WO2010070076A1 - Dérivés de l'acide alcanoïque et leur utilisation thérapeutique en tant qu'inhibiteurs de l'hdac - Google Patents

Dérivés de l'acide alcanoïque et leur utilisation thérapeutique en tant qu'inhibiteurs de l'hdac Download PDF

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WO2010070076A1
WO2010070076A1 PCT/EP2009/067466 EP2009067466W WO2010070076A1 WO 2010070076 A1 WO2010070076 A1 WO 2010070076A1 EP 2009067466 W EP2009067466 W EP 2009067466W WO 2010070076 A1 WO2010070076 A1 WO 2010070076A1
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ethyl
biphenyl
methyl
alkyl
cyano
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Juan AYMAMÍ BOFARULL
Marc Martinell Pedemonte
Julio Castro-Palomino Laria
Franck Camille Nicolas Chevalier
Núria VALLS VIDAL
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Crystax Pharmaceuticals, S.L.
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    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with 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
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    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Definitions

  • the invention relates to novel compounds having pharmacological activity.
  • the compounds can be used for treating diseases.
  • Cancer is prevalent: there were about 3.2 million cancer cases diagnosed (53% men, 47% women) and 1 .7 million deaths from cancer (56% men, 44% women) in Europe in 2006 (Ferlay et al. (2007) Ann. Oncol.
  • Alzheimer's disease is the largest neurodegenerative disease; disease modifying drugs have long been sought, but to-date, none have been identified.
  • Other neurodegenerative conditions include Parkinson's disease, Huntington disease, and Lewy Body dementia which are all characterized by disease progression which robs the patients of their abilities to perform normal daily activities, eventually leading to death.
  • Histone deacetylases are a family of enzymes that can deacetylate acetyl lysines.
  • HDACs are primarily involved in regulation of chromatin structure and gene expression via their ability to modulate histone acetylation, although they also play roles in other important cellular functions like microtubule deacetylation (see e.g., Yang et al. (2003) Cur. Opin. Gen. Dev. 13: 143-153; Zhang et al. (2003) EMBO J 5: 1 168-1 179; Drummond et al. (2005) Annu. Rev. Pharmacol. Toxicol. 45:495-528). The pharmaceutical industry is studying HDAC inhibitors intensively.
  • HDACi HDAC inhibitor activity
  • HDACs There are at least 1 1 human HDACs which are classified into class I, class II, class III and class IV based on their sequence homology to their yeast orthologues Rpd3, Hdal and Sir2, respectively (de Ruijter et al. (2003)
  • Class I, II, and Class IV HDACs are considered the classic HDACs that have an active-site zinc ion.
  • Class III HDACs operate by an NAD+ dependent mechanism and currently are not the target of HDAC inhibitors.
  • the active site zinc ion in the classical HDACs has proven to be a major target of drug discovery efforts.
  • HDAC inhibitors fall into one of several chemical classes including benzamides, hydroxamic acids, carboxylic acids, and FK228 analogs.
  • Many of the HDACi (HDAC inhibitors) molecules in development were designed to have groups that chelate the active site zinc of the HDACs.
  • One of the most potent zinc chelators is the hydroxamic acid moiety and this explains the intense interest in compounds that have this group; compounds with this moiety have HDAC IC50s in the low nanomolar range.
  • Carboxylic acids also chelate zinc but in the context of HDACs they typically have much weaker affinity compared to other classes of HDACi.
  • the carboxylic acid class of HDACi include several FDA approved drugs with activity typically in the low millimolar range (phenylbutyrate, butyrate, and valproate (Gottiere et al. (2001 ) EMBO Journal 20:6969-6978)). Other groups have explored SAR comparisons of carboxylic acids to other types of zinc chelating moieties. Colletti et al. ((2001 ) Biorg. Med. Chem. Lett. 1 1 :107-1 1 1 ) describe apicidin derivatives (HDACi) where substitution of hydroxamic acid with carboxylic acid reduces the ability of the compound to inhibit HDAC. Wada et al. ((2003) Biorg. Med. Chem. Lett.
  • matrix metalloproteases are zinc dependent and can be inhibited by various compounds that have zinc chelating moieties (see e.g., Ferry et al. (1998) Eur. J. Pharm. 351 :225-231 ; EP 1348024; US 5,886,022; and Shian et al. MoI Pharmacol 64: 1076-1084, 2003).
  • HDACi have shown activity in numerous disease models including, but not limited to, many cancers such as colon cancer (Mariadason (2008) Epigenetics. Jan-Feb;3(1 ):28-37), lymphoma, leukemias, lung cancer, breast cancer, prostate cancer (Glozak et al. (2007) Oncogene Aug 13;26(37):5420-32); neurogenerative disease like Spinal Muscular Atrophy (Hauke et al. (2008) Hum MoI Genet. 2008 Oct 29. [Epub ahead of print] PMID: 18971205), Huntington Disease (Thomas et al. (2008) Proc Natl Acad Sci U S A.
  • cancers such as colon cancer (Mariadason (2008) Epigenetics. Jan-Feb;3(1 ):28-37), lymphoma, leukemias, lung cancer, breast cancer, prostate cancer (Glozak et al. (2007) Oncogene Aug 13;26(37):5420-32); neurogenerative
  • HDAC inhibitors are known to cause adverse affects in humans like bone marrow depression, diarrhea, weight loss, taste disturbances, electrolyte changes, disordered clotting, fatigue, and cardiac arrhythmias (Bruserud et al. (2007) Curr. Pharm. Biotechnol. 8:388-400). Safer HDACi are needed. Given the early success with some the initial HDAC inhibitors for treating disease, there is a need for new and improved HDAC inhibitors.
  • the present invention relates to novel compounds. These compounds have activity in inhibiting HDAC and are useful for treating conditions where modulating HDAC activity is desirable. Such conditions include, among other things, cancer and neurodegenerative diseases.
  • the inventors have found that compounds of Formula Ma or Mb or Example 50 can inhibit one or more HDACs.
  • an aspect of the present invention is a compound of Formula Ma or Mb:
  • R1 -R5 is a ring chosen from monocyclic aryl, monocyclic heteroaryl, and monocyclic heterocycle, wherein said ring one has from 1 - 5 substituents independently chosen from halo, alkyl, alkynyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heteroaryl, -L-heterocycle, -L- carbocycle, acylamino, acyloxy, alkylthio, amino, substituted amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl
  • R1 -R5 are independently chosen from -H, halo, alkyl, alkynyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, -L-carbocycle, -L-aryl, -L- heteroaryl, -L-heterocycle, -L-carbocycle, acylamino, acyloxy, alkylthio, amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thiocarbonyl, thiocyanato, trihalomethanesulf
  • R 25 is hydrogen; -C1 -C8alkyl; or an heterocycle, heteroaryl, aryl, or carbocycle optionally substituted with one or more substituents independently chosen from -Q-heterocycle, -Q-heteroaryl, -Q-aryl, -Q- carbocycle, -C1 -C8 alkyl, -OH, -Q-substituted amino, -Q-NH 2 , -O-Q- substituted amino, -0-Q-NH 2 , -CF 3 , -OCF 3 , -CN, aryloxy, alkyloxy and halo; and
  • L and L 2 are independently selected from the group consisting of: -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, and -CH 2 CH 2 -;
  • compounds of the invention are able to efficiently inhibit HDAC, owing to the proper combination of the different radicals R-1-R7, their three-dimensional disposition, as well as to the nature of L 2 linker.
  • compounds of Formula Ma or Mb having as R 6 a carboxylic acid based zinc chelating moieties or analog or derivatives thereof are surprisingly potent HDAC inhibitors having IC50 values for HDACs and in some disease models much lower than other carboxylic acid based HDAC inhibitors like valproate and phenylbutyrate.
  • Another aspect of the invention is the provision of a method for identifying an inhibitor of HDAC comprising providing a compound of Formula I
  • A is an optionally substituted ring system chosen from an aryl and heteroaryl ring
  • B is an optionally substituted ring system chosen from an aryl, carbocyclic, heterocyclic, and heteroaryl ring;
  • each L, L-i , and L 2 can be saturated, partially saturated, or unsaturated, and is independently chosen from -(CH 2 )n-(CH 2 )n-, -(CH2)nNH(CH 2 )n-, - (CH2)nO(CH 2 )n-, and -(CH 2 )nS(CH2) n -, and where each n is independently chosen from 0, 1 , 2, 3, and 4, and wherein each carbon and/or nitrogen can be optionally substituted with one or more substituents independently chosen from hydroxyl, halo, alkoxy, alkyl, and amino; or a pharmaceutically acceptable salt thereof.
  • the invention provides a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula I.
  • the therapeutically effective amount of a compound of Formula I is an amount effective to inhibit HDAC.
  • the invention provides a compound of Formula I for use in the treatment of cancer.
  • the invention provides a pharmaceutical composition for treating and/or preventing cancer wherein said composition comprises a therapeutically effective amount of a compound of Formula I sufficient for treating and/or preventing cancer.
  • the therapeutically effective amount of a compound of Formula I is an amount effective to inhibit HDAC.
  • the invention provides a compound of Formula I for use in the treatment of neurodegeneration.
  • the invention provides a pharmaceutical composition for treating and/or preventing neurodegeneration wherein said composition comprises a therapeutically effective amount of a compound of Formula I sufficient for treating and/or preventing neurodegeneration.
  • the therapeutically effective amount of a compound of Formula I is an amount effective to inhibit HDAC.
  • the invention provides a compound of Formula I for the treatment of a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS), and rheumatoid arthritis, and for stimulating, reprogramming, and regenerating stem cells.
  • a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS), and rheumatoid arthritis
  • the invention provides a pharmaceutical composition for treating and/or preventing a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS), and rheumatoid arthritis and for stimulating, reprogramming, and regenerating stem cells
  • a pharmaceutical composition for treating and/or preventing a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS), and rheumatoid arthritis
  • said composition comprises a therapeutically effective amount of a compound of Formula I sufficient for treating and/or preventing the said disease or for stimulating, reprogramming, and regenerating stem cells.
  • the invention provides a compound of Formula I for inhibiting HDAC.
  • the invention provides a compound of Formula I for the treatment of a disease by modulating histone acetylation.
  • the invention provides a compound of Formula I for the treatment of a disease characterized by aberrant gene expression.
  • the present invention relates to the finding that a group of alkanoic acid derivatives inhibit histone deacetylase (HDAC). It was found that a class of molecules having a carboxylic acid based zinc chelating group, or a derivative thereof, linked to a substituted A-ring and an optionally substituted B-ring, where the A-ring is subtituted with a monocyclic substituted ring or a multicyclic optionally substitued ring, potently inhibit HDAC. These compounds were found to have activity against cancer cell line models.
  • HDAC histone deacetylase
  • the invention provides a method for identifying an inhibitor of HDAC comprising contacting an HDAC enzyme or enzymes with a compound of Formula I and determining the ability of said compound to inihibit HDAC:
  • A is an optionally substituted ring system chosen from an aryl and heteroaryl ring;
  • B is an optionally substituted ring system chosen from an aryl, carbocyclic, heterocyclic, and heteroaryl ring;
  • the ability to inhibit HDAC can be determined by any method known in the art, e.g., in vitro assays to measure acetylation of histones or peptides, or monitoring gene expression levels or other phenotypes related to histone acetylation.
  • the invention relates to a method of determining the HDAC inhibition of a compound of Formula I.
  • the method comprises providing a compound of Formula I and determining the level of inhibition of HDACs, subgroups of HDACs and/or specific HDAC isozymes.
  • the HDAC or HDACs are chosen from HDAC1 , HDAC2, HDAC3, HDAC4,
  • the HDAC is HDAC1.
  • the HDAC is HDAC2.
  • the HDAC is HDAC3.
  • the HDAC is HDAC4.
  • the HDAC is HDAC5.
  • the HDAC is HDAC6.
  • the HDAC is HDAC7.
  • the HDAC is HDAC8.
  • the HDAC is HDAC9.
  • a compound of Formula I is an inhibitor of HDACs, subgroups of HDACs, and/or specific HDAC isozymes if it has an IC50 value of 5000 uM or less.
