirred for 3 days at room temp, before treatment with IM aqueous HCI solution and extraction with EtOAc. The organic layer was dried and concentrated to leave 6 mg (75%) of 4-[(5,6,7,8- tetrahydro-5,5,8,8-tetramethyl-3-methyl-2-naphthalenyl)(benzamido)methyl]benzoic acid (compound 162) as a white solid. ]H NMR (500 MHz, CDC13) δ: 8.01 (d, J= 8.5 Hz, 2H), 7.80 (d, J= 8.5 Hz, 2H), 7.47 (tt, J= 1.2, 7.3 Hz, IH), 7.40 (d, J= 7.9 Hz, IH) 7.39 (d, J= 7.0 Hz, IH), 7.35 (d, J= 8.2 Hz, 2H), 7.07 (s, IH), 6.87 (s, IH), 6.86 (d, J= 7.9, IH), 6.56 (d, J= 7.6, IH), 2.23 (s, 3H), 1.59 (m, 4H), 1.23 (s, 3H), 1.22 (s, 3H), 1.10 (s, 3H), 1.01 (s, 3H).
Example 63
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methyl-2-naphthalenyl)(3- fluorobenzylamino) methyl]benzoic acid (Compound 163)
Figure imgf000133_0002
A suspension of methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)
(hydroxymethyl] benzoate (106 mg, 0.29 mmol) in 2 mL CH2C12 was slowly added to
1.5 mL of cone. HCI. The mixture was stirred vigorously overnight, then diluted with 10 mL of CH2C12. The solution was washed with 10 mL of water and 10 mL of brine, dried and concentrated to leave 106 mg of methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl)(chloromethyl] benzoate as a pale yellow oil. To a solution of this chloride (100 mg, 0.26 mmol) and 3-fluorobenzylamine (0.10 mL, 0.88 mmol) in
1 mL of CH3CN was added K2CO3 (75 mg, 0.54 mmol). The reaction mixture was stirred at room temp, for 18 h, then at reflux for 3 h before dilution with 15 mL of
EtOAc. The mixture was washed with 10 mL of water and 10 mL of brine, dried and concentrated to leave 136 mg of crude methyl-4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-
3-methyl-2-naphthalenyl)(3-fluorobenzylamino) methyl]benzoate as a yellow oil. This material was dissolved in 1 mL of THF and 1 mL of methanol. To this solution was added LiOH monohydrate (45 mg, 1.1 mmol) and 0.5 mL of water, and the resulting mixture was stirred overnight at ROOM TEMP.. The mixture was diluted with 5 mL of
0.1 M aqueous HCI solution and extracted with 15 mL of EtOAc. The organic layer was dried and concentrated to leave an oily residue that was purified by reverse-phase HPLC
(2" C18 column, 80 mL/min 80:20:0.1 methanol/water/trifluoroacetic acid) to afford 43 mg (34%> from alcohol x) of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methyl-2- naphthalenyl)(3-fluorobenzylamino)methyl] benzoic acid (compound 163) as a white solid. 'HNMR (500 MHz, CDC13) δ: 8.00 (s, IH), 7.74 (d, J= 8.3 Hz, 2H), 7.38 (d, J =
8.3 Hz, 2H), 7.36 (m, J= 7.3 Hz, IH), 7.09 (m, J= 7.3 Hz, 2H), 7.07 (s, IH), 6.99 (d, J=
9.3 Hz, IH), 5.19 (s, IH), 4.21 (d, J= 12.2 Hz, IH), 3.95 (d, J= 13.2 Hz, IH), 2.01 (s,
3H), 1.73 (m, 4H), 1.45 (s, 3H), 1.38 (s, 3H), 1.30 (s, 3H), 1.24 (s, 3H). Example 64
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methyl-2-naphthalenyl)(4- fluorobenzylamino) methyfjbenzoic acid (Compound 164)
Figure imgf000135_0001
Compound 164 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl)(hydroxymethyl] benzoate according to the procedure described in Example 63 using 4-fluorobenzylamine. 1H NMR (500 MHz, CDC13) δ: 8.05 (s, IH), 7.69 (d, J= 8.3 Hz, 2H), 7.35 (d, J= 8.3 Hz, 2H), 7.30 (dd, J= 8, 8 Hz, 2H), 7.11 (dd, J= 8.3, 2H), 7.08 (s, IH), 5.15 (s, IH), 4.28 (d, J= 13 Hz, IH), 3.95 (d, J = 13 Hz, IH), 2.03 (s, 3H), 1.74 (m, 4H), 1.46 (s, 3H), 1.40 (s, 3H), 1.31 (s, 3H), 1.24 (s, 3H).
Example 65
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2- naphthalenyl)(benzylamino)methyl]benzoic acid (Compound 165)
Figure imgf000135_0002
Compound 165 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl)(hydroxymethyl] benzoate according to the procedure described in Example 63 using benzylamine. Η NMR (500 MHz, CDC13) δ: 8.09 (s,
2H), 7.88 (s, IH), 7.75 (d, J= 8.0 Hz, 2H), 7.51 (d, J= 8.0 Hz, IH), 7.29-7.07 (m, 5H),
4.89 (s, 2H), 1.76 (broad s, 4H), 1.37 (s, 6H), 1.25 (s, 6H). Example 66
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4-trifluoromethylphenoxy) methyfjbenzoic acid (Compound 166)
Figure imgf000136_0001
To a suspension of methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) (chloromethyl] benzoate (150 mg, 0.39 mmol) in 3 mL DMF was added 64 mg (0.40 mmol) and 100 mg (0.722 mmol) of K2CO3. The mixture was stirred overnight at room temperature, then diluted with 10 mL of water and extracted with EtOAc. The solution was washed with 3 mL of water (3 times) and 3 ml of brine, then dried over MgSO4. After filtration, the solvents were removed under reduced pressure and the crude oil was directly diluted into 6 ml of a 1/1/1 mixture of THF/MeOH/2N aqueous LiOH. After complexion and work-up the crude acid was recrystallized from hexanes to afford 149 mg (0.3 mmol, yield: 85 %) of 4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2- naphthalenyl)(4-trifluoromethylphenoxy) methyl]benzoic acid (compound 166) as a white solid. 1H NMR (500 MHz, CDC13) δ: 8.10 (d, J= 7.9 Hz, 2H), 7.48 (d, J= 8.5 Hz, 4H), 7.11 (s, IH), 7.07 (s, IH), 6.97 (d, J= 8.5 Hz, 2H), 6.40 (s, IH), 2.28 (s, 3H), 1.64 (m, 4H), 1.27 (s, 3H), 1.26 (s, 3H), 1.12 (s, 6H).
Example 67
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4-tert- butylbenzylthio)methyl] benzoic acid (Compound 167)
Figure imgf000137_0001
Compound 167 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3, 5,5,8,8- pentamethyl-2-naphthalenyι) (chloromethyl] benzoate according to the procedure described in Example 66 using 4-tert-butylbenzylmercaptan as alkylating reagent. H NMR (500 MHz, CDCI3) δ: 8.02 (d, J= 8.5 Hz, 2H), 7.47 (s, IH), 7.45 (d, J= 8.2 Hz, 2H), 7.31 (d, J= 8.2 Hz, 2H), 7.10 (d, J= 8.0, 2H), 6.99 (s, IH), 5.06 (s, IH), 3.56 (q, J = 13.1Hz, 2H), 2.01 (s, 3H), 1.65 (m, 4H), 1.32 (s, 9H), 1.29 (s, 3H), 1.26 (s, 3H), 1.23 (s, 3H), 1.19 (s, 3H).
Example 68
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4-fluorophenyloxy)methyl] benzoic acid (Compound 168)
Figure imgf000137_0002
Compound 168 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl) (chloromethyl] benzoate according to the procedure described in Example 66 using 4-fluorophenol as alkylating reagent. !H NMR (500 MHz, CDCI3) δ: 8.08 (d, J= 7.9 Hz, 2H), 7.48 (d, J= 7.9 Hz, 2H), 7.10 (s, 2H), 6.90 (dd, J= 9.2, 8.2 Hz, 2H), 6.84 (m, 2H), 6.26 (s, IH), 2.27 (s, 3H), 1.64 (m, 4H), 1.26 (s, 3H), 1.25 (s, 3H), 1.13 (s, 3H), 1.12 (s, 3H). Example 69
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4-tert-butylphenyloxy) methyl] benzoic acid (Compound 169)
Figure imgf000138_0001
Compound 169 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl) (chloromethyl)] benzoate according to the procedure described in Example 66 using 4-tert-butylphenol as alkylating reagent. XH NMR (500 MHz, CDC13) δ: 8.09 (d, J= 7.6 Hz, 2H), 7.50 (d, J= 7.9 Hz, 2H), 7.22 (d, J= 8.9 Hz, 2H), 7.10 (s, IH), 7.04 (s, IH), 6.84 (d, J= 8.9 Hz, 2H), 6.32 (s, IH), 2.28 (s, 3H), 1.63 (m, 4H), 1.26 (s, 15H), 1.13 (s, 3H), 1.10 (s, 3H).
Example 70
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4-phenylphenyloxy) methy jbenzoic acid (Compound 170)
Figure imgf000138_0002
Compound 170 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl) (chloromethyl)] benzoate according to the procedure described in Example 66 using 4-phenylphenol as alkylating reagent. JH NMR (500 MHz, CDC13) δ: 8.10 ( d, J= 7.9 Hz, 2H), 7.52 (dd, J = 9.5, 8.2 Hz, 2H), 7.45 (d, J= 8.9 Hz, 2H), 7.39 (dd, J= 8.5, 8.5 Hz, IH), 7.29 (d, J= 8.5 Hz, 2H), 7.11 (s, IH), 7.09 (s, IH), 6.98 (d, J= 8.9 Hz, 2H), 6.40 (s, IH), 2.31 (s, 3H), 1.64 (m, 4H), 1.27 (s, 3H), 1.26 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H).
Example 71
4-[(5,6,7,8-tetrahydro-3, 5,5,8, 8-pentamethyl-2-naphthalenyl)(4-phenoxy)methyl]benzoic acid (Compound 171)
Figure imgf000139_0001
Compound 171 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl) (chloromethyl)] benzoate according to the procedure described in Example 66 using phenol as alkylating reagent. 1H NMR (500 MHz, CDC13) δ: 8.09 ( d, J= 8.2 Hz, 2H), 7.50 (d, J= 8.2 Hz, 2H), 7.10 (s, IH), 7.08 (s, IH), 6.919 (m, 3H2.29 (s, 3H), 1.63 (m, 4H), 1.27 (s, 3H), 1.26 (s, 3H), 1.13 (s, 3H), 1.11 (s, 3H).
Example 72
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl)(4-tert- butylbenzylthio) methyl]benzoic acid (Compound 172)
Figure imgf000139_0002
Compound 172 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-ethoxy-2-naphthalenyl) (chloromethyl)] benzoate according to the procedure described in Example 66 using 4-tert-butylbenzylmercaptan as alkylating reagent. !H NMR (500 MHz, CDC13) δ: 7.99 (d, J= 8.2 Hz, 2H), 7.52 (s, IH), 7.50 (d, J= 8.5 Hz, 2H), 7.29 (d, J= 8.2 Hz, 2H), 6.66 (s, IH), 5.46 (s, IH), 3.89 (m, 2H), 3.56 (ABq, JAB = 13.1 Hz, 2H), 1.65 (m, 4H), 1.31 (s, 9H), 1.29 (s, 3H), 1.26 (t, J= 7.0 Hz, 3H), 1.25 (s, 3H), 1.22 (s, 6H).
Compounds of formula 17 and 19 may be synthesized using the following procedures:
1/ Hydrazone formation 2/ Saponification
Route 1
Figure imgf000140_0001
Figure imgf000140_0002
Oxime formation Route 2 1/ Alkylation 2/ Saponification
Figure imgf000140_0003
Figure imgf000140_0004
Example 73
4-[(phenylhydrazino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)] benzoic acid (Compound 173)
Figure imgf000140_0005
To a mixture of 4.7 g (13.99 mmol) of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)] benzoic acid and 4.5 g (41.96 mmol) of phenyl hydrazine in 15 ml of EtOH, was added 1 ml of AcOH. The mixture was refluxed overnight and after cooling at room temperature, the solvents were removed under reduced pressure. The yellow crude product was recrystallized twice from Et2O and EtOAc to afford 2.0 g (4.69 mmol, yield: 34 %) of 4-[(phenylhydrazino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)] benzoic acid as a bright yellow solid. !H NMR (500 MHz, CDC13) δ: 8.05 (s, J= 8.5 Hz, 2H), 7.85 (s, IH), 7.71 (d, J= 10.0 Hz, 2H), 7.51 (d, j= 8.0 Hz, IH), 7.29 (d, J= 7.0 Hz, IH), 7.12 (d, J= 7.5, 2H), 7.07 (dd, J= 8.0, 2.0 Hz, IH), 6.89 (t, J= 7.5 Hz, IH), 1.76 (broad s, 4H), 1.38 (s, 6H), 1.29 (s, 6H).
Example 74
4-[(phenylhydrazino)(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)] benzoic acid (Compound 174)
Figure imgf000141_0001
Compound 174 was synthesized from methyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-ethoxy-2-naρhthalenyl)benzoyl benzoate according to the procedure described in Example 73 using phenylhydrazine. !H NMR (500 MHz, CDCI3) δ: 8.05 (s, J= 8.5 Hz, 2H), 7.85 (s, IH), 7.71 (d, J= 10.0 Hz, 2H), 7.51 (d, J= 8.0 Hz, IH), 7.29 (d, J= 7.0 Hz, IH), 7.12 (d, J= 7.5, 2H), 7.07 (dd, J= 8.0, 2.0 Hz, IH), 6.89 (t, j = 7.5 Hz, IH), 1.76 (broad s, 4H), 1.38 (s, 6H), 1.29 (s, 6H).