  • the IC50 value is 2500 uM or less. In an even more specific aspect, the IC50 value is 1000 uM or less. In yet an even more specific embodiment, the IC50 value is 750 uM or less. In yet an even more specific embodiment, the IC50 value is 500 uM or less. In yet an even more specific aspect, the IC50 value is 250 uM or less. In yet an even more specific aspect, the IC50 value is 100 uM or less.
  • the HDAC inhibitors of Formula I can be used to prepare pharmaceutical compositions and methods of treatment as described herein.
  • the compounds of Formula I include those where the A-ring is an optionally substituted phenyl group; the B-ring is an optionally substituted phenyl group;
  • the compounds of Formula I have a B-ring that is an optionally substituted heterocycle.
  • the B-ring is an optionally substituted heterocycle chosen from morpholino, piperidyl, piperazinyl, pyrrolidinyl, thiomorpholino, homopiperazinyl, imidazolyl, imidazolidinyl, indolyl, indazolyl, indolinyl, pyrazolidinyl, dioxanyl, dioxolanyl, pyrazolyl, pyrazinyl, pyridinyl, pyridinyl N-oxide, pyrimidinyl, thiophenyl, and thiazolyl.
  • the B-ring is an optionally substituted ring chosen from thiophenyl, pyrazolyl, furanyl, pyridinyl, indolinyl, and pyridinyl N-oxide.
  • said heterocycle ring system is non-aromatic.
  • the compounds of Formula I have an A-ring that is a heteroaryl.
  • the A-ring is a heteroaryl chosen from thienyl (thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl), 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purin
  • the compounds of Formula I have a B-ring that is an optionally substituted heteroaryl.
  • the B-ring is an optionally substituted heteroaryl chosen from thienyl (thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, 2H- pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl), 2-pyridyl, 3 -pyridyl, 4- pyridyl, pyridinyl N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indo
  • the compounds of Formula I have a B-ring that is an optionally substituted aryl.
  • the B-ring is an optionally substituted aryl chosen from phenyl and napthyl.
  • L e.g., L, l_i , and L 2
  • the compounds of Formula I have each L (e.g., L, l_i, L 2 , L 3 ) independently chosen from -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 -, and -CH 2 -.
  • L e.g., L, l_i, L 2 , L 3
  • the compounds of Formula I have a number of bonds directly connecting the A-ring to the B-ring in a linear manner chosen from 5, 6, 7, 8, 9, and 10 bonds. In a more specific aspect, the number of bonds is chosen from 6, 7, 8, or 9. In this context, a double bond is equivalent to one single bond (i.e., a double bond does not count as two bonds).
  • the compounds of Formula I have a sum of n- values for Li and L 2 chosen from 4, 5, 6, 7, and 8.
  • the invention provides a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compund of Formula I.
  • the therapeutically effective amount of a compound of Formula I is an amount effective to inhibit HDAC.
  • the invention provides a compound of Formula I for use in the treatment of cancer.
  • This aspect can be formulated as the use of a compound of Formula I for the manufacture of a medicament for treating cancer.
  • the invention provides a method for treating an individual having cancer by identifying a patient with cancer and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I.
  • the invention provides a pharmaceutical composition for treating and/or preventing neurodegeneration wherein said composition comprises a therapeutically effective amount of a compound of Formula I sufficient for treating and/or preventing cancer.
  • the therapeutically effective amount of a compound of Formula I is an amount effective to inhibit HDAC.
  • the invention provides a compound of Formula I for use in the treatment of neurodegeneration.
  • This aspect can be formulated as the use of a compound of Formula I for the manufacture of a medicament for treating neurodegeneration.
  • the invention provides a method for treating an individual having a neurodegenerative condition by identifying a patient with a neurodegenerative condition and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I.
  • the invention provides a pharmaceutical composition for treating and/or preventing neurodegeneration wherein said composition comprises a therapeutically effective amount of a compound of Formula I sufficient for treating and/or preventing neurodegeneration.
  • the therapeutically effective amount of a compound of Formula I is an amount effective to inhibit HDAC.
  • the invention provides a compound of Formula I for the treatment of a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS), and rheumatoid arthritis, and for stimulating, reprogramming, and regenerating stem cells.
  • This aspect can be formulated as the use of a compound of Formula I for the manufacture of a medicament for treating a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis, and for stimulating, reprogramming, and regenerating stem cells.
  • a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis
  • the invention provides a method for treating an individual having a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis by identifying a patient with said disease and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I.
  • a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis
  • the invention provides a pharmaceutical composition for treating and/or preventing a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS), and rheumatoid arthritis and for stimulating, reprogramming, and regenerating stem cells
  • a pharmaceutical composition for treating and/or preventing a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS), and rheumatoid arthritis
  • said composition comprises a therapeutically effective amount of a compound of Formula I sufficient for treating and/or preventing the said disease or for stimulating, reprogramming, and regenerating stem cells.
  • the invention provides a compound of Formula I for inhibiting HDAC.
  • This aspect can be formulated as the use of compound of Formula I for the manufacture of a medicament for inhibiting HDAC.
  • the invention provides a method for treating an individual having a disease treatable by HDAC inhibition by identifying a patient in need of such treatment and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I.
  • the invention provides a compound of Formula I for the treatment of a disease by modulating histone acetylation.
  • This aspect can be formulated as the use of a compound of Formula I for the manufacture of a medicament for modulating histone acetylation.
  • the invention provides a method for treating an individual having a disease treatable by modulating histone acetylation by identifying a patient in need of such treatment and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I.
  • the invention provides a compound of Formula I for the treatment of a disease characterized by aberrant gene expression.
  • This aspect can be formulated as the use of a compound of Formula I for the manufacture of a medicament modulating gene expression.
  • the invention provides a method for treating an individual having disease characterized in part by having aberrant gene expression by identifying a patient in need of such treatment and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I.
  • the invention provide a compound of Formula Ma and/or Mb as mentioned above of formulas
  • one of R1 -R5 is a ring chosen from monocyclic aryl, monocyclic heteroaryl, and monocyclic heterocycle, wherein said ring one has from 1 - 5 substituents independently chosen from halo, alkyl, alkynyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heteroaryl, -L-heterocycle, -L- carbocycle, acylamino, acyloxy, alkylthio, amino, substituted amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyana
  • R1 -R5 are independently chosen from -H, halo, alkyl, alkynyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, -L-carbocycle, -L-aryl, -L- heteroaryl, -L-heterocycle, -L-carbocycle, acylamino, acyloxy, alkylthio, amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thiocarbonyl, thiocyanato, trihalomethanesulf
  • the compound of formula Ma or Mb is one wherein:
  • R3 is chosen from a monocyclic aryl, monocyclic heteroaryl, and monocyclic heterocycle, wherein said ring has from 1 -5 substituents; or R3 is chosen from a heteroaryl, heterocyclic, or aryl ring system having two or more fused rings; and
  • the optional substituents on R7 are independently chosen from -Q-R25, -Q-L 4 -Q-R 2 S, and -L 4 -R 2 5, wherein each Q is independently chosen from a bond, -CH 2 -, - CH 2 CH 2 -, and -CH 2 CH 2 CH 2 -; each L 4 is independently chosen from - N(R 30 )C(O)-, -C(O)N(R 30 )-, -N(R 30 )S(O) 2 -, -S(O) 2 N(R 30 )-, -C(O)-, - NHC(O)O-, -S(O) 2 -, -OC(O)NH-, -NHC(O)NH-, -N(R 30 )-, -0-, and -S-; R 30 is chosen from -H, -C1 -C4 alkyl optionally substituted with
  • the invention provides a compound of Formula Ma and/or Mb, wherein R3 is a phenyl having from 1 -5 substituents independently chosen from hydroxyl, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, -N(Ci -3 alkyl) 2 , -NH(Ci -3 alkyl), -NHC(O)(Ci -3 alkyl), -C(O)OH, -C(O)O(C L ealkyl), -C(O)(Ci -3 alkyl), -C(O)NH 2 , -C(O)NH(Ci -3 alkyl), -
  • R3 is a phenyl and has 1 -5 substituents independently chosen from alkyl, haloalkyl, haloalkoxy, hydroxyl, -NH 2 , -CN, halo, alkoxy, tetrazolyl, -
  • C(O)Z and -NH-Y, wherein Z is chosen from -OH, -0(C L6 alkyl), -N H(C L 6 alkyl), -N H (C L6 alkyl) 2 , -NH(cycloalkyl) wherein Y is chosen from alkyl and -(CO)(C L3 alkyl).
  • R3 is a phenyl and has 1 -5 substituents independently chosen from -CN, chloro, fluoro, methoxy, ethoxy, hydroxyl, methyl, tetrazolyl, -OCF 3 , -C(O)OH, -C(O)O- alkyl, -NC(O)CH 3 , -C(O)NH 2 , -C(O)CH 3 , and -C(0)NH-cyclopropyl.
  • L 2 is chosen from - CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 -, and -CH 2 -.
  • the invention provides compounds of Formula Ma and/or Mb where R1 and R5 are each hydro, and the other variables are as defined herein. In a more specific aspect, the invention provides compounds of Formula Ma and Mb where R1 , R2, R4, R5 are each hydro.
  • the compounds of Formula Ma and/or Mb have a number of bonds directly connecting the A-ring to R7 in a linear manner chosen from 5, 6, 7, 8, 9, and 10 bonds. In a more specific aspect, the number of bonds is chosen from 6, 7, 8, or 9. In this context, a double bond (or triple) is equivalent to one single bond (i.e., a double bond does not count as two bonds).
  • the compounds of Formula Ma and/or Mb have a sum of n-value for L 2 chosen from 2, 3, and 4.
  • the invention provides compounds of Formula Ma and/or Mb, wherein
  • R3 is chosen from a monocyclic aryl, monocyclic heteroaryl, and monocyclic heterocycle, wherein said ring one has from 1 -5 substituents; or R3 is chosen from a heteroaryl, heterocyclic, or aryl ring system having two or more fused rings which may be substituted with 1 -5 optional substituents;
  • R7 is chosen from a carbocyclic, heteroaryl, heterocyclic, and aryl ring each of which can be optionally substituted with 1 -5 independently chosen optional substituents;
  • L 2 is chosen from -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 -, and -CH 2 -
  • the invention provides a pharmaceutical composition comprising a compound of Formula Ma and/or Mb and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compund of Formula Il and/or Mb.
  • the therapeutically effective amount of a compound of Formula Ma or Mb is an amount effective to inhibit HDAC.
  • the invention provides a compound of Formula Ma and/or Mb for use in the treatment of cancer.
  • This aspect can be formulated as the use of a compound of Formula Ma and/or Mb for the manufacture of a medicament for treating cancer.
  • the invention provides a method for treating an individual having cancer by identifying a patient with cancer and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula Ma or Mb.
  • the invention provides a pharmaceutical composition for treating and/or preventing neurodegeneration wherein said composition comprises a therapeutically effective amount of a compound of Formula M and/or Mb sufficient for treating and/or preventing cancer.
  • the therapeutically effective amount of a compound of Formula Ma and/or Mb is an amount effective to inhibit HDAC.
  • the invention provides a compound of Formula Ma or Mb for use in the treatment of neurodegeneration.
  • This aspect can be formulated as the use of a compound of Formula Ma or Mb for the manufacture of a medicament for treating neurodegeneration.
  • the invention provides a method for treating an individual having a neurodegenerative condition by identifying a patient with a neurodegenerative condition and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula Ma or Mb.
  • the invention provides a pharmaceutical composition for treating and/or preventing neurodegeneration wherein said composition comprises a therapeutically effective amount of a compound of Formula I sufficient for treating and/or preventing neurodegenration.
  • the therapeutically effective amount of a compound of Formula I is an amount effective to inhibit HDAC.
  • the invention provides a compound of Formula Ma or Mb for the treatment of a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis, and for stimulating, reprogramming, and regenerating stem cells.
  • a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis
  • This aspect can be formulated as the use of a compound of Formula Ma or Mb for the manufacture of a medicament for treating a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis, and for stimulating, reprogramming, and regenerating stem cells.
  • a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis
  • the invention provides a method for treating an individual having a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis by identifying a patient with said disease and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula Ma or Mb.
  • a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis
  • the invention provides a pharmaceutical composition for treating and/or preventing a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS), and rheumatoid arthritis and for stimulating, reprogramming, and regenerating stem cells
  • said composition comprises a therapeutically effective amount of a compound of Formula Ma and/or Mb sufficient for treating and/or preventing the said disease or for stimulating, reprogramming, and regenerating stem cells.
  • the therapeutically effective amount of a compound of Formula Il and/or Mb is an amount effective to inhibit HDAC.
  • the invention provides a compound of Formula Ma and/or Mb for inhibiting HDAC.
  • This aspect can be formulated as the use of compound of Formula Ma or Mb for the manufacture of a medicament for inhibiting HDAC.
  • the invention provides a method for treating an individual having a disease treatable by HDAC inhibition by identifying a patient in need of such treatment and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula Ma and/or Mb.
  • the invention provides a compound of Formula Ma and/or Mb for the treatment of a disease by modulating histone acetylation.
  • This aspect can be formulated as the use of a compound of Formula Ma and/or Mb for the manufacture of a medicament for modulating histone acetylation.
  • the invention provides a method for treating an individual having a disease treatable by modulating histone acetylation by identifying a patient in need of such treatment and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula Ma and/or Mb.
  • the invention provides a compound of Formula Ma and/or Mb for the treatment of a disease characterized by aberrant gene expression.
  • This aspect can be formulated as the use of a compound of Formula Ma and/or Mb for the manufacture of a medicament modulating gene expression.
  • the invention provides a method for treating an individual having disease characterized in part by having aberrant gene expression by identifying a patient in need of such treatment and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula Ma and/or Mb.
  • the invention provides a compound of Formula III:
  • R1 -R5 and R8-R12 is a ring chosen from monocyclic aryl, monocyclic heteroaryl, and monocyclic heterocyclic, wherein said one ring has from 1 -5 substituents independently chosen from halo, alkyl, alkynyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heteroaryl, -L-heterocycle, -L-carbocycle, acylamino, acyloxy, alkylthio, amino, substituted amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulf
  • R3 and R10 is a ring chosen from a monocyclic aryl, monocyclic heteroaryl and monocyclic heterocycle, each having from 1 -5 susbtituents independently chosen from halo, alkyl, alkynyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, -L-carbocycle, -L-aryl, -L-heteroaryl, -L-heterocycle, -L-carbocycle, acylamino, acyloxy, alkylthio, amino, substituted amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfin,
  • the invention provides a pharmaceutical composition comprising a compound of Formula III and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compund of Formula III.
  • the therapeutically effective amount of a compound of Formula III is an amount effective to inhibit HDAC.
  • the invention provides a compound of Formula III for use in the treatment of cancer.
  • This aspect can be formulated as the use of a compound of Formula III for the manufacture of a medicament for treating cancer.
  • the invention provides a method for treating an individual having cancer by identifying a patient with cancer and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula III.
  • the invention provides a pharmaceutical composition for treating and/or preventing neurodegeneration wherein said composition comprises a therapeutically effective amount of a compound of Formula III sufficient for treating and/or preventing cancer.
  • the therapeutically effective amount of a compound of Formula III is an amount effective to inhibit HDAC.
  • the invention provides a compound of Formula III for use in the treatment of neurodegeneration.
  • This aspect can be formulated as the use of a compound of Formula III for the manufacture of a medicament for treating neurodegeneration.
  • the invention provides a method for treating an individual having a neurodegenerative condition by identifying a patient with a neurodegenerative condition and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula III.
  • the invention provides a pharmaceutical composition for treating and/or preventing neurodegeneration wherein said composition comprises a therapeutically effective amount of a compound of Formula III sufficient for treating and/or preventing neurodegeneration.
  • the therapeutically effective amount of a compound of Formula III is an amount effective to inhibit HDAC.
  • the invention provides a compound of Formula III for the treatment of a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS), and rheumatoid arthritis, and for stimulating, reprogramming, and regenerating stem cells.
  • a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS), and rheumatoid arthritis
  • This aspect can be formulated as the use of a compound of Formula III for the manufacture of a medicament for treating a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis, and for stimulating, reprogramming, and regenerating stem cells.
  • a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis
  • the invention provides a method for treating an individual having a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis by identifying a patient with said disease and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula III.
  • a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis
  • the invention provides a pharmaceutical composition for treating and/or preventing a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS), and rheumatoid arthritis and for stimulating, reprogramming, and regenerating stem cells
  • a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS), and rheumatoid arthritis
  • said composition comprises a therapeutically effective amount of a compound of Formula III sufficient for treating and/or preventing the said disease or for stimulating, reprogramming, and regenerating stem cells.
  • the therapeutically effective amount of a compound of Formula III is an
  • the invention provides a compound of Formula III for inhibiting HDAC.
  • This aspect can be formulated as the use of compound of Formula III for the manufacture of a medicament for inhibiting HDAC.
  • the invention provides a method for treating an individual having a disease treatable by HDAC inhibition by identifying a patient in need of such treatment and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula III.
  • the invention provides a compound of Formula III for the treatment of a disease by modulating histone acetylation.
  • This aspect can be formulated as the use of a compound of Formula III for the manufacture of a medicament for modulating histone acetylation.
  • the invention provides a method for treating an individual having a disease treatable by modulating histone acetylation by identifying a patient in need of such treatment and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula III.
  • the invention provides a compound of Formula III for the treatment of a disease characterized by aberrant gene expression.
  • This aspect can be formulated as the use of a compound of Formula III for the manufacture of a medicament modulating gene expression.
  • the invention provides a method for treating an individual having disease characterized in part by having aberrant gene expression by identifying a patient in need of such treatment and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula III.
  • the invention provides a compound of Formula IV:
  • R1 -R4 are independently chosen from -H, halo, alkyl, alkynyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, -L-carbocycle, -L-aryl, -L-heteroaryl, -L-heterocycle, -L-carbocycle, acylamino, acyloxy, alkylthio, amino, substituted amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thiocarbonyl, thiocyanato, trihalomethan
  • R7 can be optionally substituted and is chosen from a carbocyclic, heterocyclic, heteroaryl, and aryl ring; each L and L 2 can be saturated, partially saturated, or unsaturated, and are independently chosen from -(CH 2 )n-(CH2) n -, -(CH2)nNH(CH 2 )n-, -(CH2)nO(CH 2 )n-, and -(CH 2 )nS(CH2) n -, and where each n is independently chosen from 0, 1 , 2, 3, and 4, and wherein each carbon and/or nitrogen can be optionally substituted with one or more substituents independently chosen from hydroxyl, halo, alkoxy, alkyl, and amino; at least one R Y is chosen from halo, alkyl, alkynyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, -L-carbocycle, -L-aryl, -L-heteroaryl,
  • the invention provides a pharmaceutical composition comprising a compound of Formula IV and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compund of Formula IV.
  • the therapeutically effective amount of a compound of Formula IV is an amount effective to inhibit HDAC.
  • the invention provides a compound of Formula IV for use in the treatment of cancer.
  • This aspect can be formulated as the use of a compound of Formula IV for the manufacture of a medicament for treating cancer.
  • the invention provides a method for treating an individual having cancer by identifying a patient with cancer and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula IV.
  • the invention provides a pharmaceutical composition for treating and/or preventing neurodegeneration wherein said composition comprises a therapeutically effective amount of a compound of Formula IV sufficient for treating and/or preventing cancer.
  • the therapeutically effective amount of a compound of Formula IV is an amount effective to inhibit HDAC.
  • the invention provides a compound of Formula IV for use in the treatment of neurodegeneration.
  • This aspect can be formulated as the use of a compound of Formula IV for the manufacture of a medicament for treating neurodegeneration.
  • the invention provides a method for treating an individual having a neurodegenerative condition by identifying a patient with a neurodegenerative condition and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula IV.
  • the invention provides a pharmaceutical composition for treating and/or preventing neurodegeneration wherein said composition comprises a therapeutically effective amount of a compound of Formula IV sufficient for treating and/or preventing neurodegeneration.
  • the therapeutically effective amount of a compound of Formula IV is an amount effective to inhibit HDAC.
  • the invention provides a compound of Formula IV for the treatment of a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS), and rheumatoid arthritis, and for stimulating, reprogramming, and regenerating stem cells.
  • a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS), and rheumatoid arthritis
  • This aspect can be formulated as the use of a compound of Formula IV for the manufacture of a medicament for treating a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis, and for stimulating, reprogramming, and regenerating stem cells.
  • a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis
  • the invention provides a method for treating an individual having a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis by identifying a patient with said disease and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula IV.
  • a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis
  • the invention provides a pharmaceutical composition for treating and/or preventing a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS), and rheumatoid arthritis and for stimulating, reprogramming, and regenerating stem cells
  • a pharmaceutical composition for treating and/or preventing a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS), and rheumatoid arthritis
  • said composition comprises a therapeutically effective amount of a compound of Formula IV sufficient for treating and/or preventing the said disease or for stimulating, reprogramming, and regenerating stem cells.
  • the invention provides a compound of Formula IV for inhibiting HDAC.
  • This aspect can be formulated as the use of compound of Formula IV for the manufacture of a medicament for inhibiting HDAC.
  • the invention provides a method for treating an individual having a disease treatable by HDAC inhibition by identifying a patient in need of such treatment and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula IV.
  • the invention provides a compound of Formula IV for the treatment of a disease by modulating histone acetylation.
  • This aspect can be formulated as the use of a compound of Formula IV for the manufacture of a medicament for modulating histone acetylation.
  • the invention provides a method for treating an individual having a disease treatable by modulating histone acetylation by identifying a patient in need of such treatment and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula IV.
  • the invention provides a compound of Formula IV for the treatment of a disease characterized by aberrant gene expression.
  • This aspect can be formulated as the use of a compound of Formula IV for the manufacture of a medicament modulating gene expression.
  • the invention provides a method for treating an individual having disease characterized in part by having aberrant gene expression by identifying a patient in need of such treatment and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula IV.
  • R7 is an optionally substituted heteroaryl.
  • R7 can be optionally substituted and is a heteroaryl chosen from thienyl (thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl), 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, thienyl (thi
  • the heteroaryl can be optionally substituted and is chosen from thiophenyl, pyrazolyl, furanyl, pyridinyl, and pyridinyl N- oxide.
  • R7 is an optionally substituted heterocycle.
  • R7 can be optionally substituted and is a heterocycle chosen from morpholino, piperidyl, piperazinyl, pyrrolidinyl, thiomorpholino, homopiperazinyl, imidazolyl, imidazolidinyl, indolyl, indazolyl, indolinyl, pyrazolidinyl, dioxanyl, dioxolanyl, pyrazolyl, pyrazinyl, pyridinyl, pyridinyl N-oxide, pyrimidinyl, thiophenyl, and thiazolyl.
  • morpholino piperidyl, piperazinyl, pyrrolidinyl, thiomorpholino, homopiperazinyl, imidazolyl, imidazolidinyl, indolyl, indazolyl, indolinyl, pyrazolidinyl, dioxanyl, dioxolanyl,
  • the heterocycle can be optionally substituted and is chosen from thiophenyl, pyrazolyl, furanyl, pyridinyl, indolinyl, and pyridinyl N-oxide.
  • the heterocycle is a non- aromatic heterocycle.
  • R7 is an optionally substituted aryl. In a more specific one aspect, R7 can be optionally substituted and is an aryl group chosen from phenyl and naphthyl.
  • R7 is an optionally substituted carbocyclic group.
  • R7 is an optionally substituted carbocycle chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl and cycloheptyl.