Example 75
4-[(phenylhydrazonyl)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)] benzoyl benzoic acid (Compound 175)
Figure imgf000142_0001
Compound 175 was synthesized from methyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-ethoxy-2-naphthalenyl)benzoyl benzoate according to the procedure described in Example 73 using phenylhydrazine. !H NMR (500 MHz, DMSO-d6) 8.05(d, J=8.3 Hz, 2H), 7.78 (s, IH), 7.72 (d, J=8.3 Hz, 2H), 7.31-7.27 (m, 4H), 7.17-7.14 (m, 2H), 7.11 (s, IH), 6.99 (s, IH), 6.89 (t, J=7.3 Hz, IH), 4.00(q, J=6.8 Hz, 2H), 1.80-1.70 (m, 4H), 1.60 (br. s, IH), 1.39 (s, 6H), 1.25(s, 6H), 1.15 (t, J=6.8 Hz, 3H).
Example 76
4-[(Pyridine-2-hydrazonyl)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)]benzoyl benzoic acid (Compound 176)
Figure imgf000142_0002
Compound 176 was synthesized from methyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-ethoxy-2-naphthalenyl)benzoyl benzoate according to the procedure described in Example 73 using 2-pyridylhydrazine. *H NMR (500 MHz, DMSO-d6) 12.95 (br. s, IH), 8.20 (s, IH), 8.07(m, IH), 7.94 (d, J=8.7 Hz, 2H), 7.74 (m, IH), 7.62 (d, J=8.7 Hz, 2H), 7.45 (d, J=8.3 Hz, IH), 7.15 (s, IH), 7.13 (s, IH), 6.86 (m, IH), 4.06(q, J=6.8 Hz, 2H), 1.70-1.60 (m, 4H), 1.36 (s, 6H), 1.21(s, 6H), 1.03 (t, J=6.8 Hz, 3H). Example 77
4-[(2,4-Difluorophenylhydrazonyl)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)] benzoyl benzoic acid (Compound 177)
Figure imgf000143_0001
Compound 177 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-ethoxy-2-naphthalenyl)benzoyl benzoate according to the procedure described in Example 73 using 2,4-difluorophenylhydrazine. *H NMR (500 MHz, DMSO-d6) 12.92 (br. s, IH), 7.93(d, J=8.8 Hz, 2H), 7.89 (d, J=2.0 Hz, IH), 7.70-7.64 (m, IH), 7.61 (d, J=8.8 Hz, 2H), 7.28-7.22 (m, IH), 7.18 (s, IH), 7.15 (s, IH), 7.11-7.06 (m, IH), 4.05(q, J=6.8 Hz, 2H), 1.72-1.64 (m, 4H), 1.35 (s, 6H), 1.20(s, 6H), 1.02 (t, J=6.8 Hz, 3H).
Example 78
4-[(2,5-Difluorophenylhydrazonyl)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)] benzoyl benzoic acid (Compound 178)
Figure imgf000143_0002
Compound 178 was synthesized from methyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-ethoxy-2-naphthalenyι)benzoyl benzoate according to the procedure described in Example 73 using 2,5-difluorophenylhydrazine. 1H NMR (500 MHz, DMSO-d6) 12.93 (br. s, IH), 8.02 (s, IH), 7.94 (d, J=8.8 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 7.47-7.42 (m, IH), 7.24-7.18 (m, IH), 7.19 (s, IH), 7.16 (s, IH), 6.68-6.62 (m, IH), 4.05(q, J=6.8 Hz, 2H), 1.72-1.64 (m, 4H), 1.35 (s, 6H), 1.20(s, 6H), 1.02 (t, J=6.8 Hz, 3H).
Example 79
4-[(2,5-Dimethylphenylhydrazonyl)(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2- naphthalenyl)] benzoyl benzoic acid (Compound 179)
Figure imgf000144_0001
Compound 179 was synthesized from methyl 4-(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl)benzoyl benzoate according to the procedure described in Example 73 using 2,5-dimethylphenylhydrazine. !H NMR (500 MHz, DMSO-de) 12.95 (br. s, IH), 8.00 (s, IH), 7.93 (d, J=8.8 Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 7.43-7.46 (m, IH), 7.20-7.14 (m, IH), 7.12 (s, IH), 7.11 (s, IH), 6.65-6.60 (m, IH), 4.03 (q, J=6.9 Hz, 2H), 2.10 (s, 3H), 2.05 (s, 3H), 1.70-1.65 (m, 4H), 1.34 (s, 6H), 1.20 (s, 6H), 1.01 (t, J=6.9 Hz, 3H).
Example 80
4-[(2-fluorophenylhydrazonyl)(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2- naphthalenyl)] benzoyl benzoic acid (Compound 180)
Figure imgf000144_0002
Compound 180 was synthesized from methyl 4-[(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl)benzoyl benzoate according to the procedure described in Example 73 using 2-fluorophenylhydrazine. !H NMR (500 MHz, DMSO-d6) 12.90 (br. s, IH), 8.02 (s, IH), 7.94 (d, J=8.8 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 7.47-7.42 (m, IH), 7.24-7.18 (m, IH), 7.19 (s, IH), 7.16 (s, IH), 6.68-6.62 (m, IH), 4.05(q, J=6.8 Hz, 2H), 1.72-1.64 (m, 4H), 1.35 (s, 6H), 1.20(s, 6H), 1.02 (t, J=6.8 Hz, 3H).
Example 81
Methyl-4-[(oxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl)] benzoate (Compound 181)
Figure imgf000145_0001
To a solution of Methyl-4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2- naphthalenyl)] benzoate (1.61 g, 4.22 mmol) in Ethanol (14 mL), was added pyridine (0.52 mL, 1.5 eq.), followed by hydroxylamine hydrochloride (0.587 g, 8.45 mmol). The solution was heated to reflux and stirred overnight. The reaction mixture was allowed to cool to room temperature, poured onto water (50 mL), and extracted with EtOAc (2 x 50 mL). The organic layers were combined, washed with brine (50 mL), and dried (MgSO4). The solvent was removed under reduced pressure, and the compound purified by flash chromatography (silica gel, 15% EtOAc/Hexanes) to give 1.24 g (72%) of the desired oxime (example 81) as a white solid. Η NMR (500 MHz, CDC13) δ: 7.98 (d, J= 8.2 Hz, 2H), 7.57 (d, J= 8.2 Hz, 2H), 7.12 (s, IH), 6.88 (s, IH), 3.94 (dd, J= 13.7, 7.0 Hz, 2H), 3.92 (s, 3H), 1.70 (m, 4H), 1.33 (s, 6H), 1.24 (s, 6H), 1.11 (t, J= 7.0 Hz, 3H). Example 82
Methyl-4-[(4,4,4-trifluorobutoxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3- ethyloxy-2-naphthalenyl)] benzoate (Compound 182)
Figure imgf000146_0001
In a round bottom flask equipped with a magnetic stir bar, methyl-4-[(oxyimino)(5,6,7,8- tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl)] benzoate (1.24 g, 3.02 mmol) was dissolved in 14 mL dry ethanol and cooled to 0°C. Sodium hydride (60% in mineral oil, 0.138 g, 3.43 mmol) was added in one portion and the mixture was allowed to stir for 30 min. Via syringe, l-iodo-4,4,4-trifluorobutane (1.30 g, 5.44 mmol) was added dropwise, and the reaction was allowed to warm to room temperature overnight. The reaction was poured onto water (50 mL), and extracted with EtOAc (2 x 50 mL). The organic layers were combined, washed with brine (50 mL), and dried (MgSO4). The solvent was removed under reduced pressure, and the compound purified by flash chromatography (silica gel, 25% EtOAc/Hexanes) to yield 1.09 g (70%) of methyl-4- [(4,4,4-trifluorobutoxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)] benzoate as an oil. Η NMR (400 MHz, CDC13) δ: 7.96 (d, J= 8.7 Hz, 2H), 7.55 (d, J= 8.4 Hz, 2H), 7.05 (s, IH), 6.83 (s, IH), 4.25 (t, J= 6.0 Hz, 2H), 3.91 (s, 3H), 3.88 (dd, J= 13.9, 6.9 Hz, 2H), 2.15 (m, 2H), 1.96 (m, 2H), 1.70 (m, 4H), 1.32 (s, 6H), 1.23 (s, 6H), 1.06 (t, J= 6.8 Hz, 3H). Example 83
4-[(phenylimino)(5,6,7,8-terrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)] benzoyl benzoic acid (Compound 183)
Figure imgf000147_0001
Compound 183 was synthesized from methyl 4-(5,6,7,8-tetrahydro-3, 5,5,8,8- pentamethyl-2-naphthalenyl)benzoyl benzoate according to the procedure described in Example 81 using ( -phenylhydroxylamine hydrochloride. !H NMR (500 MHz, DMSO- de) 9.31 (br. s, IH), 8.11 (d, J= 6.7 Hz, 2H), 7.73 (d, J= 6.7 Hz, 2H), 7.33 (m, IH), 7.28 (m, 2H), 7.22 (m, 2H), 7.07 (m, 2H), 2.11 (s, 3H), 1.72 (s, 4H), 1.35 (s, 6H), 1.25 (s, 6H).
Example 84
4-[(l , 1 , 1 -trifluorobutoxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)] benzoic acid (Compound 184)
Figure imgf000147_0002
To a round bottom flask equipped with a magnetic stir bar was added 1.09 g of methyl-4- [(1,1,1 -trifluorobutoxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)] benzoate (2.10 mmol) followed by 10 mL THF, 5 mL water, 3 mL MeOH, and lithium hydroxide monohydrate (0.880 g, 20.97 mmol). The mixture was stirred overnight at room temperature. The reaction was poured onto water (50 mL), and extracted with EtOAc (2 x 50 mL). The organic layers were combined, washed with brine (50 L), and dried (MgSO4). The solvent was removed under reduced pressure, and the compound purified by flash chromatography (silica gel, 50% EtOAc/Hexanes) to yield 0.354 g (35%) of 4-[(l,l,l-trifluorobutoxyimino)(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-3-ethyloxy-2-naphthalenyl)] benzoic acid as a white solid. !H NMR (400 MHz, CDC13) δ: 8.03 (d, J= 8.4 Hz, 2H), 7.58 (d, J= 8.5 Hz, 2H), 7.06 (s, IH), 6.84 (s, IH), 4.26 (t, J= 6.0 Hz, 2H), 3.89 (dd, J= 14.0, 6.9 Hz, 2H), 2.16 (m, 2H), 1.96 (m, 2H), 1.70 (m, 4H), 1.32 (s, 6H), 1.23 (s, 6H), 1.06 (t, J= 7.1 Hz, 3H).
Example 85
4-[(ethoxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)]benzoic acid (Compound 185)
Figure imgf000148_0001
Compound 185 was synthesized from methyl-4-[(oxyimino)(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-3-ethoxy-2-naphthalenyl)] benzoate according to the procedure described in Example 76 using ethyl iodide as alkylating agent. Η NMR (400 MHz, CDC13) δ: 8.00 (d, J= 8.6 Hz, 2H), 7.59 (d, J= 8.4 Hz, 2H), 7.14 (s, IH), 6.83 (s, IH), 4.27 (dd, J= 14.1, 7.2 Hz, 2H), 3.88 (dd, J= 13.8, 6.9 Hz, 2H), 1.69 (m, 4H), 1.31 (m, 9H), 1.23 (s, 6H), 1.05 (t, J = 7.0 Hz, 3H). Example 86
4-[(propoxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy -2-naphthalenyl)] benzoic acid (Compound 186)
Figure imgf000149_0001
Compound 186 was synthesized from methyl-4-[(oxyimino)(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-3-ethoxy-2-naphthalenyl)] benzoate according to the procedure described in Example 84 using 1-iodopropane as alkylating agent !H NMR (500 MHz, CDC13) δ: 8.01 (d, J= 8.5 Hz, 2H), 7.58 (d, J= 8.5 Hz, 2H), 7.14 (s, IH), 6.83 (s, IH), 4.17 (dd, J= 6.7, 6.7 Hz, 2H), 3.87 (dd, J= 14.0, 7.0 Hz, 2H), 1.72 (m, 2H), 1.69 (m, 4H), 1.31 (s, 6H), 1.24 (s, 6H), 1.04 (t, J= 7.0 Hz, 3H), 0.94 (t, J= 7.3 Hz, 3H).
Example 87
4-[(butoxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)]benzoic acid (Compound 187)
Figure imgf000149_0002
Compound 187 was synthesized from methyl-4-[(oxyimino)(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-3-ethoxy-2-naphthalenyl)] benzoate according to the procedure described in
Example 84 using butyl iodide as alkylating agent. H NMR (500 MHz, CDC13) δ: 8.00
(d, J= 8.2 Hz, 2H), 7.58 (d, J= 8.2 Hz, 2H), 7.13 (s, IH), 6.82 (s, IH), 4.22 (dd, J= 6.7,
6.7 Hz, 2H), 3.87 (dd, J= 13.7, 7.0 Hz, 2H), 1.68 (m, 4H), 1.31 (s, 6H), 1.24 (s, 6H),
1.04 (t, J= 7.0 Hz, 3H), 0.92 (t, J= 7.3 Hz, 3H). Example 88
4-[(pentoxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy -2-naphthalenyl)] benzoic acid (Compound 188)
Figure imgf000150_0001
Compound 188 was synthesized from methyl-4-[(oxyimmo)(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-3-ethoxy-2-naphthalenyl)] benzoate according to the procedure described in Example 84 using pentyl iodide as alkylating agent. 1H NMR (400 MHz, CDCI3) δ: 8.00 (d, J= 8.5 Hz, 2H), 7.57 (d, J= 8.5 Hz, 2H), 7.13 (s, IH), 6.82 (s, IH), 4.20 (dd, J= 6.9, 6.9 Hz, 2H), 3.86 (dd, J= 14.0, 6.9 Hz, 2H), 1.69 (m, 4H), 1.33-1.25 (m, 6H), 1.31 (s, 6H), 1.23 (s, 6H), 1.03 (t, J= 6.9 Hz, 3H), 0.90 (m, 3H).