  • the optional substituents on R7 are chosen from halo, alkyl, alkynyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, -L-carbocycle, -L-aryl, -L- heteroaryl, -L-heterocycle, -L-carbocycle, acylamino, acyloxy, alkylthio, amino, substituted amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thiocarbonyl, thiocyanato, trihalomethanesul
  • the optional substituents on R7 are independently chosen from -Q-R 2 S, -Q-L 4 -Q-R 25 , and -L 4 -R 25 , wherein each Q is independently chosen from a bond, -CH 2 -, -CH 2 CH 2 -, and -CH 2 CH 2 CH 2 -; each L 4 is independently chosen from -N(R 30 )C(O)-, -C(O)N(R 30 )-, -N(R 30 )S(O) 2 -, -S(O) 2 N(R 30 )-, -C(O)-, -NHC(O)O-, -S(O) 2 -, -OC(O)NH-, -NHC(O)NH-, -N(R 30 )-, -O-, and -S-; R 30 is chosen from -H, -C1 -C4 alkyl optionally substituted with
  • R7 is phenyl
  • L 2 is -CH 2 CH 2 CH 2 -
  • R6 is COOH
  • y is 1
  • R6 is -COOH or a pharmaceutically acceptable salt thereof.
  • L 2 is chosen from -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 -, and -CH 2 -.
  • the invention provides a compound of Formula V:
  • R1 , R2, R4, R5, and R8-R12 are each independently chosen from -H, halo, alkyl, alkynyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, -L-carbocycle, -L-aryl, -L-heteroaryl, -L-heterocycle, -L-carbocycle, acylamino, acyloxy, alkylthio, amino, substituted amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thiocarbonyl,
  • Y is chosen from 1 , 2, 3, 4, 5; each L can be saturated, partially saturated, or unsaturated, and is independently chosen from -(CH 2 )n-(CH 2 )n-, -(CH2)nNH(CH 2 )n-, -(CH2)nO(CH 2 )n-, and -(CH 2 )nS(CH2) n -, and where each n is independently chosen from 0, 1 , 2, 3, and 4, and wherein each carbon and/or nitrogen can be optionally substituted with one or more substituents independently chosen from hydroxyl, halo, alkoxy, alkyl, and amino; or a pharmaceutically acceptable salt thereof.
  • the invention provides a compound of Formula V wherein each L is independently chosen from -CH2CH2CH2CH2-, - CH 2 CH 2 CH 2 -, -CH 2 CH 2 -, and -CH 2 -.
  • the invention provides a compound of Formula V wherein R10 is chosen from sulphonamide, -CH 2 (carbocycle), -CH 2 (aryl), and -CH 2 (heterocycle), and O-benzyl.
  • the invention provides a pharmaceutical composition comprising a compound of Formula V and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compund of Formula V.
  • the therapeutically effective amount of a compound of Formula V is an amount effective to inhibit HDAC.
  • the invention provides a compound of Formula V for use in the treatment of cancer.
  • This aspect can be formulated as the use of a compound of Formula III for the manufacture of a medicament for treating cancer.
  • the invention provides a method for treating an individual having cancer by identifying a patient with cancer and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula V.
  • the invention provides a pharmaceutical composition for treating and/or preventing neurodegeneration wherein said composition comprises a therapeutically effective amount of a compound of Formula V sufficient for treating and/or preventing cancer.
  • the therapeutically effective amount of a compound of Formula V is an amount effective to inhibit HDAC.
  • the invention provides a compound of Formula
  • the invention provides a method for treating an individual having a neurodegenerative condition by identifying a patient with a neurodegenerative condition and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula V.
  • the invention provides a pharmaceutical composition for treating and/or preventing neurodegeneration wherein said composition comprises a therapeutically effective amount of a compound of Formula V sufficient for treating and/or preventing neurodegeneration.
  • the therapeutically effective amount of a compound of Formula V is an amount effective to inhibit HDAC.
  • the invention provides a compound of Formula
  • V for the treatment of a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS), and rheumatoid arthritis, and for stimulating, reprogramming, and regenerating stem cells.
  • a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS), and rheumatoid arthritis
  • This aspect can be formulated as the use of a compound of Formula V for the manufacture of a medicament for treating a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis, and for stimulating, reprogramming, and regenerating stem cells.
  • a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis
  • the invention provides a method for treating an individual having a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis by identifying a patient with said disease and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula V.
  • a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS) and rheumatoid arthritis
  • the invention provides a pharmaceutical composition for treating and/or preventing a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS), and rheumatoid arthritis and for stimulating, reprogramming, and regenerating stem cells
  • a pharmaceutical composition for treating and/or preventing a disease chosen from breast cancer, lung cancer, prostate cancer, colon cancer, leukemia, lymphoma, Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, inflammation, thalassemias, acne, asthma, fungal infections, HIV (and/or AIDS), and rheumatoid arthritis
  • said composition comprises a therapeutically effective amount of a compound of Formula V sufficient for treating and/or preventing the said disease or for stimulating, reprogramming, and regenerating stem cells.
  • the invention provides a compound of Formula
  • the invention provides a method for treating an individual having a disease treatable by HDAC inhibition by identifying a patient in need of such treatment and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula V.
  • the invention provides a compound of Formula
  • the invention provides a method for treating an individual having a disease treatable by modulating histone acetylation by identifying a patient in need of such treatment and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula V.
  • the invention provides a compound of Formula V for the treatment of a disease characterized by aberrant gene expression.
  • This aspect can be formulated as the use of a compound of Formula V for the manufacture of a medicament modulating gene expression.
  • the invention provides a method for treating an individual having disease characterized in part by having aberrant gene expression by identifying a patient in need of such treatment and administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula V.
  • the compound of Formulae I-V is used as a radiosensitizer and/or a chemosensitizer.
  • the invention provides a method that involves identifying a patient having a neurodegenerative disease or CNS related condition and treating the individual with a therapeutically effective amount of a compound of Formulae I-V.
  • the neurodegenerative disease is chosen from Alzheimer's disease, Huntington disease, Parkinson's disease, Dementia, Lewy Body Dementia, and Amyloid Lateral Sclerosis (ALS).
  • the condition is chosen from depression, epilepsy, and mood disorders.
  • the disease is a polyglutamine-repeat diseases.
  • the invention provides a method, comprising identifying a patient having cancer and administering to said patient a therapeutically effective amount of a compound of a formula chosen from Formula I, II, III, IV, and V.
  • the cancer is chosen from breast cancer, colon cancer, prostate cancer, pancreatic cancer, leukemias, lymphomas, ovarian cancers, neuroblastomas, head and neck cancer, lung cancer, and melanoma.
  • the invention provides a method comprising identifying a patient having a disease which is chosen from inflammatory diseases/immune system disorders, angiofibroma, cardiovascular diseases (e.g. restenosis, arteriosclerosis), thalassaemias, fibrotic diseases (e.g. liver fibrosis), diabetes, and autoimmune diseases and administering to said patient a therapeutically effective amount of a compound of a formula chosen from Formula I, II, III, IV, and V
  • each L (e.g., L, l_i, and/or L 2 ) is independently chosen from CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, and -CH 2 CH 2 -.
  • the number of bonds directly connecting the A-ring to the B-ring in a linear manner is chosen from 6, 7, or 8.
  • n-values for L 1 and L 2 is 4, 5, 6, or 7.
  • Ry is an optionally substituted heteroaryl.
  • R ⁇ can be optionally substituted and is a heteroaryl independently chosen from thienyl (thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, including without limitation 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl) 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl
  • R ⁇ is an optionally substituted heterocycle.
  • R ⁇ can be optionally substituted and is a heterocycle independently chosen from morpholino, piperidyl, piperazinyl, pyrrolidinyl, thiomorpholino, homopiperazinyl, imidazolyl, imidazolidinyl, pyrazolidinyl, dioxanyl and dioxolanyl.
  • R ⁇ is an optionally substituted aryl.
  • R Y can be optionally substituted and is an aryl group independently chosen from phenyl, naphthyl and anthracenyl.
  • each R ⁇ can be optionally substituted and is independently chosen from thiophenyl, furanyl, phenyl, pyridinyl, and pyrazole.
  • the optional substituents on R ⁇ are chosen from halo, alkyl, alkynyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, -L-carbocycle, -L-aryl,
  • -L-heteroaryl -L-heterocycle, -L-carbocycle, acylamino, acyloxy, alkylthio, amino, substituted amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, and C-amido.
  • the compounds of Formulae I-V do not include those having a structure as in CAS registry no.179544-25-3 (4'-(3-Ethoxy-3-oxopropyl)- ⁇ -(3-phenylpropyl)[1 , 1 '- biphenyl]-4-butanoic acid), CAS registry no. 179544-26-4 (4'-(2-aminoethyl)- ⁇ -(3-phenylpropyl)[1 , 1 '- biphenyl]-4-butanoic acid), CAS registry no. 179544-26-4 (4'-(2-a structure as in CAS registry no.179544-25-3 (4'-(3-Ethoxy-3-oxopropyl)- ⁇ -(3-phenylpropyl)[1 , 1 '- biphenyl]-4-butanoic acid), CAS registry no. 179544-26-4 (4'-(2-aminoethyl)- ⁇ -(3-phenylpropyl)
  • the invention provides a compound of Formulae I-V or a pharmaceutically acceptable salt thereof, wherein said compound is chosen from 5-(1 -Naphthyl)-2- ⁇ 2-[3'-cyano-1 ,1 '-biphenyl-4- yl)]ethyl ⁇ pentanoic acid; 2- ⁇ 2-[3'-(Aminocarbonyl)-1 ,1 '-biphenyl-4-yl]ethyl ⁇ - 5-phenylpentanoic acid; 2- ⁇ 2-[3'-(Acetylamino)-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoic acid; 2- ⁇ 2-[4'-(Trifluoromethyl)-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoic acid; 2- ⁇ 2-[3'-Trifluoromethoxy-1 ,1 '-b
  • the invention provides a compound of Formulae I-V or a pharmaceutically acceptable salt thereof, wherein said compound is chosen from 2- ⁇ 2-[4-(1 H-tetrazol-5-yl)phenyl]ethyl ⁇ -5-phenyl-pentanoic acid; 2- ⁇ 2-[2'-hydroxy-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoic acid; 2- ⁇ 2-([2'-cyano-1 ,1 '-biphenyl-4-yl])ethyl ⁇ -5-phenylpentanoic acid; 2- ⁇ 2-[3'- hydroxy-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoic acid; 2- ⁇ 2-[3'-(tert- butoxycarbonyl)-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoic acid;
  • the invention provides a compound or a pharmaceutically acceptable salt thereof chosen from 2- ⁇ 2-([3'-Cyano-1 ,V- biphenyl-4-yl])ethyl ⁇ -5-phenylpentanoic acid; 2- ⁇ 2-[4'-methoxy-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoic acid; 2- ⁇ 2-[4'-Chloro-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoic acid; 2- ⁇ 2-[3'-Fluoro-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoic acid; 2- ⁇ 2-[3'-Methoxy-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoic acid;
  • a pahrmaceutical composition comprising a compound or pharmaceutically acceptable salt as described above and a pharmaceutically acceptable carrier.
  • the invention provides a compound or a salt thereof chosen from Methyl 2- ⁇ 2-[3'-cyano-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoate;
  • the compounds of this embodiment can be used as synthetic intermediates and/or as ester prodrugs.
  • the invention provides a method for synthesizing a compound of Formulae I-V, see scheme I below.
  • Commercially available carboxylic acid derivatives of formula (Vl) were transformed to the methyl ester derivatives of formula (VII) by 3 successive reactions as shown in the Scheme below.
  • the methyl ether was removed using hydrobromic acid to give the phenol, which was esterified using methanol and a strong acid like hydrochloric or sulphuric acid.
  • methyl ester derivatives were benzylated with benzyl bromide under basic conditions to afford the compounds of formula (VII).
  • triflate is used as a leaving group in order to react with boronic-based reagents.
  • other leaving groups such as bromine and others known to the skilled artisan can be used instead of triflate.
  • the invention also provides compounds as defined in the synthetic schemes below as intermediates. These intermediates are useful for synthesizing compounds of the invention.
  • alkyl refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups.
  • the alkyl group has 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 the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms).
  • it is a medium size alkyl having 1 to 10 carbon atoms.
  • it is a lower alkyl having 1 to 6 carbon atoms, and in a more specific embodiment, 1 to 4 carbon atoms.
  • alkenyl refers to an unsaturated hydrocarbon including straight chain and/or branched chain groups, comprising at least one carbon-to-carbon double bond.
  • the alkenyl group is further defined as having 2 to 20 carbon atoms.
  • it is an alkenyl having 2 to 10 carbon atoms.
  • it is an alkenyl having 2 to 6 carbon atoms, and in yet another more specific definition, it is an alkenyl having 2 to 4 carbon atoms.
  • alkynyl refers to an unsaturated hydrocarbon including straight chain and/or branched chain groups, comprising at least one carbon-to-carbon triple bond.
  • the alkynyl group is further defined as having 2 to 20 carbon atoms.
  • it is an alkynyl having 2 to 10 carbon atoms.
  • it is an alkynyl having 2 to 6 carbon atoms, and in yet another more specific definition, it is an alkynyl having 2 to 4 carbon atoms.
  • halo refers to chloro, fluoro, bromo, and iodo.
  • hydro refers to a hydrogen atom (-H group).
  • hydroxy or “hydroxyl” refers to an -OH group.
  • alkoxy refers to both an -O-alkyl and an -O- cycloalkyl group, as defined herein.
  • Lower alkoxy refers to -O-lower alkyl groups.
  • aryloxy refers to both an -O-aryl.
  • heteroaryloxy refers to an -O-heteroaryl group, as defined herein.
  • mercapto refers to an -SH group.
  • alkylthio refers to both an S-alkyl and an -S-cycloalkyl group, as defined herein.
  • arylthio refers to both an -S-aryl and an - S- heteroaryl group, as defined herein.
  • aldehyde refers to a carbonyl group where R" is hydro.
  • esters is a C-carboxy group, as defined herein, wherein R" is as defined herein other than hydro.
  • M + is selected from the group consisting of lithium, sodium, potassium, calcium, magnesium, barium, iron, zinc and quaternary ammonium.
  • carboxylic acid refers to a C-carboxy group in which R" is hydro.
  • haloalkyl refers to an alkyl group substituted with 1 to 6 halo groups.
  • haloalkyl is a -CX 3 group wherein X is a halo group.
  • the halo groups can be independently selected.
  • cyano refers to a -C ⁇ N group.
  • cyanato refers to a -CNO group.
  • isocyanato refers to a -NCO group.
  • thiocyanato refers to a -CNS group.
  • isothiocyanato refers to a -NCS group.
  • R-17 and Ri 8 are independently chosen from hydro, alkyl, aryl, carbocycle, heterocycle, -(CH 2 )aryl, -(CH 2 )carbocycle, and - (CH 2 )heterocycle.
  • amino refers to a -NRR group, with R and R both being hydro.
  • substituted amino refers to a -NR22R23 wherein R22 and R23 are independently chosen from -H, C1 -C8 alkyl, and phenyl wherein at least one of R22 and R23 is not -H.
  • nitro refers to a -NO2 group.
  • quaternary ammonium refers to a -NR20R21 R22 group wherein R 2 o, R21, and R22 are independently selected from the group consisting of hydro and unsubstituted lower alkyl.
  • methylenedioxy refers to a -OCH2O- group wherein the oxygen atoms are bonded to adjacent ring carbon atoms.
  • ethylenedioxy refers to a -OCH 2 CH 2 O- group wherein the oxygen atoms are bonded to adjacent ring carbon atoms.
  • carbocyclic refers to an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group wherein one or more of the rings does not have a completely conjugated pi-electron system.
  • carbocyclic groups are cycloalkyls such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, adamantane, cycloheptane and cycloalkenes such as cycloheptatriene, cyclopentene, and cyclohexadiene.
  • cycloalkyl refers to an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group wherein one or more of the rings does not have a completely conjugated pi-electron system.
  • examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclohexane, adamantane, and cycloheptane.
  • heterocycle refers to a saturated or partially saturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring system, which consists of carbon atoms and from one to four heteroatoms independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, the nitrogen can be optionally quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the heterocyclic ring can be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • Non- limiting saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetronoyl and tetramoyl groups.
  • heterocycles or “heterocyclic” rings also include, but are not limited to, morpholino, piperidyl, piperazinyl, pyrrolidinyl, thiomorpholino, homopiperazinyl, imidazolyl, imidazolidinyl, pyrazolidinyl, dioxanyl and dioxolanyl.
  • Heterocycle can include heteroaryls when the pi-electron system of a heterocycle is completely conjugated.
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl.
  • heteroaryl refers to groups having 5 to 14 ring atoms; 6, 10 or 14 pi electrons shared in a cyclic array; and containing carbon atoms and 1 , 2 or 3 oxygen, nitrogen or sulfur heteroatoms.
  • Non- limiting heteroaryl groups include thienyl (thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, including without limitation 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl), including without limitation 2-pyridyl, 3 -pyridyl, and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyrid
  • nitrogen atom may be in the form of an N-oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.
  • N-oxide e.g., a pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.
  • arylalkyl refers to an alkyl group asdefined herein above substituted by an aryl group as defined herein above.
  • arylalkyl refers to a C ⁇ _i 0 alkyl grou p (an alkyl group having 1 -10 carbon atoms), as defined herein above, substituted by a C 6- -I 4 aryl group (an aryl group having 6 to 14 carbon atoms), as defined herein above.
  • Non-limiting examples of arylalkyl groups include benzyl, phenethyl, and naphthylmethyl.
  • arylalkenyl refers to an alkenyl group as defined herein above substituted by an aryl group as defined herein.
  • arylalkenyl refers to a C 2- io alkenyl group substituted by a C 6- I 4 aryl group (an aryl group having 6 to 14 carbon atoms), as defined herein above.
  • arylalkynyl refers to an alkynyl group as defined herein above substituted with an aryl group as defined herein above.
  • arylalkynyl refers to a C 2- io alkynyl group substituted by a C 6- -I 4 aryl group (an aryl group having 6 to 14 carbon atoms), as defined herein above.
  • arylalkoxy refers to an alkoxy group as defined herein above substituted by an aryl group as defined herein above.
  • arylalkoxy refers to a Ci--I 0 alkoxy group, as defined herein above, substituted by an aryl group, as defined herein above.
  • Examples of arylalkoxy groups include benzyloxy and phenethyloxy.
  • heteroarylalkoxy refers to an alkoxy group as defined herein above substituted by an heteroaryl group as defined herein above.
  • heteroarylalkoxy refers to a Ci--I 0 alkoxy group, as defined herein above, substituted by an heteroaryl group, as defined herein above.
  • arylalkoxy groups include benzyloxy and phenethyloxy.
  • haloalkoxy refers to an alkoxy group which is substituted with 1 to 6 halo groups, wherein the alkoxy group and the halo groups are as defined herein above, and further wherein the halo groups are independently selected.
  • haloaryl refers to an aryl group which is substituted with 1 to 6 halo groups, wherein the aryl group and the halo groups are as defined herein above, and further wherein the halo groups are independently selected.
  • substituents covalently linked the parent group where said substituents are independently chosen from halo, alkyl, alkynyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, -L- carbocycle, -L-aryl, -L-heteroaryl, -L-heterocycle, acylamino, acyloxy, alkylthio, amino, substituted amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, s
  • preventing an increase in a symptom refers to both not allowing a symptom to increase or worsen, as well as reducing the rate of increase in the symptom.
  • a symptom can be measured as the amount of particular disease marker, i.e., a protein.
  • the symptom can be cognitive decline.
  • Preventing an increase means that the amount of symptom (e.g., protein or cognitive decline) does not increase or that the rate at which it increases is reduced.
  • treating a disease or disorder refers to a slowing of or a reversal of the progress of the disease. Treating a disease or disorder includes treating a symptom and/or reducing the symptoms of the disease.
  • the term "preventing a disease or disorder” refers to a slowing of the disease or of the onset of the disease or the symptoms thereof. Preventing a disease or disorder can include stopping the onset of the disease or symptoms thereof.
  • unit dosage form refers to a physically discrete unit, such as a capsule or tablet suitable as a unitary dosage for a human patient. Each unit contains a predetermined quantity of a compound of Formulae I-V, which was discovered or believed to produce the desired pharmacokinetic profile which yields the desired therapeutic effect.
  • the dosage unit is composed of a compound of Formulae I-V in association with at least one pharmaceutically acceptable carrier, salt, excipient, or combination thereof.
  • a 40 mg dose of a compound of Formulae I-V refers to, in the case of a twice-daily dosage regimen, a situation where the individual takes 40 mg of a compound of Formulae I-V twice a day, e.g., 40 mg in the morning and 40 mg in the evening.
  • the 40 mg of a compound of Formulae I-V dose can be divided into two or more dosage units, e.g., two 20 mg dosage units of a compound of Formulae I-V in tablet form or two 20 mg dosage units of a compound of Formulae I-V in capsule form.
  • a pharmaceutically acceptable prodrug is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound.
  • a pharmaceutically active metabolite is intended to mean a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein.
  • a pharmaceutically acceptable salt is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable.
  • a compound for use in the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4 dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates
  • a "pharmaceutically acceptable carrier” refers to a non- API (API refers to Active Pharmaceutical Ingredient) substances such as disintegrators, binders, fillers, and lubricants used in formulating pharmaceutical products. They are generally safe for administering to humans according to established governmental standards, including those promulgated by the United States Food and Drug Administration and the European Medical Agency.
  • API Active Pharmaceutical Ingredient
  • certain variables in the list of substituents are repetitive (different name for the same substituent), generic to other terms in the list, and/or partially overlap in content with other terms.
  • substituents may be attached to the remainder of the molecule via a number of positions and the preferred positions are as illustrated in the Examples.
  • the compounds of Formulae I-V can contain asymmetric carbon atoms and can therefore exist in racemic and optically active forms.
  • optical isomers or enantiomers, racemates, tautomers, and diastereomers are also encompassed in the compounds of Formulae I-V.
  • the methods of present invention include the use of all such isomers and mixtures thereof. Methods of separation of enantiomeric and diastereomeric mixtures are well known to one skilled in the art.
  • the present invention encompasses any isolated racemic or optically active form of compounds described in Formulae I-V, or any mixture thereof.
  • the active compounds can be incorporated into a formulation that includes pharmaceutically acceptable carriers such as binders (e.g., gelatin, cellulose, gum tragacanth), excipients (e.g., starch, lactose), lubricants (e.g., magnesium stearate, silicon dioxide), disintegrating agents (e.g., alginate, Primogel, and corn starch), and sweetening or flavoring agents (e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint).
  • binders e.g., gelatin, cellulose, gum tragacanth
  • excipients e.g., starch, lactose
  • lubricants e.g., magnesium stearate, silicon dioxide
  • disintegrating agents e.g., alginate, Primogel, and corn starch
  • sweetening or flavoring agents e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint
  • the capsules and tablets can also be coated with various coatings known in the art to modify the flavors, tastes, colors, and shapes of the capsules and tablets.
  • liquid carriers such as fatty oil can also be included in capsules.
  • Suitable oral formulations can also be in the form of suspension, syrup, chewing gum, wafer, elixir, and the like. If desired, conventional agents for modifying flavors, tastes, colors, and shapes of the special forms can also be included.
  • the active compounds can be dissolved in an acceptable lipophilic vegetable oil vehicle such as olive oil, corn oil and safflower oil.
  • the active compounds can also be administered parenterally in the form of solution or suspension, or in lyophilized form capable of conversion into a solution or suspension form before use.
  • diluents or pharmaceutically acceptable carriers such as sterile water and physiological saline buffer can be used.
  • Other conventional solvents, pH buffers, stabilizers, anti-bacteria agents, surfactants, and antioxidants can all be included.
  • useful components include sodium chloride, acetates, citrates or phosphates buffers, glycerin, dextrose, fixed oils, methyl parabens, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, and the like.
  • the parenteral formulations can be stored in any conventional containers such as vials and ampoules.
  • Topical administration examples include nasal, bucal, mucosal, rectal, or vaginal applications.