Example 89
4-[(hexyloxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy -2-naphthalenyl)] benzoic acid (Compound 189)
Figure imgf000150_0002
Compound 189 was synthesized from methyl-4-[(oxyimino)(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-3-ethoxy-2-naphthalenyl)] benzoate according to the procedure described in
Example 84 using 1-iodohexane as alkylating agent. Η NMR (500 MHz, CDCI3) δ:
8.00 (d, J= 8.5 Hz, 2H), 7.57 (d, J= 8.5 Hz, 2H), 7.14 (s, IH), 6.82 (s, IH), 4.20 (dd, J=
6.7, 6.7 Hz, 2H), 3.86 (dd, J= 13.9, 6.9 Hz), 1.69 (m, 4H), 1.31 (s, 3H), 1.26 (m, 7H),
1.23 (s, 3H), 1.03 (s, 3H), 0.87 (m, 4H). Example 90
4-[(3-methyl-butoxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy -2- naphthalenyl)]benzoic acid (Compound 190)
Figure imgf000151_0001
Compound 190 was synthesized from methyl-4-[(oxyimino)(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-3-ethoxy-2-naphthalenyl)] benzoate according to the procedure described in Example 84 using l-iodo-3-methylbutane as alkylating agent. H NMR (400 MHz, CDC13) δ: 8.01 (d, J= 8.5 Hz, 2H), 7.58 (d, J= 8.5 Hz, 2H), 7.12 (s, IH), 6.82 (s, IH), 4.24 (dd, J= 6.9, 6.9 Hz, 2H), 3.86 (dd, J= 14.0, 6.9 Hz, 2H), 1.69 (m, 4H), 1.58 (m, 3H), 1.31 (s, 6H), 1.23 (s, 6H), 1.03 (t, J= 6.9 Hz, 3H), 0.91 (s, 3H), 0.89 (s, 3H).
Example 91
4-[(decyloxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy -2-naphthalenyl)] benzoic acid (Compound 191)
Figure imgf000151_0002
Compound 191 was synthesized from methyl-4-[(oxyimino)(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-3-ethoxy-2-naphthalenyl)] benzoate according to the procedure described in
Example 84 using 1-iododecane as alkylating agent. H NMR (500 MHz, CDCI3) δ:
8.02 (d, J= 8.5 Hz, 2H), 7.58 (d, J= 8.5 Hz, 2H), 7.14 (s, IH), 6.82 (s, IH), 4.20 (dd, J=
7.0, 7.0 Hz, 2H), 3.87 (dd, J= 14.0, 7.0 Hz, 2H), 1.69 (m, 4H), 1.28 (m, 28H), 1.04 (t, J
= 7.0 Hz, 3H), 0.88 (t, J= 7.0 Hz, 3H). Example 92
4-[(2,3-difluorobenzyloxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy -2- naphthalenyl)] benzoic acid (Compound 192)
Figure imgf000152_0001
Compound 192 was synthesized from methyl-4-[(oxyimino)(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-3-ethoxy-2-naphthalenyl)] benzoate according to the procedure described in Example 84 using 2,3-difluorobenzyl bromide as alkylating agent. H NMR (500 MHz, CDC13) δ: 8.02 (d, J= 8.3 Hz, 2H), 7.58 (d, J= 8.3 Hz, 2H), 7.20 (m, IH), 7.11 (m, IH), 7.06 (s, IH), 6.85 (s, IH), 5.35 (s, 2H), 3.89 (dd, J= 13.7, 6.8 Hz, 2H), 1.70 (m, 4H), 1.33 (s, 6H), 1.23 (s, 6H), 1.05 (t, j = 6.8 Hz, 3H).
Compounds possessing a heteroatom at the Y position may be synthesized using the following scheme:
Scheme 11 Route 1
Figure imgf000152_0003
Figure imgf000152_0002
A X = 0
Figure imgf000152_0004
Example 93
(Route 1)
3-[(3-methyl)but-3-ene]thio anisole (Compound 193)
Figure imgf000153_0001
To a suspension of 1.73 g (36.1 mmol) of NaH in 20 ml of dry THF was added dropwise 4.23 g (3.75 ml, 30.1 mmol) of 3-methoxy thiophenol diluted in 50ml of dry THF at 0° C. The mixture was stirred 30 minutes at this temperature then 5g (3.9 ml, 33.5 mmol) of l-bromo-3-methyl-3-butene diluted in 5 ml of dry THF was added slowly. The resulting solution was warmed to room temperature and stirred 3 hours. Cold water (100 ml) was carefully added and the mixture was extracted twice with EtOAc. The organic layers were collected, washed with water (2 times 10 ml) and brine (10 ml), dried over MgSO4, filtrated and concentrated under reduced pressure. The resulting oil was purified over silica gel column chromatography (eluent: 90/10: hexane/EtOAc to afford 5 g (24.0 mmol, yield: 80 %) of 3-[(3-methyl)but-3-ene]thio anisole as a clear oil. H NMR (500 MHz, CDC13) δ: 7.18 (t, J= 8.2 Hz, IH), 6.92 (d, J= 8.2 Hz, IH), 6.91 (d, J = 0.5 Hz, IH), 6.68 (dd, /= 8.2, 0.5 Hz, IH), 5.30 (m, IH), 3.79 (s, 3H), 3.78 (d, J= 3.4 Hz, 2H), 1.72 (s, 3H), 1.63 (s, 3H).
Example 94
(Route 2)
Ethyl-(3-methoxybenzyl)thiopropionate (Compound 194)
Etθ2C. ^^"O e
To a suspension of 858 m g (12 mmol) of NaH in 10 ml of dry THF was added dropwise 1.4 g (1.2 ml, 10.0 mmol) of 3-methoxy thiophenol and 2.17 g (1.5 ml, 10.0 mmol) of ethyl-3-bromopropionate diluted in 10ml of dry THF at 0° C. The mixture was warmed to room temperature and stirred 3 hours at 50° C. After cooling at room temperature, cold water (100 ml) was carefully added and the mixture was extracted twice with EtOAc. The organic layers were collected, washed with water (2 times 10 ml) and brine (10 ml), dried over MgSO4, filtrated and concentrated under reduced pressure. The resulting oil was purified over silica gel column chromatography (eluent: 90/10: hexane/EtOAc to afford 2.36 g (9.8 mmol, yield: 98 %) of 3-[(3-methyl)but-3-ene]thio anisole as a clear oil. !H NMR (500 MHz, CDC13) δ: 7.21 (t, J= 7.9 Hz, IH), 6.93 (d, J = 7.9 Hz, IH), 6.90 (d, J= 1.5 Hz, IH), 6.65 (dd, J= 7.9, 15 Hz, IH), 4.15 (dd, J= 14.3, 7.2 Hz, 2H), 3.81 (s, 3H), 3.17 (t, J= 7.6 Hz, 2H), 2.64 (t, J= 7.6 Hz, 2H), 1.26 (t, J= 7.2 Hz, 3H).
Example 95
(Route 1)
2,3-dihydro-4,4-dimethyl-7-methoxybenzothiopyrane (Compound 195)
Figure imgf000155_0001
To a solution of 2 g (9.6 mmol) of substrate diluted in 25 ml of benzene was added 1.9 g (1.1 ml, 19.4 mmol) of H3PO4 and the mixture was refluxed for 2 hours. After cooling at room temperature, 4.1 g (14.4 mmol) of P2O5 was added and the solution is refluxed for an extra 2 hours. After cooling at room temperature, ice (100 g) was added and the mixture was extracted with EtOAc. The organic layers were collected and washed with water and brine, then dried over MgSO . After filtration and concentration, the resulting oil was purified over silica gel column chromatography (eluent: 95/5 hexane/EtOAc) to afford 1.5 g (7.2 mmol, yield: 75 %) of desired product as a pale brown oil. Η NMR (500 MHz, CDC13) δ: 7.26 (d, J= 8.8 Hz, IH), 6.61 (d, J= 8.8 Hz, IH), 6.59 (s, IH), 3.75 (s, 3H), 3.02 (t, J= 6.1 Hz, 2H), 1.95 (d, J= 6.1 Hz, 2H), 1.30 (s, 6H).
Example 96
(Route 1)
3-[(3-methyl)but-3-eneoxy] anisole (Compound 196)
Figure imgf000155_0002
To a suspension of 3.5 g (72.2 mmol) of NaH in 70 ml of THF was added dropwise 7.5 g
(diluted in 3 ml of dry THF) at 0° C. After 10 minutes, 10 gm (67.1 mmol, 7.9 ml, diluted in 10 ml of dry THF) was added slowly and the mixture was stirred at room temperature overnight. After work-up, the crude ether was purified over SiO2 column chromatography to afford 9.27 g (48.2 mmol, 80 %) of 3-[(3-methyl)but-3-eneoxy] anisole as pale brown oil. 'HNMR (500 MHz, CDC13) δ: 7.19 (t, J= 8.1 Hz, IH), 6.90 (dd, J= 8.1, 1.6 Hz, IH), 6.80 (d, j= 1.5 Hz, IH), 5.45 ( , IH), 4.50 (d, J= 7.02 Hz, 2H), 3.79 (s, 3H), 1.80 (s, 3H), 1.75 (s, 3H).
Example 97
3-[(3-methyl-3-hydroxy)butanoxy]anisole (Compound 197)
Figure imgf000156_0001
To a suspension of 3.0 g (15.6 mmol) of 3-[(3-methyl)but-3-eneoxy] anisole in 40 ml of a 1/1 mixture of THF/water was added 4.97 g (15.6 mmol) of Hg(OAc)2 at 0° C. After 1 hour, 10 ml of a 2N aqueous NaOH solution was added followed by 1.2 g (31.2 mmol) of NaBH . The ash-colored solution was then filtrated over a celite plug, extracted with EtOAc, dried over MgSO , filtrated and concentrated. The crude alcohol was purified over SiO2 plug to afford 1.65 g 7.61 mmol, 49 %) of 3-[(3-methyl-3-hydroxy)butanoxy] anisole as clear oil. !H NMR (500 MHz, CDC13) δ: 7.18 (t, J= 8.1 Hz, IH), 6.91 (dd, J = 8.1, 1.5 Hz, IH), 6.85 (d, J= 1.5 Hz, IH), 4.17 (t, J= 6.4 Hz, 2H), 3.79 (s, 3H), 1.99 (t, J= 6.4 Hz, 2H), 1.59 (s, 6H).
Example 98
2,3-dihydro-4,4-dimethyl-7-methoxybenzopyran (Compound 198)
Figure imgf000157_0001
To a solution of 1.0 g (7.5 mmol) of A1C13 diluted in 10 ml of CH3NO2 was added dropwise 1.6 g (7.6 mmol) of 3-[(3-methyl-3-hydroxy)butanoxy] anisole diluted in 5 ml of CH3NO2 at 0° C. The mixture was warmed-up to room temperature and stirred for 2 hours, quenched with ice and extracted with CH2C12. The organic layers were dried over MgSO4, filtrated and concentrated under reduced pressure. The crude product was purified over silica gel column chromatography to afford 850 mg (4.42 mmol, yield: 58 %) of the desired adduct as a pale brown oil. !H NMR (500 MHz, CDC13) δ: 7.26 (d, J= 8.8 Hz, IH), 6.61 (d, J= 8.8 Hz, IH), 6.59 (s, IH), 3.75 (s, 3H), 3.02 (t, J= 6.1 Hz, 2H), 1.95 (d, J= 6.1 Hz, 2H), 1.30 (s, 6H).
Example 99
Methyl-6-[(2,3-dihydro-4,4-dimethyl-7-hydroxy-benzopyranyl)]benzoyl benzoate (Compound 199)
Figure imgf000157_0002
To a mixture of 850 mg (4.4 mmol) of substrate with 858 mg (4.6 mmol) of methyl-4- chlorocarbonyl benzoate in 15 ml of dry 1,2-dichloroethane was added 1.76 g (13.2 mmol) of AICI3 at room temperature. The reddish mixture was refluxed for 4 hours and poured into ice (50 g) after cooling down to room temperature. The yellowish mixture was separated and the aqueous layer extracted twice with CH2C12. The organic layers were collected, dried over MgSO4, filtrated and concentrated. The crude product was purified over silica gel column chromatography to afford 360 mg (0.1.06 mmol, yield: 24 %) of the desired adduct as a pasty yellow pasty oil. H NMR (500 MHz, CDC13) δ: 12.0 (s, IH), 8.18 (d, J= 1.9 Hz, 2H), 7.69 (d, J= 7.9 Hz, 2H), 7.39 (s, IH), 6.43 (s, IH), 4.28 (t, J= 5.5 Hz, 2H), 3.98 (s, 3H), 1.82 (t, J= 5.5 Hz, 2H), 1.21 (s, 6H).
Example 100
Methyl-6-[(2,3-dihydro-4,4-dimethyl-7-hydroxy-benzothiopyranyl)]benzoyl benzoate (Compound 200)
Figure imgf000158_0001
To a mixture of 700 mg (3.36 mmol) of substrate with 667 mg (3.36 mmol) of methyl-4- chlorocarbonyl benzoate in 15 ml of dry 1,2-dichloroethane was added 1.35 g (10.1 mmol) of AICI3 at room temperature. The reddish mixture was refluxed for 4 hours and poured into ice (50 g) after cooling down to room temperature. The yellowish mixture was separated and the aqueous layer extracted twice with CH2C12. The organic layers were collected, dried over MgSO4, filtrated and concentrated. The crude product was purified over silica gel column chromatography to afford 60 mg (0.168 mmol, yield: 5 %) of the desired adduct (as well as 110 mg - 0.308 mmol, yield: 9 %- of the other adduct) as a yellow pasty oil. !H NMR (500 MHz, CDCI3) δ: 11.8 (s, IH), 8.22 (d, J= 7.8 Hz, 2H), 7.71 (d, J= 7.8 Hz, 2H), 7.45 (s, IH), 6.81 (s, IH), 3.98 (s, 3H), 3.02 (m, 2H), 1.92 (m, 2H), 1.20 (s, 6H). Example 101
6-[(2,3-dihydro-4,4-dimethyl-7-ethoxy-benzopyranyl)]benzoyl benzoic acid (Compound 201)
Figure imgf000159_0001
Example 93 was synthesized from Methyl-6-[(2,3-dihydro-4,4-dimethyl-7-hydroxy- benzopyranyl)]benzoyl benzoate according to the procedure described in Example 3 using ethyl iodide as alkylating agent. *H NMR (400 MHz, CDC13) δ: 8.14 (d, J= 8.2 Hz, 2H), 7.78 (d, J= 8.2 Hz, 2H), 7.56 (s, IH), 6.33 (s, IH), 4.27 (t, J= 5.5 Hz, 2H), 3.81 (dd, J= 13.7, 7.0 Hz, 2H), 1.86 (t, J= 5.2 Hz, 2H), 1.35 (s, 6H), 0.92 (t, J= 7.0 Hz, 3H).
Example 102
6-[(2,3-dihydro-4,4-dimethyl-7-ethoxy-benzothiopyranyl)]benzoyl benzoic acid (Compound 202)
Figure imgf000159_0002
Example 102 was synthesized from Methyl-6-[(2,3-dihydro-4,4-dimethyl-7-hydroxy- benzothiopyranyl)]benzoyl benzoate according to the procedure described in Example 3 using ethyl iodide as alkylating agent. Η NMR (400 MHz, CDC13) δ: 8.11 (d, J= 8.2 Hz, 2H), 7.80 (d, J= 8.2 Hz, 2H), 7.57 (s, IH), 6.63 (s, IH), 3.83 (dd, J= 14.0, 7.0 Hz, 2H), 3.08 (t, J= 6.1 Hz, 2H), 1.98 (m, 2H), 1.34 (s, 6H), 0.93 (t, J= 7.0 Hz, 3H).
Example 103
6-[(2,3-dihydro-4,4,7-trimethyl-8-nitrobenzopyranyl)]benzoic acid (Compound 203)
Figure imgf000160_0001
Example 103 was synthesized from 6-[(2,3-dihydro-4,4,7- trimethylbenzopyranyl)]benzoic acid according to the procedure described for the synthesis of compound 108.
Scheme 12 1/ Reduction 2/ Alkylation Fnedel Craft 1/ Reduction 2/ Friede| Craft
Figure imgf000160_0005
Figure imgf000160_0004
Figure imgf000160_0003
Figure imgf000160_0002
1/ O-Alkylation
Figure imgf000160_0006
2/ N-Alkylation 33// SSaaopoonniiffiiccaattlioonn Friedel Craft
Figure imgf000160_0008
Figure imgf000160_0007
Example 104
2-methyl-3 -nitro anisole (Compound 204)
Figure imgf000160_0009
A solution of 3-nitro,2-methylphenol (5g, 33mmol), in a flame dried flask in dry DMF (160 mis) under nitrogen was cooled to 0C using an ice/water bath. To the cooled mix was added sodium hydride (1.96g, 49mmol), and the reaction mix turned a blood red color and allowed to stir for 4hrs. The reaction was diluted down with hexanes and directly purified using a silica packed plug (Hexanes/EtoAc) resulting in a yellow solid which was the desired product (4.8g, 89%). !H NMR (500 MHz, CDC13) δ 7.40 (dd, J = 1.2, 8.2 Hz, IH), 7.27 (m, IH), 7.04 (d, j= 8.2 Hz, IH), 3.89 (s, 3H), 2.36 (s, 3H).
Example 105
3-amino-2-methyl anisole (Compound 205)
Figure imgf000161_0001
To a solution of 3-nitro,2-methylmethoxybenzene (4.85g, 29mmol) in lOOmls ethylacetate was added approximately 750mgs of Palladium/carbon. The reaction vessel atmosphere was evacuated and the mix was put under hydrogen atmosphere using a balloon. The reaction was allowed to stir 48 hrs at which time the mix was filtered through silica/celite packed frit (hexanes/ethylacetate) affording the desired product as a red oil (3.87g, 97%). 1H NMR (500 MHz, CDC13) δ 6.97 (dd, J= 7.94 Hz, IH), 6.36 (d, J= 7.9 Hz, IH), 6.35 (d, J= 7.9 Hz, IH), 3.80 (s, 3H), 3.62 (bs, 2H), 2.04 (s, 3H).
Example 106
2-methyl-3-(3-methyl-2-butenamido)anisole (Compound 206)
Figure imgf000161_0002
3-methoxy-2-methylaniline (3.87g, 28 mmol) was taken up in acetone and cooled to OC using a water/ice bath under nitrogen. Potassium carbonate (5.86g, 42 mmol) was added, followed by addition of 3,3-Dimethylacryloylchloride (3.78mls, 34mmol). The reaction was allowed to warm to room temperature and stir for 12 hrs. The mix was concentrated under reduced pressure to an off white solid. The solid was purified using a silica packed plug (hexanes/EtoAc) affording a dull orange solid, which was recrystallized from hexanes and a minimal amount of ethylacetate to generate 2-methyl-3-(3-methyl-2- butenamido) anisole as crystals (2.6g, yield: 42%). !H NMR (500 MHz, CDC13) δ 7.49 (bs, IH), 7.14 (dd, J= 8.2 Hz, IH), 6.84 ( bs, IH), 6.68 (bd, J= 7.94 Hz, IH), 5.74 (bs, IH), 3.81 (s, 3H), 2.20 (d, J= 0.9 Hz, 3H), 2.11 (s, 3H), 1.89 (bs, 3H), 1.56 (bs, 2H).
Example 107
4,4,8-trimethyl-7-methoxy-3,3-dihydroquinolone (Compound 207)
Figure imgf000162_0001
The amide (2.5g, 11.5mmol) was taken up in dry methylene chloride (60ml) in a flame dried flask under nitrogen and aluminum chloride (15.2g, 115mmol) was added. The reaction was heated to reflux for 1.5 hrs at which time the reaction was poured over ice. The water ethylacetate mix was extracted three times with ethyl acetate (100mls/X3) from water, the organic layers were collected and washed with brine, dried over solid sodium sulfate, filtered, and concentrated under reduced pressure to a solid. The solid was recrystallized from 50%Etoac/Hexanes to afford the desired product as a crystal (1.65g, yield: 66%). ]H NMR (500 MHz, CDC13) δ 7.43 (bs, IH), 7.10 (d, J= 8.5 Hz, IH), 6.58 (d, J= 8.5 Hz, IH), 3.82 (s, 3H), 2.46 (s, 2H), 2.10 (s, 3H), 1.30 (s, 6H).
Example 108
4,4,8-trimethyl-7-methoxy-l,2,3-tetrahydroquinoline (Compound 208)
Figure imgf000163_0001
4,4,8-trimethyl-7-methoxy-3,3-dihydroquinolone (lg, 4.6mmol) was taken up in 23 ml dry THF under nitrogen in a flame dried flask and boranedimethylsulphide complex (22.8 ml of a 2 M solution in toluene, 46 mmol) was added and the reaction was heated to reflux for 4 hours. The reaction mixture was cooled and quenched with methanol (5 eq.) and the mixture was concentrated under reduced pressure to a clear oil. The oil was purified using a silica packed plug (hexanes/10%EtoAc/hexanes) to afford the desired 4,4,8-trimethyl-7-methoxy-l,2,3-tetrahydroquinoline as a clear oil (940 mg, quantitative). !H NMR (500 MHz, CDC13) δ 7.04 (d, J= 8.5 Hz, IH), 6.28 (d, J= 8.5 Hz, IH), 3.78 (s, 3H), 3.38 (m, 2H), 1.97 (s, 3H), 1.73 (m, 2H), 1.29 (s, 6H).
Example 109
Methyl-6-(4,4,8-trimethyl-7-hydroxy-l,2,3,4-tetrahydroquinolino)benzoyl benzoate (Compound 209)
Figure imgf000163_0002
4,4,8-trimethyl-7-methoxy-l,2,3-tetrahydroquinoline (500mg, 2.4mmol) was taken up in 15 ml dry CH2C12 in a flame dried flask under nitrogen and the acid chloride (726mgs, 3.7mmol) was added followed by addition of aluminum chloride (3.25g, 24mmol). The reaction was heated to reflux for 8 hrs at which time the reaction was poured over ice. The mix was extracted three times with ethyl acetate (100mls X3) from water, the organic layers were collected and washed with brine, dried over solid sodium sulfate, filtered, and concentrated under reduced pressure to a yellow solid. The solid was first purified using a flash silica column chromatography (EtoAc/Hex) and preparative HPLC (80%methanol/20%water) to afford the desired product as a yellow solid (50 mgs, 6%). Η NMR (500 MHz, CDC13) δ 13.01 (s, IH), 8.15 (d, J= 8.2 Hz, 2H), 7.66 (d, J= 8.2 Hz, 2H), 7.18 (s, IH), 4.72 (s, IH), 3.97 (s, 3H), 3.50 (m, 2H), 2.03 (s, 3H), 1.64 (m,2H), 1.16 (s, 6H).
Example 110
Methyl-6-(4,4,8-trimethyl-7-ethoxy-l,2,3,4-tetrahydroquinolino)benzoyl benzoate (Compound 210)
Figure imgf000164_0001
To a mixture of methyl-6-(4,4,8-trimethyl-7-hydroxy-l, 2,3,4- tetrahydroquinolino)benzoyl benzoate (50mg, 0.14mmol) in DMF (2ml) under nitrogen was added Iodoethane (O.Olmls, 0.16 mmol), and potassium carbonate (23mgs,
0.17mmol). The reaction was allowed to stir 48 hrs at which time the reaction was quenched with water and extracted three times with ethyl acetate (100mls/X3), the organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to a yellow oil. The oil was purified twice using flash silica column chromatography (gradient Hexanes to 15% EtoAc/Hexanes) affording the desired product (32mg, 60%). !H NMR (500 MHz, CDC13) δ 8.07 (d, J= 8.2 Hz, 2H), 7.80 (d, J= 7.94 Hz, 2H), 7.41 (s, IH), 4.3 (bs, IH), 3.94 (s, 3H), 3.57 (q, J= 7.0 Hz, 2H), 3.48 (m, 2H), 2.00 (s, 3H), 1.74 (m, 2H), 1.29 (s, 6H), 0.90 (t, J= 7.0, 3H).
Example 111
Methyl-6-( 1 ,4,4, 8-texramethyl-7-methoxy- 1 ,2,3 ,4-tetrahydroquinolino)benzoyl benzoate (Compound 211)
Figure imgf000165_0001
To a mixture of the Methyl-6-(4,4,8-trimethyl-7-hydroxy-l,2,3,4- tetrahydroquinolino)benzoyl benzoate (15 mg, 0.04 mmol) in DMF (2ml) under nitrogen was added methyliodide (0.01 ml, 0.17 mmol), and sodium hydride (8 mg, 0.17 mmol).
The reaction was allowed to stir 2 hrs at which time the reaction was quenched with water and extracted three times with ethyl acetate (100ml/X3), the organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to a yellow oil. The oil was purified using flash silica column chromatography (gradient
Hexanes to 10% EtoAc/Hexanes) affording methyl-6-(l, 4,4,8-tetramethyl-7-methoxy- l,2,3,4-tetrahydroquinolino)benzoyl benzoate as a yellow oil (14mgs, 88%). Η NMR
(500 MHz, CDC13) 8.1 (d, J= 8.2 Hz, 2H), 7.85 (d, J= 8.5 Hz, 2H), 7.30 (s, IH), 3.95 (s,
3H), 3.51 (s, 3H), 3.20 (m, 2H), 2.86 (s, 3H), 2.20 (s, 3H), 1.70 (m, 2H), 1.26 (s, 6H). Example 112
6-( 1 ,4,4,8-tetramethyl-7-methoxy- 1 ,2,3 ,4-tetrahydroquinolino)benzoyl benzoic acid (Compound 212)
Figure imgf000166_0001
To a solution of methyl-6-(l,4,4,8-tetramethyl-7-methoxy-l,2,3,4- tetrahydroquinolino)benzoyl benzoate (14 mg, 0.04 mmol) in a 1:1:1 mixture of THF/Water/Ethanol was added Lithium hydroxide (8 mg, 0.2 mmol). The reaction was allowed to stir at room temperature for 5 hrs at which time the reaction was quenched with water and acidified to pH 3 using 6N HCI. The solution was extracted three times with ethyl acetate (100mls/X3), the organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to the desired product; 6- (l,4,4,8-tetramethyl-7-methoxy-l,2,3,4-tetrahydroquinolino)benzoyl benzoic acid. !H NMR (500 MHz, CDC13) δ 8.17 (d, J= 8.2 Hz, 2H), 7.88 (d, J= 8.2 Hz, 2H), 7.33 (s, IH), 3.51 (s, 3H), 3.22 (bs, 2H), 2.89 (s, 3H), 2.22 (s, 3H), 1.72 (s, 2H), 1.28 (s, 6H).