  • the active compounds can be formulated into lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, drops and aerosols.
  • one or more thickening agents, humectants, and stabilizing agents can be included in the formulations. Examples of such agents include, but are not limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum, beeswax, or mineral oil, lanolin, squalene, and the like.
  • a special form of topical administration is delivery by a transdermal patch. Methods for preparing transdermal patches are disclosed, e.g., in Brown, et al., (1988) Annual Review of Medicine, 39:221 -229, which is incorporated herein by reference.
  • Subcutaneous implantation for sustained release of the active compounds may also be a suitable route of administration. This entails surgical procedures for implanting an active compound in any suitable formulation into a subcutaneous space, e.g., beneath the anterior abdominal wall. See, e.g., Wilson et al., (1984) J. Clin. Psych. 45:242-247.
  • Hydrogels can be used as a carrier for the sustained release of the active compounds. Hydrogels are generally known in the art. They are typically made by crosslinking high molecular weight biocompatible polymers into a network, which swells in water to form a gel like material. Preferably, hydrogels are biodegradable or biosorbable.
  • hydrogels made of polyethylene glycols, collagen, or poly(glycolic-co-L-lactic acid) may be useful. See, e.g., Phillips et al., (1984) J. Pharmaceut. Sci., 73: 1718- 1720.
  • the compounds of Formulae I-V also include prodrugs and metabolites thereof.
  • the active compounds for example, can be conjugated, to a water soluble non- immunogenic non-peptidic high molecular weight polymer to form a polymer conjugate.
  • an active compound is covalently linked to polyethylene glycol to form a conjugate.
  • such a conjugate exhibits improved solubility, stability, and reduced toxicity and immunogenicity.
  • the active compound in the conjugate can have a longer half-life in the body, and exhibit better efficacy. See generally, Burnham (1994) Am. J. Hosp. Pharm. 15:210-218.
  • PEGylated proteins are currently being used in protein replacement therapies and for other therapeutic uses.
  • PEGylated interferon PEG-INTRON A®
  • PEGylated adenosine deaminase ADAGEN®
  • SCIDS severe combined immunodeficiency disease
  • PEGylated L-asparaginase ONCAPSPAR®
  • ALL acute lymphoblastic leukemia
  • Controlled release of an active compound can also be achieved by incorporating the active ingredient into microcapsules, nanocapsules, or hydrogels generally known in the art.
  • Other pharmaceutically acceptable prodrugs of the compounds of this invention include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, aminoacid conjugates, phosphate esters, metal salts and sulfonate esters.
  • Liposomes can also be used as carriers for the active compounds of the present invention.
  • Liposomes are micelles made of various lipids such as cholesterol, phospholipids, fatty acids, and derivatives thereof. Various modified lipids can also be used. Liposomes can reduce the toxicity of the active compounds, and increase their stability. Methods for preparing liposomal suspensions containing active ingredients therein are generally known in the art. See, e.g., U.S. Patent No. 4,522,81 1 ; Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y. (1976).
  • the active compounds can also be administered in combination with another active agent that synergistically treats or prevents the same symptoms or is effective for another disease or symptom in the patient treated so long as the other active agent does not interfere with or adversely affect the effects of the active compounds of this invention.
  • Such other active agents include but are not limited to anti-inflammation agents, antiviral agents, antibiotics, antifungal agents, antithrombotic agents, cardiovascular drugs, cholesterol lowering agents, anti-cancer drugs, hypertension drugs, and the like.
  • Molecule names were generated using IsisDraw version 2.4. For molecules larger than 50 atoms, the molecule was fragmented to generate the name. In the case of a conflict between a name and a drawing of the structure, the drawing is controlling.
  • Method E Hydrogenation. Methyl (4E)-2-[2-(4-benzyloxyphenyl)ethyl]-5-phenylpent- 4-enoate (3.45 g, 8.613 mmol) was added to a suspension of Pd/C (900 mg, 10% Pd/C, 0.845 mmol) in MeOH (60 ml_). The reaction mixture was stirred under H 2 atmosphere (balloon) for 8 h. It was filtered through Celite (eluted with EtOAc) and solvent was concentrated off.
  • Methyl 2-[2-(4-benzyloxyphenyl)ethyl]-5-(1 -naphthyl)pent-4-ynoate A solution of methyl 4-[4-(benzyloxy)phenyl]butanoate (1.5 g, 5.27 mmol) in THF (5 ml_) was added to a -78 0 C cooled solution of LDA (6 ml_, 1 M THF solution, 6 mmol) in THF (30 ml_).
  • Methyl 2- [2-(4-benzyloxyphenyl)ethyl]-5-(1 -naphthyl)pent-4-ynoate (940 mg, 2.095 mmol) was added to a suspension of Pd/C (220 mg, 10% Pd/C, 0.210 mmol) in MeOH (20 ml_). The reaction mixture was stirred under H 2 atmosphere (balloon) for 2 h. It was filtered through Celite (eluted with EtOAc) and solvent was concentrated off.
  • the crude residue was purified by flash chromatography on SiO 2 (2 ⁇ 10% EtOAc/hexanes), to give 645 mg of methyl 2-[2-(4- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ phenyl)ethyl]-5-(1 -naphthyl)pentanoate (colourless oil, yield: 83%).
  • Example 2 Methyl 2- ⁇ 2-[3'-cyano-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoate.
  • Method F Suzuki coupling.
  • Example 3 2- ⁇ 2-([3'-Cyano-1 , 1 '-biphenyl-4-yl])ethyl ⁇ -5-phenylpentanoic acid .
  • Method B ester hydrolysis. LiOH (4 mL, 2M solution in H 2 O, 8 mmol) was added to a solution of methyl 2- ⁇ 2-[3'-cyano-1 , 1 '-biphenyl-4-yl]ethyl ⁇ - 5-phenylpentanoate (234 mg, 0.562 mmol) in a mixture of THF (14 mL) and MeOH (14 mL). It was warmed up to reflux, and stirred until no unreacted ester was detected by TLC analysis (2 h).
  • the reaction mixture was allowed to reach r.t. and poured into H 2 O (100 mL). It was acidified with HCI (10% aqueous solution) until pH 2-3, and extracted with EtOAc (150 mL). The organic layer was dried over Na 2 SO 4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO 2 (10 ⁇ 80% EtOAc/hexanes) to furnish 2- ⁇ 2-([3'- cyano-1 , 1 '-biphenyl-4-yl])ethyl ⁇ -5-phenylpentanoic acid (51 mg, white solid, yield: 24%).
  • Example 5 2- ⁇ 2-[4'-methoxy-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoic acid.
  • the compound was synthesized from methyl 2- ⁇ 2-[4'-methoxy-1 , 1 '- biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (10 ⁇ 40% EtOAc/hexanes) to give a white solid (yield: 60%).
  • Example 6 Methyl 2- ⁇ 2-[4'-chloro-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoate.
  • the compound was synthesized from Intermediate A and 4-chlorophenylboronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO 2 (2 ⁇ 4% EtOAc/hexanes) to give a white solid (yield: 80%).
  • Example 7 2- ⁇ 2-[4'-Chloro-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoic acid.
  • the compound was synthesized from methyl 2- ⁇ 2-[4'-chloro-1 , 1 '- biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (10 ⁇ 60% EtOAc/hexanes) to give a white solid (yield: 73%).
  • Example 8 Methyl 2- ⁇ 2-[3'-fluoro-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoate.
  • the compound was synthesized from Intermediate A and 3-fluorophenylboronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO 2 (5% EtOAc/hexanes) to give a colourless oil (yield: 70%).
  • Example 9 2- ⁇ 2-[3'-Fluoro-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoic acid.
  • the compound was synthesized from methyl 2- ⁇ 2-[3'-fluoro-1 , 1 '- biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (20 ⁇ 50% EtOAc/hexanes) to give an off-white solid (yield: 60%).
  • Example 10 Methyl 2- ⁇ 2-[3'-methoxy-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoate.
  • the compound was synthesized from Intermediate A and 3-methoxyphenylboronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO 2 (0 ⁇ 10% EtOAc/hexanes) to give a yellow coloured oil (yield: 83%).
  • El MS: m/z 403 (M + 1 ), 420 (M + 18).
  • Example 1 1 2- ⁇ 2-[3'-Methoxy-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoic acid.
  • the compound was synthesized from methyl 2- ⁇ 2-[3'methoxy-1 ,1 '- biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (10 ⁇ 40% EtOAc/hexanes) to afford a yellow coloured oil (yield: 50%).
  • Example 13 2- ⁇ 2-[2'-Trifluoromethyl-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoic acid.
  • the compound was synthesized from methyl 2- ⁇ 2- [2'-trifluoromethyl-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (20 ⁇ 40% EtOAc/hexanes) to afford a yellow coloured oil (yield: 52%).
  • Example 14 Methyl 2- ⁇ 2-[2'-methoxy-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoate.
  • the compound was synthesized from Intermediate A and 2-methoxyphenylboronic acid pinacol ester, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO 2 (5 ⁇ 10% EtOAc/hexanes) to give a yellow coloured oil (yield: 64%).
  • Example 15 2- ⁇ 2-[2'-Methoxy-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoic acid.
  • the compound was synthesized from methyl 2- ⁇ 2-(4-[2'-methoxy- 1 , 1 '-biphenyl-4-yl])ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (20 ⁇ 40% EtOAc/hexanes) to give a colourless oil (yield: 68%).
  • Example 16 Methyl 2- ⁇ 2-[(2'-methoxypyridinyl)-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoate.
  • the compound was synthesized from Intermediate A and 2-methoxypyridine-3-boronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO 2 (5 ⁇ 50% EtOAc/hexanes) to give an orange coloured oil (yield: 55%).
  • Example 17 2- ⁇ 2-[(2'-Methoxypyridinyl)-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoic acid.
  • the compound was synthesized from methyl 2- ⁇ 2- [(2'-methoxypyridinyl)-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on Si ⁇ 2 (30 ⁇ 50% EtOAc/hexanes) to give a colourless oil (yield: 51 %).
  • Example 18 Methyl 2- ⁇ 2-[(1 -methyl-1 H-pyrazol-4-yl)phenyl]ethyl ⁇ -5- phenylpentanoate.
  • the compound was synthesized from Intermediate A and i -methylpyrazole-4-boronic acid pinacol ester, following the experimental procedure detailed in Method F. It was purified by flash chromatography on Si ⁇ 2 (30 ⁇ 50% EtOAc/hexanes) to give an orange coloured oil (yield: 48%).
  • the compound was synthesized from methyl 2- ⁇ 2-[(1 -methyl-1 H-pyrazol-4- yl)phenyl]ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on Si ⁇ 2 (0 ⁇ 10% MeOH/EtOAc) to furnish an off-white solid (yield: 35%).
  • Example 20 Methyl 2- ⁇ 2-[(3'- ⁇ /-cyclopropylamide)-1 ,1 '-biphenyl-4-yl]ethyl ⁇ - 5-phenylpentanoate.
  • the compound was synthesized from Intermediate A and 3-( ⁇ /-cyclopropylaminocarbonyl)phenylboronic acid, pinacol ester, following the experimental procedure detailed in Method F. It was purified by flash chromatography on Si ⁇ 2 (20 ⁇ 70% EtOAc/hexanes) to afford a yellow coloured oil (yield: 19%).
  • Example 21 2- ⁇ 2-[(3'- ⁇ /-cyclopropylamide)-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoic acid.
  • the compound was synthesized from methyl 2- ⁇ 2- [(3'- ⁇ /-cyclopropylamide)-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (20 ⁇ 100% EtOAc/hexanes) to give a white solid (yield: 33%).
  • Example 22 Methyl 2- ⁇ 2-[2'-fluoro-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoate.
  • the compound was synthesized from Intermediate A and 2-fluorophenylboronic acid following the experimental procedure detailed in Method F. It was purified by flash chromatography on Si ⁇ 2 (5 ⁇ 10% EtOAc/hexanes) to give a colourless oil (yield: 80%).
  • Example 23 2- ⁇ 2-[2'-Fluoro-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoic acid.