Example 113
6-(l,4,4,8-tetramethyl-7-ethoxy-l,2,3,4-tetrahydroquinolino)benzoyl benzoic acid (Compound 213)
Figure imgf000166_0002
Example 113 was synthesized from methyl-6-(4,4,8-trimethyl-7-ethoxy-l,2,3,4- tetrahydroquinolino)benzoyl benzoate according to the procedure described for Example 112. 1H NMR (500 MHz, CDC13) δ 8.06 (d, J= 8.2 Hz, 2H), 7.81 (d, J= 7.93 Hz, 2H), 7.40 (s, IH), 3.94 (s, 3H), 3.55 (q, J= 7.0 Hz, 2H), 3.48 (m, 2H), 2.00 (s, 3H), 1.74 (m, 2H), 1.29 (s, 6H), 0.90 (t, J= 7.0 Hz, 3H).
Example 114
4-[(5,6,7,8-tetrahydro-3,8,8-trimethyl-2-naphthalenyl)ethenyl] benzoic acid (Compound 214)
Compound 214 was synthesized as described by Boehm and Al (J. Med. Chem., 1995, 38, 3146-3155), the entire disclosure of which is incorporated by reference herein.
Figure imgf000167_0001
Compounds possessing R5 as C(R'5R"5)COOH may be synthesized using the following synthetic scheme:
Scheme 13 carbonyl Insertion
Figure imgf000167_0003
Figure imgf000167_0002
1/Hyfdrogenolysιs 2/ Saponification
Figure imgf000167_0005
Figure imgf000167_0004
Example 115 l-Cyano-l-(triphenylphosphoranylidene)-2-oxo-2-[4-[5,6,7,8-Tetrahydro-5, 5,8,8- tetramethyl-3 -ethyloxy-2-naphthalenyl]phenyl]ethane (compound 215)
Figure imgf000168_0001
To a solution of 4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl]benzoyl benzoic acid (1.8998 g, 5.0 mmol, example 3) in 30 mL of CH2C12 was sequentially (cyanomethylene) friphenylphosphorane (1.6551 g, 5.5 mmol), DMAP (61.0 mg, 0.5 mmol) and triethylamine (0.76 mL, 5.5 mmol) followed by EDCI (1.0530 g, 5.5 mmol). The resulting mixture was stirred at 23° C for 24 h. After TLC analysis indicating the completion of reaction. The solvent was removed under reduced pressure. The residue was taken into 150 mL of ethyl acetate and washed with H2O (3 x 80 mL) and brine (80 mL). The organic layer was dried over MgSO , filtered and concentrated under reduced pressure. The crude product was further purified by flash column chromatography (SiO2, 4 x 20 cm, 1 : 1 ratio of ethyl acetate : hexane as eluant) to give desired product 1.0332 g (31%, theo. 3.3144 g) as a white solid. *H NMR (500 MHz, CDC13) 8.02(d, J=8.8 Hz, 2H), 7.85(d, J=8.8 Hz, 2H), 7.75-7.55(m, 15H), 7.38(s, IH), 6.85(s, IH), 3.94(q, J=6.8 Hz, 2H), 1.71(m, 4H), 1.33(s, 6H), 1.27(s, 6H), 1.1 l(t, J=6.8 Hz, 3H). Example 116 Methyl 2-oxo-2-[4-[5,6,7,8-texrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl]phenyl]acetate (compound 216).
Figure imgf000168_0002
To a solution of l-cyano-l-(triphenylphosphoranylidene)-2-oxo-2-[4-[5,6,7,8- Tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2-naphthalenyl]phenyl]ethane (0.8208 g, 1.24 mmol) in 40 mL of a 1:1 ratio mixture of CH2Cl2:MeOH was cooled to -78° C in a dry ice/acetone bath. A stream of ozone was bubbled into reaction mixture for 10 min until a blue colored solution persisted. The reaction mixture was allowed to slowly warm to 23° C, meanwhile a stream of nifrogen was bubbled into the solution to remove excess ozone. The solvent was removed under reduced pressure. The residue was taken into 40 mL of THF and treated with 10 L of 1.0 M aqueous AgNO3 solution. This mixture was stirred at 23° C for 24h. Filtered through a pad of celite and the celite cake was further rinsed with 200 mL of EtOAc. The filtrate was washed with H2O (3x100 mL) and brine (100 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was further purified by flash column chromatography (SiO2, 4 x 20 cm, 10% EtOAc/hexane as eluant) to give desired product 0.4072 g (78%, theo. 0.5225 g) as a pale yellow solid. !H NMR (500 MHz, CDC13) 8.08(d, J=8.3 Hz, 2H), 7.88(d, J=8.3 Hz, 2H), 7.48(s, IH), 6.84(s, IH), 4.02 (s, 3H), 3.90(q, J=6.8 Hz, 2H), 1.73(m, 4H), 1.33(s, 6H), 1.29(s, 6H), 0.98(t, J=6.8 Hz, 3H). Example 117 2-Oxo-2-[4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl]phenyl] acetic acid (compound 217)
Figure imgf000169_0001
Saponification of methyl 2-oxo-2-[4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy- 2-naphthalenyl] phenyljacetate according to the procedure described in Example 3 affords 2-Oxo-2-[4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl]phenyl] acetic acid as a white solid. H NMR (500 MHz, DMSO-d6) 7.82(d, J=8.8 Hz, 2H), 7.73 (d, J=8.8 Hz, 2H), 7.36(s, IH), 7.0 l(s, IH), 3.93(q, J=6.8 Hz, 2H), 1.67(m, 4H), 1.31(s, 6H), 1.23(s, 6H), 0.83(t, J=6.8 Hz, 3H). Example 118 2-Oxo-2-[4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methyl-2- naphthalenyl]phenyl] acetic acid (compound 218)
Figure imgf000170_0001
Compound 218 was synthesized from 4-[5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethyl-2- naphthalenyl]benzoyl benzoic acid according to the procedure described for the synthesis of Compound 217. *H NMR (500 MHz, DMSO-d6) 8.10(d, J=8.8 Hz, 2H), 7.87(d, J=8.8 Hz, 2H), 7.34(s, IH), 7.28(s, IH), 2.26(s, 3H), 1.66(m, 4H), 1.29(s, 6H), 1.17(s, 6H).
Example 119
Binding Assays [0192] Compounds of the invention were separately incubated with HNF-4α at varying concentrations in the presence of varying concentrations of radiolabeled methyl 4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2-naphthalenyl]benzoyl benzoate (Compound 103; Example 3) to determine each compound's binding affinity for HNF- 4α. Compounds were also separately incubated with RXRα in the presence of varying concentrations of radiolabeled 9-cis-retinoic acid to determine each compound's binding affinity for RXRα. Data for 20 compounds is provided in Table 1.
Figure imgf000171_0001
Table 1: Binding affinity. l Ki determined using [3H]-compound 103.2 Ki determined using [3H]-9-cis-RA.
Example 120
Co-Transfection
[0193] CV-1 cells (African green monkey kidney fibroblasts) were cultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% charcoal resin- stripped fetal bovine serum (CH-FBS) then transferred to 96-well microtiter plates one day prior to transfection. [0194] To determine HNF-4α receptor agonist and antagonist activity of the compounds of the present invention, the CV-1 cells were transiently transfected by FuGENE 6 transfection reagent in 175 cm2 flask with the following plasmids: pCMX- HNF-4αDF (3μg/flask), apoAl-LUC reporter (lμg/flask), and filler DNA (pcDNA; 3μg/flask). The receptor plasmid, pCMX-HNF-4αDF, contains the rat HNF-4αl under constitutive control of the CMV promoter, as more fully described in Fraser et al, "DNA binding and franscription activation specificity of hepatocyte nuclear factor 4" Nucl Acids Res., 16: 2702-2707 (1998). [0195] The reporter plasmid, apoAl-LUC, contains the cDNA for firefly luciferase (LUC) under control of a multimerized HNF-4α response element (the A site from the apo Al promoter) linked to the TK minimal promoter. See e.g., Fraser et al. supra. Twenty hours four after transfection, the cells were harvested and plated in 96 well plates at 10,000 cells/well. Media containing reference compounds (compound
168) as an HNF-4α receptor antagonist; and/or the modulator compounds of the present invention in concentrations ranging from 10-10 to 10-5 M were added to the cells. Three to four replicates were used for each sample. Transfections and subsequent procedures were performed on a Biomek 1000 automated laboratory work station. [0196] After 24 hours, the cells were washed with PBS, lysed with a Triton X- 100-based buffer and assayed for LUC activity using a NORTHSTAR HTS workstation. [0197] The mean and standard error of the mean (SEM) of the luciferase response were calculated. Data were plotted as the response of the compound compared to the reference compounds over the range of the dose-response curve. For agonist experiments, the effective concentration that produced 50% of the maximum response (EC50) was quantified. Agonist efficacy was a function (%) of LUC expression relative to the maximum LUC production by the reference agonist. Antagonist activity was determined by testing the amount of LUC expression in the absence of exogenous compound (presence only of any endogenous ligand) as HNF-4α receptor agonist. The concentration of a test compound that inliibited 50% of LUC expression was quantified (IC50). In addition, the efficacy of antagonists was determined as a function (%) of maximal inhibition. Data for 18 compounds are reported in Table 2.
Table 2: Agonist, partial agonist, antagonist and binding activity of HNF-4α receptor modulator compounds of present invention and the reference agonist compound, (compound 103) and reference antagonist compounds (compound 173). Efficacy (%) for HNF-4α agonist is determined by comparing activity (e.g., luciferase production) of putative agonist to that LGO 100695. Efficacy (%) for HNF~4α antagonist is determined by the percentage amount by which the luciferase production was reduced (maximum concentration of antagonist) from the luciferase production without compound.
Figure imgf000174_0001
1 na = not active (i.e. efficacy of <20 and potency of > 10,000 nM for the cotransfection assay and K; > 1000 nM for the binding assay) nd = not determined
[0198] The present invention includes any combination of the various species and subgeneric groupings falling within the generic disclosure. This invention therefore includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein. [0199] While in accordance with the patent statutes, description of the various embodiments and processing conditions have been provided, the scope of the invention is not to be limited thereto or thereby. Modifications and alterations of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention. [0200] Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims, rather than by the specific examples which have been presented merely to illustrate certain embodiments of the present invention.

Claims

What is claimed is:
1. A compound of formula I:
Figure imgf000176_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
R1 is selected from H, a halogen, SH, and OH;
R2 is selected from H, a halogen, a NR12R13, a sulfonamide, a nitro, a formyl, an acyl, a C1-C3 alkyl optionally substituted with one or more fluorines, a O2-C3 alkenyl optionally substituted with one or more fluorines, a C2-C3 akynyl, optionally substituted with one or more fluorines, a Ci-C2 alkoxy optionally substituted with one or more fluorines, a C1-C2 thioalkyl optionally substituted with one or more fluorines, a C2 alkenyl optionally substituted with one or more fluorines, a C2 akynyl optionally substituted with one or more fluorines, and a hydroxylamine optionally substituted with a CrC2 alkyl, a C2 alkenyl, a C2- akynyl, a Cι-C2 fluoroalkyl, a C2 fluoroalkenyl, or a C2 akynyl;
R is selected from H, a halogen, a nitro, a Ci- o alkyl optionally substituted with one or more halogens, C2-Cι0 alkenyl optionally substituted with one or more halogens, C2-C10 akynyl optionally substituted with one or more halogens, a Cι-C10 alkoxy optionally substituted with one or more halogens, a Ci-Cio thioalkyl optionally substituted with one or more halogens, a C2-C10 thioalkenyl optionally substituted with one or more halogens, C2-Cιo thioakynyl optionally substituted with one or more halogens, a NR14R15, and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with up to two R19 groups;
R4 is selected from H, a halogen, and OH;
RD is selected from CH2OH, CHO, COOH, and a C(RD)( R 5D\ )(COOH);
R5 and R5 are each independently selected from H, O, S and F; or R5 and R5" together form an O or S;
R6 and R7 are each independently selected from H, a halogen, a Cι-Cι2 alkyl optionally substituted with one or more R19 , a C2-Cι2 alkenyl optionally substituted with one or more Rlθ, a C2-Cι2 akynyl optionally substituted with one or more R19, a C]-Cι2 alkoxy optionally substituted with one or more R19, a d-Cι2 thioalkyl optionally substituted with one or more R19 , a C2-Cι2 thioalkenyl optionally substituted with one or more R19, a C2- 2 thioakynyl optionally substituted with one or more R19, a NR16R17, a NHC(O)R18 and null; or R6 and R7 taken together form an O, S, NH or CH2;
R8 and R9 are each independently selected from H, halogen, a methyl optionally substituted with one or more halogens, and null; or R8 and R9 taken together with Y form a three to five-membered optionally substituted carbocyclic ring; each R10 is independently selected from H, a halogen, and a methyl optionally substituted with one or more halogens; R11 and R1 ' are each independently selected from H, a halogen and OH; or R11 and R11 taken together form an O;
R12 and R13 are each independently a -C3 alkyl, optionally substituted with one or more halogens, a C2-C3 alkenyl optionally substituted with one or more halogens, or a C2-C3 akynyl optionally substituted with one or more halogens; or R12 and R13 taken together with the nitrogen atom to which they are both bound form a five to six- membered heterocyclic ring;
R14 and R15 are each independently selected from a Cι-C2 alkyl optionally substituted with one or more halogens, a C2 alkenyl optionally substituted with one or more halogens, and C2 akynyl optionally substituted with one or more halogens;
R16 and R17 are each independently selected from a Cι-Cι2 alkyl optionally substituted with one or more R19 , a C2-Cι2 alkenyl optionally substituted with one or more R , C2-C12 akynyl optionally substituted with one or more R19, and a five to six- membered carbocyclic or heterocyclic ring optionally substituted with one or more R19; or R16 and R17 taken together with the nifrogen atom to which they are both bound form a five to six-membered heterocyclic ring;
R18 is selected from a - o alkyl optionally substituted with one or more halogens, a C2-C10 alkenyl optionally substituted with one or more halogens, a C2-Cι0 akynyl optionally substituted with one or more halogens, and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with one or more R19;
R19 is selected from a halogen, a Cι-C4 alkyl optionally substituted with one or more fluorines, a C2-C4 alkenyl optionally substituted with one or more fluorines, C2-C akynyl, optionally substituted with one or more fluorines, a C1-C4 alkoxy optionally substituted with one or more halogens, a C1-C3 thioalkyl optionally substituted with one or more halogens, a C2-C3 thioalkenyl optionally substituted with one or more halogens, a C2-C3 thioakynyl optionally substituted with one or more halogens, a formyl and a nitro;
X and Y are each independently selected from O, S, N and C; wherein: if X is O or S, then each of R6 and R7 is null; if X is N, then one of R6 and R7 is null; if Y is O or S, then each of R and R is null; and if Y is N, then one of R and R is null.