  • the compound was synthesized from methyl 2- ⁇ 2-[2'-fluoro-1 , 1 '- biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (20 ⁇ 50% EtOAc/hexanes) to give a colourless oil (yield: 75%).
  • Example 24 Methyl 2- ⁇ 2-[(4'-fluoro, 3'-cyano)-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoate.
  • the compound was synthesized from Intermediate A and 3-cyano-4-fluorophenylboronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO 2 (10 ⁇ 20% EtOAc/hexanes) to give a yellow-coloured oil (yield: 99%).
  • Example 25 2- ⁇ 2-[(4'-Methoxy, 3'-cyano)-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoic acid.
  • the compound was synthesized from methyl 2- ⁇ 2- [(4'-fluoro,3'-cyano)-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on Si ⁇ 2 (25 ⁇ 30% EtOAc/hexanes) to give a white solid (yield: 39%).
  • Example 26 2- ⁇ 2-[(4'-Fluoro, 3'-cyano)-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoic acid.
  • the compound was synthesized from methyl 2- ⁇ 2- [(4'-fluoro,3'-cyano)-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B, by using a mixture of H 2 O and THF as reaction solvent (MeOH was not present). It was purified by flash chromatography on SiO 2 (25 ⁇ 30% EtOAc/hexanes) to give a colourless oil (yield:22%).
  • Example 27 Methyl 2- ⁇ 2-[3'-acetyl-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoate.
  • the compound was synthesized from Intermediate A and 3-acetylphenylboronic acid following the experimental procedure detailed in Method F. It was purified by flash chromatography on Si ⁇ 2 (5 ⁇ 20% EtOAc/hexanes) to give a colourless oil (yield: 25%).
  • Example 28 2- ⁇ 2-[3'-Acetyl-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoic acid.
  • the compound was synthesized from methyl 2- ⁇ 2-[3'-acetyl-1 ,1 '- biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (10 ⁇ 50% EtOAc/hexanes) to give a colourless oil (yield: 86%).
  • Example 29 Methyl 2- ⁇ 2-[3'-(trifluoromethyl)-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoate.
  • the compound was synthesized from Intermediate A and 3-(trifluoromethyl)phenylboronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO 2 (2 ⁇ 4% EtOAc/hexanes) to give a colourless oil (yield: 88%).
  • Example 30 2- ⁇ 2-[3'-(Trifluoromethyl)-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoic acid.
  • the compound was synthesized from methyl 2- ⁇ 2- [3'-(trifluoromethyl)-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (5 ⁇ 30% EtOAc/hexanes) to give a white solid (yield: 87%).
  • Example 31 Methyl 2- ⁇ 2-[4'-fluoro-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoate.
  • the compound was synthesized from Intermediate A and 4-fluorophenylboronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO 2 (0 ⁇ 5% EtOAc/hexanes) to give a white solid (yield: 91 %).
  • Example 32 2- ⁇ 2-[4'-Fluoro-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoic acid.
  • the compound was synthesized from methyl 2- ⁇ 2-[4'-fluoro-1 , 1 '- biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (5 ⁇ 30% EtOAc/hexanes) to give a white solid (yield: 45%).
  • Example 33 Methyl 2- ⁇ 2-[4'-cyano-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoate.
  • the compound was synthesized from Intermediate A and 4-cyanophenylboronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO 2 (5 ⁇ 7% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 27%).
  • Example 34 2- ⁇ 2-[4'-Cyano-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoic acid.
  • the compound was synthesized from methyl 2- ⁇ 2-[4'-cyano-1 ,V- biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (5 ⁇ 20% EtOAc/hexanes) to give a white solid (yield: 18%).
  • Example 35 Methyl 2- ⁇ 2-[3'-trifluoromethoxy-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoate.
  • Example 36 2- ⁇ 2-[3'-Trifluoromethoxy-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoic acid.
  • the compound was synthesized from methyl 2- ⁇ 2- [3'-trifluoromethoxy-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on Si ⁇ 2 (5 ⁇ 20% EtOAc/hexanes) to give a waxy solid (yield: 26%).
  • Example 37 Methyl 2- ⁇ 2-[4'-(trifluoromethyl)-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoate.
  • the compound was synthesized from Intermediate A and 4-(trifluoromethyl)benzeneboronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO 2 (0 ⁇ 10% EtOAc/hexanes) to give a white solid (yield: 56%).
  • Example 38 2- ⁇ 2-[4'-(Trifluoromethyl)-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoic acid.
  • the compound was synthesized from methyl 2- ⁇ 2- [4'-(trifluoromethyl)-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (5 ⁇ 20% EtOAc/hexanes) to give a white solid (yield: 58%).
  • Example 40 2- ⁇ 2-[3'-(Acetylamino)-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoic acid.
  • the compound was synthesized from methyl 2- ⁇ 2- [3'-(acetylamino)-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (0 ⁇ 20% MeOH/EtOAc) to give a brown-coloured solid (yield: 26%).
  • Example 41 Methyl 2- ⁇ 2-[3'-(aminocarbonyl)-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoate.
  • the compound was synthesized from Intermediate A and 3-carbamoylphenylboronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO 2 (30 ⁇ 80% EtOAc/hexanes) to give a yellow-coloured oil (yield: 52%).
  • Example 42 2- ⁇ 2-[3'-(Aminocarbonyl)-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoic acid.
  • the compound was synthesized from methyl 2- ⁇ 2- [3'-(aminocarbonyl)-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (0 ⁇ 10% MeOH/CH 2 CI 2 ) to give a colourless oil (yield: 42.6%).
  • Example 43 Methyl 5-(1 -naphthyl)-2- ⁇ 2-[3'-cyano-1 , 1 '-biphenyl-4- yl)]ethyl ⁇ -pentanoate.
  • the compound was synthesized from Intermediate B and 3-cyanophenylboronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO 2 (5 ⁇ 20% EtOAc/hexanes) to give a yellow coloured oil (yield: 47%).
  • El MS: m/z 448 (M + 1 ).
  • Example 44 5-(1 -Naphthyl)-2- ⁇ 2-[3'-cyano-1 , 1 '-biphenyl-4- yl)]ethyl ⁇ pentanoic acid.
  • the compound was synthesized from methyl 5-(1 - naphthyl)-2- ⁇ 2-[3'-cyano-1 , 1 '-biphenyl-4-yl)]ethyl ⁇ -pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on Si ⁇ 2 (30 ⁇ 70% MeOH/EtOAc) to give a colourless oil (yield: 51 %).
  • Example 45 Methyl 2- ⁇ 2-[4-(1 -oxidopyridin-3-yl)phenyl]ethyl ⁇ -5- phenylpentanoate.
  • H 2 O 2 (35% aqueous solution, 0.16 ml_, 1.75 mmol) was added to a solution of methyl 2-[2-(4-pyridin-3'-ylphenyl)ethyl]-5- phenylpentanoate (132 mg, 0.353 mmol) in CH 2 CI 2 (5 ml_).
  • Example 46 2- ⁇ 2-[4-(1 -Oxidopyridin-3-yl)phenyl]ethyl ⁇ -5-phenylpentanoic acid.
  • the compound was synthesized from methyl 2- ⁇ 2-[4-(1 -oxidopyridin- 3-yl)phenyl]ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on Si ⁇ 2 (0 ⁇ 7% MeOH/CH 2 CI 2 ), and slurred with hexanes to give a white solid (yield: 38%).
  • Example 47 Methyl 4-(4- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ phenyl)butanoate.
  • Trifluoromethanesulfonic anhydride (1.68 g, 5.94 mmol) was added to a - 18 °C cooled solution of methyl 4-(4-hydroxyphenyl)butanoate (1 .0 g, 5.148 mmol) and DIPEA (1.7 ml_, 9.930 mmol) in CH 2 CI 2 (30 ml_).
  • Example 48 Methyl 4-(3'-cyano-1 , 1 '-biphenyl-4-yl)butanoate.
  • the compound was synthesized from methyl 4-(4- ⁇ [(trifluoromethyl)sulfonyl] oxy ⁇ phenyl)butanoate and 3-cyanophenylboronic acid following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO 2 (5 ⁇ 20% EtOAc/hexanes) to give a white solid (yield: 81 %).
  • Example 49 Methyl 2- ⁇ 2-[3'-nitrile-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpent-4- enoate.
  • the compound was synthesized from methyl 4-(3'-cyano-1 ,1 '- biphenyl-4-yl)butanoate and [(1 E)-3-bromoprop-1 -enyl]benzene following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO 2 (10 ⁇ 20% EtOAc/hexanes) to give a yellow- coloured oil (yield: 76%).
  • Example 50 2- ⁇ 2-[3'-nitrile-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5-phenylpent-4-enoic acid.
  • the compound was synthesized from methyl 2- ⁇ 2-[3'-nitrile-1 ,1 '- biphenyl-4-yl]ethyl ⁇ -5-phenylpent-4-enoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (30 ⁇ 70% MeOH/EtOAc) to give a white solid (yield: 22%).
  • Example 51 Methyl 5-[3-(tert-butoxycarbonyl-4-methylanilinosulfonyl) phenyl]-2-[2-(3'-cyano-1 ,1 '-biphenyl-4-yl)ethyl]pent-4-ynoate.
  • the compound was synthesized from methyl 4-(3'-cyano-1 ,1 '-biphenyl-4- yl)butanoate and tert-butyl [3-(3-bromoprop-1 -ynyl)phenyl]sulfonyl(4- methylphenyl)carbamate, following the experimental procedure detailed in Method A.
  • Example 52 Methyl 5-[3-(tert-butoxycarbonyl-4-methylanilinosulfonyl) phenyl]-2-[2-(3'-cyano-1 ,1 '-biphenyl-4-yl)ethyl]pentanoate.
  • the compound was synthesized from methyl 5-[3-(tert-butoxycarbonyl-4-methylanilino sulfonyl)phenyl]-2-[2-(3'-cyano-1 ,1 '-biphenyl-4-yl)ethyl]pent-4-ynoate following the experimental procedure detailed in Method E.
  • Example 53 5-[3-(4-methylanilinosulfonyl)phenyl]-2-[2-(3'-cyano-1 ,Y- biphenyl-4-yl)ethyl]pentanoic acid.
  • the compound was synthesized from methyl 5-[3-(tert-butoxycarbonyl-4-methylanilinosulfonyl)phenyl]-2-[2-(3'- cyano-1 , 1 '-biphenyl-4-yl)ethyl]pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (10 ⁇ 40% MeOH/EtOAc) to give a white solid (yield: 56%).
  • Example 54 4-(3'-cyano-1 , 1 '-biphenyl-4-yl)-2-(4-benzyloxybenzyl)butanoic acid.
  • Methyl 4-(3'-cyano-1 , 1 '-biphenyl-4-yl)-2-(4-benzyloxybenzyl)butanoate The compound was synthesized from methyl 4-(3'-cyano-1 ,1 '-biphenyl-4- yl)butanoate and 1 -(benzyloxy)-4-(bromomethyl)benzene, following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO 2 (5 ⁇ 20% EtOAc/hexanes) to give a colourless oil (yield: 78%).
  • Example 55 Methyl 5-[4-(tert-butoxycarbonylanilinosulfonyl)phenyl]-2-[2- (3'-cyano-1 , 1 '-biphenyl-4-yl)ethyl]pent-4-ynoate.
  • the compound was synthesized from methyl 4-(3'-cyano-1 , 1 '-biphenyl-4-yl)butanoate and tert- butyl [4-(3-bromoprop-1 -ynyl)phenyl]sulfonyl(phenyl)carbamate, following the experimental procedure detailed in Method A.
  • Example 56 Methyl 5-[4-(tert-butoxycarbonylanilinosulfonyl)phenyl]-2-[2- (3'-cyano-1 , 1 '-biphenyl-4-yl)ethyl]pentanoate.
  • the compound was synthesized from methyl 5-[4-(tert-butoxycarbonylanilinosulfonyl)phenyl]- 2-[2-(3'-cyano-1 , 1 '-biphenyl-4-yl)ethyl]pent-4-ynoate following the experimental procedure detailed in Method E.