2. The compound of claim 1, wherein: R1 is H or halogen;
R2 is selected from H, a halogen, a -C2 alkyl optionally substituted with one or more fluorines, a Cι-C2 alkoxy optionally substituted with one or more fluorines, a C]-C2 thioalkyl optionally substituted with one or more fluorines, and a NRπR12;
R is selected from H, a halogen, a Cι-C2 alkyl optionally substituted with one or more halogens, a C1-C2 alkoxy optionally substituted with one or more halogens, a - C2thioalkyl optionally substituted with one or more halogens, and a NR13R14;
R is H or a halogen; R5 is CH2OH, COOH or a C(R5')( R5")(COOH);
R5' and R5" are each independently selected from H and F; or R5 and R5 together form an O or S; and
R6 and R7 are each independently selected from H, a halogen, a Cι-C2 alkyl optionally substituted with one or more R19, a Cι-C2 alkoxy optionally substituted with one or more R19, a Cι-C2 thioalkyl optionally substituted with one or more R19, a NR16R17 and a NHC(O)R18; or R6 and R7 taken together form an O, S, NH or CH2.
3. The compound of claim 2, wherein: R10 is H or halogen;
R11 and R11' are each independently selected from H and a halogen; or R11 and R11 taken together form an O;
R12 and R13 are each independently selected from a -C3 alkyl optionally substituted with one or more halogens, a C2-C3 alkenyl optionally substituted with one or more halogens, a C2-C3 akynyl optionally substituted with one or more halogens;
R16 and R17 are each independently selected from a C2-C4 alkyl optionally substituted with one or more R19, a five to six membered carbocyclic or heterocyclic ring optionally substituted with one or more R19.
4. The compound of claim 3, wherein: X is C orN.
5. The compound of claim 3, wherein: X is O or S.
6. The compound of any one of claims 4 and 5, wherein: Y is C orN.
7. The compound of any one of claims 4 and 5, wherein: Y is O or S.
8. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 1.
9. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 2.
10. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound according to claim 3.
11. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 4.
12. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 5.
13. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 6.
14. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 7.
15. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 11.
16. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 2.
17. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 3.
18. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 4.
19. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 5.
20. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 6.
21. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 7.
22. The method according to any one of claims 15-21, wherein said method comprises treating said patient for a disease or condition selected from the group consisting of: syndrome X, non-insulin dependent diabetes mellitus, cancer, obesity, cardiovascular disease and dyslipidemia.
23. A compound of formula II:
Figure imgf000183_0001
II or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
R1 is selected from H, a halogen, SH, and OH;
R is selected from H, a halogen, a NR R , a sulfonamide, a nitro, a foπnyl, an acyl optionally substituted with one or more halogens, a C1-C3 alkyl optionally substituted with one or more fluorines, a -C3 alkenyl optionally substituted with one or more fluorines, a -C3 akynyl optionally substituted with one or more fluorines, a C1-C2 alkoxy optionally substituted with one or more fluorines, a Cι-C2 thioalkyl optionally substituted with one or more fluorines, a C2 thioalkenyl optionally substituted with one or more fluorines, a C2 akynyl optionally substituted with one or more fluorines, and a hydroxylamine optionally substituted with a C]-C2 alkyl, a C2 alkenyl, a C2 akynyl, a Cι-C2 fluoroalkyl, a C2 fluoralkenyl, or a C2 fluoroakynyl,;
R3 is selected from H, a halogen, a nitro, a Ci-Cio alkyl optionally substituted with one or more halogens, a C2-Cιo alkenyl optionally substituted with one or more halogens, a C2-C6 akynyl optionally substituted with one or more halogens, a -C10 alkoxy optionally substituted with one or more halogens, a -C 10 thioalkyl optionally substituted with one or more halogens, a C2-C10 thioalkenyl optionally substituted with one or more halogens, a C2-C 10 thioakynyl optionally substituted with one or more halogens, a NR R15, and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with up to two R19 groups;
R4 is selected from H, a halogen, and OH;
R5 is selected from CH2OH, CHO, COOH, and a C(R5)( R5')(COOH);
R5 and R5 are each independently selected from H, O, S and F; or R5 and R5 together form an O or S;
R6 and R7 are each independently selected from H, a halogen, a Cι-Cι2 alkyl optionally substituted with one or more R19, a C2-Cι2 alkenyl optionally substituted with one or more R19, a C2-Cι2 akynyl optionally substituted with one or more R19, a C1- 2 alkoxy optionally substituted with one or more R19, a C Cι2 thioalkyl optionally substituted with one or more R , a C2-Cι2 thioalkenyl optionally substituted with one or more R19, a C2-Cι2 thioakynyl optionally substituted with one or more R19, a NR16R17, a NHC(O)R18 and null; or R6 and R7 taken together form an O, S, NH or CH2;
R8 and R9 are each independently selected from H, halogen, a methyl optionally substituted with one or more halogens, and null; or R8 and R9 taken together with Y form a three to five-membered optionally substituted carbocyclic ring;
R12 and R13 are each independently C1-C3 alkyl optionally substituted with one or more halogens, a C2-C3 alkenyl optionally substituted with one or more halogens, or a C2-C3 akynyl optionally substituted with one or more halogens; or R12 and R13 taken together with the nitrogen atom to which they are both bound form a five to six- membered heterocyclic ring; R14 and R15 are each independently a Cι-C2 alkyl optionally substituted with one or more halogens, a C2 alkenyl optionally substituted with one or more halogens, or a C2 akynyl optionally substituted with one or more halogens;
R16 and R17 are each independently selected from a Cι-C12 alkyl optionally substituted with one or more R19, a C2-Cι2 alkenyl optionally substituted with one or more R19, a C2-C12 akynyl optionally substituted with one or more R19, and a five to six- membered carbocyclic or heterocyclic ring optionally substituted with one or more R19; or R16 and R17 taken together with the nitrogen atom to which they are both bound form a five to six-membered heterocyclic ring;
R18 is selected from a Ci-Cio alkyl optionally substituted with one or more halogens, a C2-C10 alkenyl optionally substituted with one or more halogens, a C2-Cι0 akynyl optionally substituted with one or more halogens, and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with one or more R19;
R19 is selected from a halogen, a Cι-C4 alkyl optionally substituted with one or more fluorines, a C2-C4 alkenyl optionally substituted with one or more fluorines, a C2- C4 akynyl optionally substituted with one or more fluorines, a Cι-C4 alkoxy optionally substituted with one or more halogens, a -C3 thioalkyl optionally substituted with one or more halogens, a C2-C3 thioalkenyl optionally substituted with one or more halogens, a C2-C3 thioakynyl, optionally substituted with one or more halogens, a formyl and a nitro;
X and Y are each independently selected from O, S, N and C; wherein: if X is O or S, then each of R6 and R7 is null; if X is N, then one of R6 and R7 is null; if Y is O or S, then each of R8 and R9 is null; and if Y is N, then one of R8 and R9 is null.
24. The compound of claim 23, wherein: R1 is H or halogen;
R2 is selected from H, a halogen, a Cι-C2 alkyl optionally substituted with one or more fluorines, a Cι-C2 alkoxy optionally substituted with one or more fluorines, a Cι-C2 thioalkyl optionally substituted with one or more fluorines, and a NR R ;
R3 is selected from H, a halogen, a Cι-C2 alkyl optionally substituted with one or more halogens, a Cι-C2 alkoxy optionally substituted with one or more halogens, a Cι-C2 thioalkyl optionally substituted with one or more halogens, and a NR13R14;
R is H or a halogen;
R5 is CH2OH, COOH or C(R5')( R5")(COOH);
R5 and R5 are each independently selected from H and F; or R5 and R5 together form an O or S; and
R6 and R7 are each independently selected from H, a halogen, a Cι-C2 alkyl optionally substituted with one or more R19, a Cι-C2 alkoxy optionally substituted with one or more R19, a Cι-C2 thioalkyl optionally substituted with one or more R19, a
NRI6R17 and a NHC(O)R18; or R6 and R7 taken together foπn an O, S, NH or CH2.
25. The compound of claim 24, wherein: R12 and R13 are each independently a Cι-C3 alkyl C2-C6 alkenyl, C2-C6 akynyl, optionally substituted with one or more halogens;
R16 and R17 are each independently selected from a C2-C4 alkyl optionally substituted with one or more R19, and a five to six membered carbocyclic or heterocyclic ring optionally substituted with one or more R19.
26. The compound of claim 25, wherein: X is C or N.
27. The compound of claim 25, wherein: X is O or S.
28. The compound of any one of claims 26 and 27, wherein: Y is C or N.
29. The compound of any one of claims 26 and 27, wherein: Y is O or S.
30. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound according to claim 23.
31. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound according to claim 24.
32. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound according to claim 25.
33. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound according to claim 26.
34. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound according to claim 27.
35. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound according to claim 28.
36. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound according to claim 29.
37. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 23.
38. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 24.
39. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 25.
40. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 26.
41. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 27.
42. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 28.
43. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 29.
44. The method according to any one of claims 37-43, wherein said method comprises treating said patient for a disease or condition selected from the group consisting of: syndrome X, non-insulin dependent diabetes mellitus, cancer, obesity, cardiovascular disease and dyslipidemia.
45. A compound of formula III:
Figure imgf000189_0001
III
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein
R1 is selected from H, a halogen, SH, and OH;
R2 is selected from H, a halogen, a NR12R13, a sulfonamide, a nitro, a formyl, an acyl optionally substituted with one or more halogens, a Cι-C3 alkyl optionally substituted with one or more fluorines, a C2-C3 alkenyl optionally substituted with one or more fluorines, C2-C3 akynyl optionally substituted with one or more fluorines, a C1-C2 alkoxy optionally substituted with one or more fluorines, a Cι-C2 thioalkyl optionally substituted with one or more fluorines, a C2-C6 thioalkenyl optionally substituted with one or more fluorines, aC2-C6 thioakynyl optionally substituted with one or more fluorines, and a hydroxylamine optionally substituted with a Cι-C2 alkyl, a C2 alkenyl, a C2 akynyl, a CpC2 fluoroalkyl, a C2 fluoroalkenyl, or C2 fluoroakynyl;
R3 is selected from H, a halogen, a nitro, a Cι-C10 alkyl optionally substituted with one or more halogens, C2-Cιo alkenyl optionally substituted with one or more halogens, C2-Cιo akynyl optionally substituted with one or more halogens, a -Cio alkoxy optionally substituted with one or more halogens, a Cr o thioalkyl optionally substituted with one or more halogens, C2-Cιo thioalkenyl optionally substituted with one or more halogens, C2-Cιo thioakynyl optionally substituted with one or more halogens, a NR14R15, and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with up to two R19 groups;
R4 is selected from H, a halogen, and OH;
R5 is selected from CH2OH, CHO, COOH, and a C(R5')( R5")(COOH);
R5 and R5 are each independently selected from H, O, S and F; or R5 and R5 together form an O or S;
R and R are each independently selected from H, a halogen, a methyl optionally substituted with one or more halogens, and null; or R8 and R9 taken together with Y form a three to five-membered optionally substituted carbocyclic ring; R12 and R13 are each independently a -C3 alkyl optionally substituted with one or more halogens, a C2-C3 alkenyl optionally substituted with one or more halogens, or a C2-C3 akynyl optionally substituted with one or more halogens; or R12 and R13 taken together with the nitrogen atom to which they are both bound form a five to six- membered heterocyclic ring;
R14 and R15 are each independently a Cχ-C2 alkyl optionally substituted with one or more halogens, a C2 alkenyl optionally substituted with one or more halogens, or a C2 akynyl optionally substituted with one or more halogens;
R19 is selected from a halogen, a Cι-C4 alkyl optionally substituted with one or more fluorines, a C2-C4 alkenyl optionally substituted with one or more fluorines, a C2- C4 akynyl, optionally substituted with one or more fluorines, a Cι-C4 alkoxy optionally substituted with one or more halogens, a C1-C3 thioalkyl optionally substituted with one or more halogens, a C2-C6 thioalkenyl optionally substituted with one or more halogens, a C2-C6 thioakynyl optionally substituted with one or more halogens, a formyl and a nitro;
Y is selected from O, S, N and C; wherein: ifY is O or S, then each of R and R is null; and ifY is N, then one of R and R is null.
46. The compound of claim 45, wherein: R1 is H or halogen; R2 is selected from H, a halogen, a Cι-C2 alkyl optionally substituted with one or more fluorines, a Cι-C2 alkoxy optionally substituted with one or more fluorines, a d-C2 thioalkyl optionally substituted with one or more fluorines, and a NRπR12;
R3 is selected from H, a halogen, a Cι-C2 alkyl optionally substituted with one or more halogens, a Cι-C2 alkoxy optionally substituted with one or more halogens, a Cι-C2 thioalkyl optionally substituted with one or more halogens, and a NR13R14;
R4 is H or a halogen;
R5 is CH2OH, COOH or a C(R5')( R5")(COOH); and
R5 and R5 are each independently selected from H and F; or R5 and R5 together form an O or S.
47. The compound of claim 46, wherein: R12 and R13 are each independently a C1-C3 alkyl optionally substituted with one or more halogens.
48. The compound of claim 47, wherein: Y is C orN.
49. The compound of claims 47 wherein: Y is O or S.
50. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 45.
51. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 46.
52. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 47.
53. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 48.
54. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 49.
55. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 45.
56. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 46.
57. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 47.
58. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 48.
59. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 49.
60. The method according to any one of claims 55-59, wherein said method comprises treating said patient for a disease or condition selected from the group consisting of: syndrome X, non-insulin dependent diabetes mellitus, cancer, obesity, cardiovascular disease and dyslipidemia.
61. A compound of formula TV:
Figure imgf000194_0001
rv
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
R1 is selected from H, a halogen, SH, and OH;
R2 is selected from H, a halogen, a NR12R13, a sulfonamide, a nitro, a formyl, an acyl, a C1-C3 alkyl optionally substituted with one or more fluorines, a C2-C3 alkenyl optionally substituted with one or more fluorines, a C2-C3 akynyl optionally substituted with one or more fluorines, a Cι-C2 alkoxy optionally substituted with one or more fluorines, a Q-C2 thioalkyl optionally substituted with one or more fluorines, a C2 thioalkenyl optionally substituted with one or more fluorines, a C2 thioakynyl optionally substituted with one or more fluorines, and a hydroxylamine optionally substituted with a d-C2 alkyl, a C2 alkenyl, a C2 akynyl, a d-C2 fluoroalkyl, a C2 fluoroalkenyl, or C2 fluoroakynyl;
R3 is selected from H, a halogen, a nitro, a C1-C10 alkyl optionally substituted with one or more halogens, a C2-do alkenyl optionally substituted with one or more halogens, C2-Cι0 akynyl optionally substituted with one or more halogens, a - o alkoxy optionally substituted with one or more halogens, a Cr o thioalkyl optionally substituted with one or more halogens, a C2-Cιo thioalkenyl optionally substituted with one or more halogens, a C2-C10 thioakynyl optionally substituted with one or more halogens, a NR1 R15, and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with up to two R19 groups;
R is selected from H, a halogen, and OH;
R5 is selected from CH2OH, CHO, COOH, and a C(R5')( R5")(COOH);
R5 and R5 are each independently selected from H, O, S and F; or R5 and R5 together form an O or S;
R6 is selected from H, a halogen, a Cι-Cι2 alkyl optionally substituted with one or more R19, a C2-Cj2 alkenyl optionally substituted with one or more R19, a C2-Cι2 akynyl optionally substituted with one or more R19, a Cι-Cn alkoxy optionally substituted with one or more R19, a Cι-C12 thioalkyl optionally substituted with one or more R19, a C2-Cι2 thioalkenyl optionally substituted with one or more R19, a C2-Cι2 thioakynyl optionally substituted with one or more R19, a NR16R17, a NHC(O)R18 and null;
R8 and R9 are each independently selected from H, a halogen, a methyl optionally substituted with one or more halogens, and null; or R8 and R9 taken together with Y form a tliree to five-membered optionally substituted carbocyclic ring;
R12 and R13 are each independently a C1-C3 alkyl optionally substituted with one or more halogens, a C2-d alkenyl optionally substituted with one or more halogens, or a -d akynyl optionally substituted with one or more halogens; or R12 and R13 taken together with the nitrogen atom to which they are both bound form a five to six- membered heterocyclic ring;
R14 and R15 are each independently a d-C2 alkyl optionally substituted with one or more halogens, a C2 alkenyl optionally substituted with one or more halogens, or a C2 akynyl optionally substituted with one or more halogens;
R16 and R17 are each independently selected from a Cι-Cι2 alkyl optionally substituted with one or more R19, a C2-Cι2 alkenyl optionally substituted with one or more R19, a C2-C]2 akynyl optionally substituted with one or more R19, and a five to six- membered carbocyclic or heterocyclic ring optionally substituted with one or more R19; or R16 and R17 taken together with the nifrogen atom to which they are both bound form a five to six-membered heterocyclic ring;
R18 is selected from a - o alkyl optionally substituted with one or more halogens, a C2-Cιo alkenyl optionally substituted with one or more halogens, a C2-C6 akynyl optionally substituted with one or more halogens, and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with one or more R1 ;
R19 is selected from a halogen, a d-C4 alkyl optionally substituted with one or more fluorines, a C2-C4 alkenyl optionally substituted with one or more fluorines, a C2- C4 akynyl optionally substituted with one or more fluorines, a d-C4 alkoxy optionally substituted with one or more halogens, a C1-C3 thioalkyl optionally substituted with one or more halogens, a C2-d thioalkenyl optionally substituted with one or more halogens, a C2-d thioakynyl, optionally substituted with one or more halogens, a formyl and a nitro; R20 is selected from a C4-C5 alkyl optionally substituted with one or more halogens, a C4-C5 alkenyl optionally substituted with one or more halogens, a C4-C4 akynyl optionally substituted with one or more halogens, a phenyl optionally substituted with one or more fluorines, a thienyl optionally substituted with one or more fluorines, and a benzyl optionally substituted with one or more R19;
X is selected from O and NH;
Y is selected from O, S, N, and C; and
Z is selected from CH2, NH, and phenylene; wherein: if Y is O or S, then each of R and R is null; and if Y is N, then one of R and R 9 : i„s null
62. The compound of claim 61, wherein: R1 is H or halogen;
R2 is selected from H, a halogen, a Cι-C2 alkyl optionally substituted with one or more fluorines, a Cι-C2 alkoxy optionally substituted with one or more fluorines, a Cι-C2 thioalkyl optionally substituted with one or more fluorines, and a NRUR 2;
R3 is selected from H, a halogen, a -d alkyl optionally substituted with one or more halogens, a -d alkoxy optionally substituted with one or more halogens, a fully saturated Ci- thioalkyl optionally substituted with one or more halogens, and a
NR13R14; R is H or a halogen;
R5 is CH2OH, COOH or a C(R5')( R5 )(COOH);
R5 and R5 are each independently selected from H and F; or R5 and R5" together form an O or S; and
R6 is selected from H, a halogen, a Cι-C2 alkyl optionally substituted with one or more R19, a d-d alkoxy optionally substituted with one or more R19, a d-d thioalkyl optionally substituted with one or more R19, a NR16R17 and a NHC(O)R18.
63. The compound of claim 62, wherein: R12 and R13 are each independently a d- alkyl optionally substituted with one or more halogens, a C2-d alkenyl optionally substituted with one or more halogens, a C2-d akynyl optionally substituted with one or more halogens;
R16 and R17 are each independently selected from a C2-C4 alkyl optionally substituted with one or more R19, a five to six membered carbocyclic or heterocyclic ring optionally substituted with one or more R19.
64. The compound of claim 63, wherein: X is O.
65. The compound of claim 63, wherein: X is H.
66. The compound of any one of claims 64 and 65, wherein: Y is C orN.
67. The compound of any one of claims 64 and 65, wherein: Y is O or S.
68. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 61.
69. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 62.
70. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 63.
71. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 64.
72. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 65.
73. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 66.
74. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 67.
75. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 61.
76. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a phaπnaceutically effective amount of a compound of claim 62.
77. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 63.
78. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 64.
79. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 65.
80. A method of freating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 66.
81. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 67.
82. The method according to any one of claims 75-81, wherein said method comprises treating said patient for a disease or condition selected from the group consisting of: syndrome X, non-insulin dependent diabetes mellitus, cancer, obesity, cardiovascular disease and dyslipidemia.
83. A compound of formula V:
Figure imgf000201_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
R1 is selected from H, a halogen, SH, and OH;
R2 is selected from H, a halogen, a NR12R13, a sulfonamide, a nitro, a formyl, an acyl, a C1-C3 alkyl optionally substituted with one or more fluorines, a C2-d alkenyl optionally substituted with one or more fluorines, a C2-d akynyl optionally substituted with one or more fluorines, a d- alkoxy optionally substituted with one or more fluorines, a d- thioalkyl optionally substituted with one or more fluorines, a C2 thioalkenyl optionally substituted with one or more fluorines, a C2 thioakynyl optionally substituted with one or more fluorines, and a hydroxylamine optionally substituted with a C1-C2 alkyl, a alkenyl, a C2 akynyl, a d- fluoroalkyl, a C2 fluoroalkenyl, or a C2 fluoroakynyl;
R3 is selected from H, a halogen, a nitro, a d-Cio alkyl optionally substituted with one or more halogens, a C2-Cιo alkenyl optionally substituted with one or more halogens, C2-Cιo akynyl optionally substituted with one or more halogens, a d-Cio alkoxy optionally substituted with one or more halogens, a Cj-Cio thioalkyl optionally substituted with one or more halogens, a C2-Cιo alkenyl optionally substituted with one or more halogens, a C2-Cιo akynyl optionally substituted with one or more halogens, a NR14R15, and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with up to two R19 groups;
R4 is selected from H, a halogen, and OH;
R5 is selected from CH2OH, CHO, COOH, and a C(R5')( R5")(COOH);
R5' and R5 ' are each independently selected from H, O, S and F; or R5' and R5" together form an O or S;
R8 and R9 are each independently selected from H, a halogen, a methyl optionally substituted with one or more halogens, and null; or R8 and R9 taken together with Y form a three to five-membered optionally substituted carbocyclic ring;
R12 and R13 are each independently a C1-C3 alkyl optionally substituted with one or more halogens, a C2-d alkenyl optionally substituted with one or more halogens, or a C2-C3 akynyl optionally substituted with one or more halogens; or R12 and R13 taken together with the nitrogen atom to which they are both bound form a five to six- membered heterocyclic ring;
R14 and R15 are each independently a d-C2 alkyl optionally substituted with one or more halogens, a C2 alkenyl optionally substituted with one or more halogens, or C2 akynyl optionally substituted with one or more halogens;
R19 is selected from a halogen, a Cj-C4 alkyl optionally substituted with one or more fluorines, a C2-C4 alkenyl optionally substituted with one or more fluorines, or a
C2-C4 akynyl optionally substituted with one or more fluorines, a d-C4 alkoxy optionally substituted with one or more halogens, a C1-C3 thioalkyl optionally substituted with one or more halogens, a C2-d thioalkenyl optionally substituted with one or more halogens, a C2-d thioakynyl, optionally substituted with one or more halogens, a formyl and a nitro;
R is selected from a C4-C5 alkyl optionally substituted with one or more halogens a C4-d alkenyl optionally substituted with one or more halogens, a C4-C5 akynyl optionally substituted with one or more halogens optionally substituted with one or more halogens, a phenyl optionally substituted with one or more fluorines, a thienyl optionally substituted with one or more fluorines, and a benzyl optionally substituted with one or more R19;
Y is selected from O, S, N, and C; and
Z is selected from CH2, NH, and phenylene; wherein: if Y is O or S, then each of R and R is null; and if Y is N, then one of R8 and R9 is null.
84. The compound of claim 83, wherein: R1 is H or halogen;
R2 is selected from H, a halogen, a Cι-C2 alkyl optionally substituted with one or more fluorines, a d-C2 alkoxy optionally substituted with one or more fluorines, a Cι-C2 thioalkyl optionally substituted with one or more fluorines, and a NRnR12; R3 is selected from H, a halogen, a d-C2 alkyl optionally substituted with one or more halogens, a Cι-C2 alkoxy optionally substituted with one or more halogens, a d-C2 thioalkyl optionally substituted with one or more halogens, and a NR13R14;
R4 is H or a halogen;
R5 is CH2OH, COOH or a C(R5')( R5")(COOH); and
R5 and R5 ' are each independently selected from H and F; or R5' and R5" together foπn an O or S.
85. The compound of claim 84, wherein: R12 and R13 are each independently a d-d alkyl optionally substituted with one or more halogens, a C2-d alkenyl optionally substituted with one or more halogens, or a d-d akynyl optionally substituted with one or more halogens;
86. The compound of claim 85, wherein: Y is C orN.
87. The compound claim 85, wherein: Y is O or S.
88. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 83.
89. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 84.
90. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 85.
91. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 86.
92. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 87.
93. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 83.
94. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 84.
95. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a phannaceutically effective amount of a compound of claim 85.
96. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 86.
97. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 87.
98. The method according to any one of claims 93-97, wherein said method comprises treating said patient for a disease or condition selected from the group consisting of: syndrome X, non-insulin dependent diabetes mellitus, cancer, obesity, cardiovascular disease and dyslipidemia.
99. A compound of formula VI:
Figure imgf000206_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
R1 is selected from H, a halogen, SH, and OH;
R2 is selected from H, a halogen, a NR12R13, a sulfonamide, a nitro, a formyl, an acyl optionally substituted with one or more halogens, a d- alkyl optionally substituted with one or more fluorines, a C2-d alkenyl optionally substituted with one or more fluorines, a C2-d akynyl optionally substituted with one or more fluorines, a Cj-C2 alkoxy optionally substituted with one or more fluorines, a Cι-C2 thioalkyl optionally substituted with one or more fluorines d thioalkenyl optionally substituted with one or more fluorines, a C2 thioakynyl optionally substituted with one or more fluorines, and a hydroxylamine optionally substituted with a d-C2 alkyl, a C2 alkenyl, a akynyl, a d- d fluoroalkyl, a fluoroalkenyl, or a d fluoroakynyl,;
R3 is selected from H, a halogen, a nitro, a d-do alkyl optionally substituted with one or more halogens, a d-Cio alkenyl optionally substituted with one or more halogens, a d-Cio akynyl, optionally substituted with one or more halogens, a d-do alkoxy optionally substituted with one or more halogens, a d-Cio thioalkyl optionally substituted with one or more halogens, a C2-Cιo thioalkenyl optionally substituted with one or more halogens, a C2-C10 thioakynyl optionally substituted with one or more halogens, a NR , 14- Rn lS , and a five to six-membered carbocyclic or heterocyclic ring optionally substituted with up to two R19 groups;
R4 is selected from H, a halogen, and OH;
R5 is selected from CH2OH, CHO, COOH, and a C(R5')( R5")(COOH);
R5 and R5" are each independently selected from H, O, S and F; or R5' and R5" together form an O or S;
R and R are each independently a C1-C3 alkyl optionally substituted with one or more halogens, a C2-d alkenyl optionally substituted with one or more halogens, or a C2-d akynyl optionally substituted with one or more halogens; or R12 and R13 taken together with the nitrogen atom to which they are both bound form a five to six- membered heterocyclic ring;
R14 and R15 are each independently a Cι-C2 alkyl optionally substituted with one or more halogens, a C2 alkenyl optionally substituted with one or more halogens, or a C2 akynyl, optionally substituted with one or more halogens;
R19 is selected from a halogen, a C1-C4 alkyl optionally substituted with one or more fluorines, a C2-d alkenyl optionally substituted with one or more fluorines, a C2- C4 akynyl optionally substituted with one or more fluorines, a C1-C4 alkoxy optionally substituted with one or more halogens, a C1-C3 thioalkyl optionally substituted with one or more halogens, a d-d thioalkenyl optionally substituted with one or more halogens, a d-d thioakynyl optionally substituted with one or more halogens, a formyl and a nitro; and A is selected from O, CH2, CF2, and S.
100. The compound of claim 99, wherein: R1 is H or halogen;
R2 is selected from H, a halogen, a C1-C2 alkyl optionally substituted with one or more fluorines, a d-d alkoxy optionally substituted with one or more fluorines, a Ci-d thioalkyl optionally substituted with one or more fluorines, and a NRnR12;
R3 is selected from H, a halogen, a d-d alkyl optionally substituted with one or more halogens, a Cι-C2 alkoxy optionally substituted with one or more halogens, a d-C2 thioalkyl optionally substituted with one or more halogens, and a NR^R1 ;
R4 is H or a halogen;
R5 is CH2OH, COOH or a C(R5')( R5")(COOH);
R5 and R5" are each independently selected from H and F; or R5 and R5 together form an O or S; and
101. The compound of claim 100, wherein: A is O or CH2.
102. The compound of claim 100, wherein: A is CF2 or S.
103. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 99.
104. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 100.
105. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 101.
106. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 102.
107. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 99.
108. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 100.
109. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 101.
110. A method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 102.
111. The method according to any one of claims 107- 110, wherein said method comprises treating said patient for a disease or condition selected from the group consisting of: syndrome X, non-insulin dependent diabetes mellitus, cancer, obesity, cardiovascular disease and dyslipidemia.
112. A compound selected from the group consisting of; 4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl]benzoyl benzoic acid (Compound 103);
4-[5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-l-hydroxy-2-naphthalenyl]benzoyl benzoic acid (Compound 104);
4-[5,6,7,8-tetτahydro-5,5,8,8-tetramethyl-3-(l,l,l-trifluoroethoxy)-2- naphthalenyl]benzoyl benzoic acid (Compound 105);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-propoxy-2-naphthalenyl]benzoyl benzoic acid (Compound 106);
4-[5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-4-nitro-2-naphthalenyl]benzoyl benzoic acid (Compound 108);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-4-nitro-2- naphthalenyl]benzoyl benzoic acid (Compound 109);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(2,2-difluoroethoxy)-4-nitro-2- naphthalenyl]benzoyl benzoic acid (Compound 110);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methoxy-2- naphthalenyl)methyl]benzoic acid (Compound 117);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-wo-propoxy-2- naphthalenyl)methyl]benzoic acid (Compound 118); 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2- naphthalenyl)methyl]benzoic acid (Compound 119);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(l,l,l-trifuoroethoxy)-2- naphthalenyl)methyl]benzoic acid (Compound 120);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-propoxy-2- naphthalenyl)methyl]benzoic acid (Compound 121);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-butoxy-2- naphthalenyl)methyl]benzoic acid (Compound 122);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-heptoxy-2- naphthalenyl)methyl]benzoic acid (Compound 123);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methyl-4-^»-tolenesulfonamido-2- naphthalenyl) methyl]benzoic acid (Compound 124);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methyl-4-ethylamino-2- naphthalenyl)methyl]benzoic acid (Compound 125);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methyl-4-propylamino-2- naphthalenyl)methyl] benzoic acid (Compound 126);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(2-fluorophenyl)-2- naphthalenyl]benzoyl benzoic acid (Compound 128);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-phenyl-2-naphthalenyl]benzoyl benzoic acid (Compound 129); 4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(3-thienyl)-2-naphthalenyl]benzoyl benzoic acid (Compound 130);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(4-fluorophenyl)-2- naphthalenyl]benzoyl benzoic acid (Compound 131);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(3-nitrophenyl)-2- naphthalenyl]benzoyl benzoic acid (Compound 132);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(N-methyl-N-ethylamino)-2- naphthalenyl]benzoyl benzoic acid (Compound 134);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(2-fluorophenyl)-4-nitro-2- naphthalenyl]benzoyl benzoic acid (Compound 136);
4-[(5,6,7,8-tetrahydro-3,8,8-trimethyl-4-nitro-2-naphthalenyl)benzoyl] benzoic acid (Compound 137);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-l-fluoro-3-ethoxy-2- naphthalenyl]benzoyl benzoic acid (Compound 141);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-l-fluoro-3-ethoxy-4-nitro-2- naphthalenyl] benzoyl benzoic acid (Compound 142);
4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl]benzoyl-3- chloro-benzoic acid (Compound 144);
4-[(5,6,7,8-tefrahydro-3,5,5,8,8-tetramethyl-2-naphthalenyl)(2-fluorobenzyloxy) methyl] benzoic acid (Compound 149); 4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4-fluorobenzyloxy) methyfjbenzoic acid (Compound 150);
4-[(5,6,7,8-tetrahydro-3, 5,5,8, 8-pentamethyl-2-naphthalenyl)(2-thifluoromethoxy benzyloxy) methyl]benzoic acid (Compound 151);
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-tetramethyl-2-naphthalenyl)(2,3- difluorobenzyloxy) methyl] benzoic acid (Compound 152);
4-[(5,6,7,8-tetrahydro-3, 5,5,8, 8-tetramethyl-2-naphthalenyl)(4-trifluoromethyl benzyloxy) methyl] benzoic acid (Compound 153);
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4-trifluoromethoxy benzyloxy) methyl] benzoic acid (Compound 154);
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4- trifluorothiomethoxy benzyloxy) methyl] benzoic acid (Compound 155);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl)(2,3-difluoro benzyloxy) methyl]benzoic acid (Compound 156);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl)(4-fluoro benzyloxy)methyl] benzoic acid (Compound 157);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naρhthalenyl)(2- fluorobenzyloxy)methyl] benzoic acid (Compound 158);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl) (benzyloxy)methyl]benzoic acid (Compound 159); 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethoxy-2-naphthalenyl) (butyloxy)methyl]benzoic acid (Compound 160);
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(phenylacetamido) methyl] benzoic acid (Compound 162);
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(3- fluorobenzylamino) methyl] benzoic acid (Compound 163);
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4- fluorobenzylamino) methyl] benzoic acid (Compound 164);
4-[(5,6,7,8-tefrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)( benzylamino) methyl] benzoic acid (Compound 165);
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4-trifluoromethyl phenoxy)methyl]benzoic acid (Compound 166);
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4-tert- butylbenzylthio)methyl] benzoic acid (Compound 167);
4-[(5,6,7,8-tefrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4- fluorophenyloxy)methyl]benzoic acid (Compound 168);
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4-tert- butylphenyloxy) methyl]benzoic acid (Compound 169);
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4- phenylphenyloxy) methyl]benzoic acid (Compound 170); 4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)(4-phenoxy) methyl]benzoic acid (Compound 171);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramefhyl-3-ethoxy-2-naphthalenyl)(4-tert- butylbenzylthio) methyl]benzoic acid (Compound 172);
4-[(phenylhydrazino)(5,6,7,8-tefrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)]benzoic acid (Compound 173);
4-[(phenylhydrazino)(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)] benzoic acid (Compound 174);
4-[(phenylhydrazino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4-ethoxy-2- naphthalenyl)]benzoic acid (Compound 175);
4-[(Pyridine-2-hydrazonyl)(5,6,7,8-tetrahydro-5,5,8,8-teframethyl-3-ethyloxy-2- naphthalenyl)]benzoyl benzoic acid (Compound 176);
4-[(2,4-difluorophenylhydrazino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4- ethoxy-2-naphthalenyl)]benzoic acid (Compound 177);
4-[(2,5-difluorophenylhydrazino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4- ethoxy-2-naphthalenyl)]benzoic acid (Compound 178);
4-[(2,5-dimethylphenylhydrazino)(5,6,7,8-tetτahydro-5,5,8,8-tetramethyl-4- ethoxy-2-naphthalenyl)]benzoic acid (Compound 179);
4-[(2-fluorophenylhydrazino)(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2- naphthalenyl)]benzoic acid (Compound 180); 4-[(phenylimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4-ethoxy-2- naphthalenyl)] benzoic acid (Compound 183);
4-[(4,4,4-trifluorobutoximino)(5,6,7,8-tetrahydro-5,5,8,8-teframethyl-3-ethyloxy- 2-naphthalenyl)]benzoic acid (Compound 184);
4-[(ethoxyimino)(5,6,7,8-tefrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)] benzoic acid (Compound 185);
4-[(propoxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy -2- naphthalenyl)]benzoic acid (Compound 186);
4-[(butoxyimino)(5,6,7,8-tefrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)]benzoic acid (Compound 187);
4-[(pentoxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)]benzoic acid (Compound 188);
4-[(hexyloxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)]benzoic acid (Compound 189);
4-[(3-methyl-butoxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)] benzoic acid (Compound 190);
4-[(decyloxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl)]benzoic acid (Compound 191);
4-[(2,3-difluorobenzyloxyimino)(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3- ethyloxy-2-naphthalenyl)] benzoic acid (Compound 192); 6-(2,3-dihydro-4,4-dimethyl-7-ethoxybenzopyranyl)benzoyl benzoic acid (Compound 201);
6-[(2,3-dihydro-4,4-dimethyl-7-ethoxy-benzothiopyranyl)]benzoyl benzoic acid (Compound 202);
6-(2,3-dihydro-4,4,7-frimethyl-8nitro-benzopyranyl)benzoyl benzoic acid (Compound 203);
7-[l,4,4-trimethyl-5-methyl-6-methoxyl,2,3,4-tetrahydroquinoline]benzoyl benzoic acid (Compound 212);
7-[l,4,4-trimethyl-5-methyl-6-ethoxyl,2,3,4-tetrahydroquinoline]benzoyl benzoic acid (Compound 213);
4-[(5,6,7,8-tetrahydro-3,8,8-trimethyl-2-naphthalenyl)ethenyl] benzoic acid (Compound 214);
2-Oxo-2-[4-[5,6,7,8-tefrahydro-5,5,8,8-tetramethyl-3-ethyloxy-2- naphthalenyl]phenyl]acetic acid (compound 217); and
2-Oxo-2-[4-[5,6,7,8-tetrahydro-5,5,8,8-teframethyl-3-methyl-2- naphthalenyl]phenyl] acetic acid (compound 218); and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
113. A pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of claim 112.
114. A method of treating a patient having a disease or condition selected from the group of syndrome X, non-insulin dependent diabetes mellitus, cancer, obesity, cardiovascular disease and dyslipidemia comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 112.
PCT/US2004/022907 2003-07-16 2004-07-16 HEPATOCYTE NUCLEAR FACTOR 4α MODULATOR COMPOUNDS WO2005017185A2 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
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WO2010127264A3 (en) * 2009-04-30 2010-12-23 Burnham Institute For Medical Research HNF4α ANTAGONISTS AND METHODS OF USE
WO2010127246A3 (en) * 2009-04-30 2010-12-29 Burnham Institute For Medical Research Hnf4 modulators and methods of use
AU2019203709B2 (en) * 2014-10-10 2020-10-22 High Force Research Limited Fluorescent synthetic retinoids

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US5015658A (en) * 1988-06-29 1991-05-14 Allergan, Inc. Thiochroman esters of phenols and terephthallates having retinoid-like activity
US6391287B1 (en) * 1999-05-06 2002-05-21 L'oreal Composition containing at least one bicyclic aromatic compound and at least one lipophilic sunscreen, and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5015658A (en) * 1988-06-29 1991-05-14 Allergan, Inc. Thiochroman esters of phenols and terephthallates having retinoid-like activity
US6391287B1 (en) * 1999-05-06 2002-05-21 L'oreal Composition containing at least one bicyclic aromatic compound and at least one lipophilic sunscreen, and uses thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010127264A3 (en) * 2009-04-30 2010-12-23 Burnham Institute For Medical Research HNF4α ANTAGONISTS AND METHODS OF USE
WO2010127246A3 (en) * 2009-04-30 2010-12-29 Burnham Institute For Medical Research Hnf4 modulators and methods of use
AU2019203709B2 (en) * 2014-10-10 2020-10-22 High Force Research Limited Fluorescent synthetic retinoids

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