  • Example 57 5-[4-(Anilinosulfonyl)phenyl]-2-[2-(3'-cyano-1 , 1 '-biphenyl-4- yl)ethyl]pentanoic acid.
  • the compound was synthesized from methyl 5-[4- (tert-butoxycarbonylanilinosulfonyl)phenyl]-2-[2-(3'-cyano-1 ,1 '-biphenyl-4- yl)ethyl]pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on Si ⁇ 2 (40 ⁇ 100% EtOAc/hexanes) to give a white solid (yield: 68%).
  • Example 58 was synthesized from methyl 2-[2-(4- bromophenyl)ethyl]-5-phenylpentanoate and 3-hydroxyphenylboronic acid following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO 2 (5 ⁇ 30% EtOAc/hexanes) to give a yellow-coloured oil (yield: 76%).
  • the compound was synthesized from methyl 2- ⁇ 2-[3'-hydroxy-1 , 1 '- biphenyl-4-yl]ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (5 ⁇ 30% EtOAc/hexanes) to give a white solid (yield: 53%).
  • Example 60 The title compound of Example 60 was synthesized from methyl 4-(3'- cyano-1 , 1 '-biphenyl-4-yl)butanoate and 1 -(benzyloxy)-4-(3- iodopropyl)benzene following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO 2 (5 ⁇ 20% EtOAc/hexanes) to give a colourless oil (yield: 38%).
  • the compound was synthesized from methyl 5-[4-(benzyloxy)phenyl]-2-[2- (3'-cyano-1 , 1 '-biphenyl-4-yl)ethyl]pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (20 ⁇ 40% EtOAc/hexanes) to give a white solid (yield: 35%).
  • Example 62 1 -Bromo-4-[(1 E)-3-bromoprop-1 -enyl]benzene PBr 3 (0.70 ml_) was added to a - 18 0 C cooled solution of (2E)-3-(4- bromophenyl)prop-2-en-1 -ol (1.30 g, 6.10 mmol) in Et 2 O (50 ml_). The reaction mixture was stirred at low temperature for 10 min, poured into H 2 O (100 ml_) and extracted with Et 2 O (100 ml_).
  • Example 63 Methyl (4E)-5-(4-bromophenyl)-2-[2-(3'-cyano-1 ,1 '-biphenyl- 4-yl)ethyl]pent-4-enoate
  • Example 65 Methyl 5-(1 ,1 '-biphenyl-4-yl)-2-[2-(3'-cyano-1 , r-biphenyl-4- yl)ethyl]pentanoate
  • Example 67 The title compound of Example 67 was synthesized from methyl 4-(3'- cyano-1 , 1 '-biphenyl-4-yl)butanoate and 1 -bromo-4-(bromomethyl)benzene (commercially available from e.g., Fluka ref.: 16460)following the experimental procedure detailed in Method A. It was purified by flash chromatography on Si ⁇ 2 (5 ⁇ 15% EtOAc/hexanes) to give a colourless oil (yield: 56%).
  • Example 68 2-(4-Bromobenzyl)-4-(3'-cyano-1 , 1 '-biphenyl-4-yl)butanoic acid
  • the compound was synthesized from methyl 2-(4-bromobenzyl)-4-(3'- cyano-1 , 1 '-biphenyl-4-yl)butanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on Si ⁇ 2
  • Example 69 Methyl 2-(1 ,1 '-biphenyl-4-ylmethyl)-4-(3'-cyano-1 , 1 '-biphenyl- 4-yl)butanoate
  • the compound was synthesized from methyl 2-(4-bromobenzyl)-4-(3'- cyano-1 , 1 '-biphenyl-4-yl)butanoate and phenylboronic acid following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO 2 (5 ⁇ 20% EtOAc/hexanes) to give a colourless oil (yield: 38%).
  • Example 70 2-(1 , 1 '-Biphenyl-4-ylmethyl)-4-(3'-cyano-1 ,1 '-biphenyl-4- yl)butanoic acid
  • Example 71 The title compound of Example 71 was synthesized from methyl 2-[2-(3- bromo-4-benzyloxyphenyl)ethyl]-5-phenylpentanoate and phenylboronic acid following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO 2 (10 ⁇ 20% EtOAc/hexanes) to give a yellow-coloured oil (yield: 65%).
  • Example 72 2-[2-(6-Benzyloxy-1 , 1 '-biphenyl-3-yl)ethyl]-5-phenylpentanoic acid
  • the compound was synthesized from methyl 2-[2-(6-benzyloxy-1 ,1 '- biphenyl-3-yl)ethyl]-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (20 ⁇ 50% EtOAc/hexanes) to give a colourless oil (yield: 48%).
  • the compound was synthesized from methyl 5-(1 -naphthyl)-2-[2-(4'- trifluoro-1 ,1 '-biphenyl-4-yl)ethyl]-pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (10 ⁇ 40% EtOAc/hexanes) to give a white solid (yield: 66%).
  • Example 76 5-(1-Naphthyl)-2- ⁇ 2-[3'-methoxy-1,1'-biphenyl-4- yl)]ethyl ⁇ pentanoic acid
  • the compound was synthesized from methyl 5-(1-naphthyl)-2- ⁇ 2-[3'- methoxy-1,1'-biphenyl-4-yl)]ethyl ⁇ pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (20 ⁇ 40% EtOAc/hexanes) to give a colourless oil (yield: 66%).
  • Example 78 5-(1 -Naphthyl)-2- ⁇ 2-[4'-methoxy-1 , 1 '-biphenyl-4- yl)]ethyl ⁇ pentanoic acid
  • the compound was synthesized from methyl 5-(1 -naphthyl)-2- ⁇ 2-[4'- methoxy-1 ,1 '-biphenyl-4-yl)]ethyl ⁇ pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (10 ⁇ 50% EtOAc/hexanes) to give a colourless oil (yield: 27%).
  • Example 80 5-(1 -Naphthyl)-2- ⁇ 2-[4'-cyano-1 , 1 '-biphenyl-4- yl)]ethyl ⁇ pentanoic acid
  • Example 81 Methyl 2- ⁇ 2-[4-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)phenyl]ethyl ⁇ - 5-phenylpentanoate
  • the compound was synthesized from Intermediate A and 1 ,3,5-trimethyl-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (commercially available from e.g., Boron Molecular ref: BM359) following the experimental procedure detailed in Method F. It was purified by flash chromatography on Si ⁇ 2 (30 ⁇ 80% EtOAc/hexanes) to give a yellow- coloured oil (yield: 70%).
  • Example 82 2- ⁇ 2-[4-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)phenyl]ethyl ⁇ -5- phenylpentanoic acid
  • the compound was synthesized from Intermediate A and 1 -isobutyl-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (commercially available from e.g., Aldrich ref.: 642614-G) following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO 2 (10 ⁇ 40% EtOAc/hexanes) to give a yellow-coloured oil (yield: 67%).
  • Example 84 2-(2- ⁇ [1 -lsobutyl-1 H-pyrazol-4-yl]phenyl ⁇ ethyl)-5- phenylpentanoic acid
  • the compound was synthesized from methyl 2-(2- ⁇ [1 -isobutyl-1 H-pyrazol- 4-yl]phenyl ⁇ ethyl)-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (10 ⁇ 30% EtOAc/hexanes) to give a colourless oil (yield: 12%).
  • the compound was synthesized from Intermediate A and 1 - (ethoxycarbonylmethyl)-1 H-pyrazole-4-boronic acid pinacol ester (commercial available e.g., Aldrich ref.: 683566-250MG) following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO 2 (10 ⁇ 20% EtOAc/hexanes) to give a yellow- coloured oil (yield: 28%).
  • the compound was synthesized from Intermediate A and 1 -methyl-5- (4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole (commercially available e.g., Aldrich ref.: 698628-5G) following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO 2 (10 ⁇ 50% EtOAc/hexanes) to give a yellow-coloured oil (yield: 43%).
  • Example 88 2-(2- ⁇ [1 -Methyl-1 H-pyrazol-4-yl]phenyl ⁇ ethyl)-5- phenylpentanoic acid
  • the compound was synthesized from methyl 2-(2- ⁇ [1 -methyl-1 H-pyrazol-4- yl]phenyl ⁇ ethyl)-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on Si ⁇ 2 (40 ⁇ 80% EtOAc/hexanes) to give a colourless oil (yield: 1 1 %).
  • the compound was synthesized from Intermediate A and 1 -(benzyl)-1 H- pyrazole-4-boronic acid pinacol ester (commercially available from e.g., Acros, Apollos, Flurochem or readily prepared by the skilled artisan) following the experimental procedure detailed in Method F. It was purified by flash chromatography on Si ⁇ 2 (5 ⁇ 20% EtOAc/hexanes) to give a yellow-coloured oil (yield: 70%).
  • the compound was synthesized from methyl 2-(2- ⁇ [1 -(4-methoxybenzyl)- 1 H-pyrazol-4-yl]phenyl ⁇ ethyl)-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO 2 (20 ⁇ 70% EtOAc/hexanes) to give a colourless oil (yield: 50%).
  • Example 94 Methyl 2-(2- ⁇ [3,5-dimethyl-1 H-pyrazol-4-yl]phenyl ⁇ ethyl)-5- phenylpentanoate
  • the compound was synthesized from methyl 2- ⁇ 2-(4-[3,5-dimethyl-1 -(4- methoxybenzyl)-1 H-pyrazol-4-yl)]phenyl)ethyl ⁇ -5-phenylpentanoate following the experimental procedure detailed in Method E. at reflux. It was purified by flash chromatography on SiO 2 (50 ⁇ 80% EtOAc/hexanes) to give a colourless oil (yield: 36%).
  • El MS: m/z 391 (M + 1 ).
  • Example 95 2-(2- ⁇ [3,5-Dimethyl-1 H-pyrazol-4-yl]phenyl ⁇ ethyl)-5- phenylpentanoic acid
  • Example 97 2- ⁇ 2-[(1 -Ethyl-1 H-pyrazol-4-yl)phenyl]ethyl ⁇ -5- phenylpentanoic acid
  • Example 98 Methyl 2- ⁇ 2-[4'-(Acetylamino)-1 , 1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoate
  • the compound was synthesized from Intermediate A and 4- acetamidophenylboronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO 2
  • Example 99 2- ⁇ 2-[4'-(Acetylamino)-1 ,1 '-biphenyl-4-yl]ethyl ⁇ -5- phenylpentanoic acid
  • HDAC inhibtion was determined indirectly by measuring the fluorescence generated by deacetylated fluorogenic substrate (KI-104 fluor de LysTM , Biomol®, used at 125 ⁇ M) product reacting with a developer solution (Kl- 105 Fluor de Lys TM Biomol®). All assays were carried out in the assay buffer: 50 mM Tris/CI, pH 8.0, 137 mM NaCI, 2.7 mM KCI, 1 mM MgCI 2 ).
  • HDAC1 , HDAC 2, HDAC 6 or HDAC 8 were added up to 125 nM, 33.3 nM, 25 nM and 1850 nM respectively in assay buffer. When necessary, the mixture was incubated at room temperature prior the addition of substrate.
  • HDAC1 ref. #50001 , BPS Bioscience TM
  • HDAC 2 ref. # 50002, BPS Bioscience TM
  • HDAC 6 ref. # 50006, BPS Bioscience TM
  • HDAC 8 ref. # 50008, BPS Bioscience TM
  • Table.1 Main parameters of activity assay with histone deacetylase protein.
  • IC50 values are defined as the compound concentration at which the deacetylase activity is 50% inhibited and are shown in Table 2 below. Table 2
  • the compounds of the invention also show inhibition of other human HDACs.
  • the human colon cancer cell line HCT1 16 was from the American Type Culture Collection (ATCC; CCL-247).
  • the HCT1 16 cell line was maintained in DMEM GlutaMAX (Invitrogen) supplemented with 10% fetal calf serum. Cells were grown in a humidified incubator at 37 0 C in 5% CO 2 . AlamarBlue Assay
  • the compounds of the invention show activity in various models including e.g., Compound Example 3 which had EC50 values below 100 micromolar for various cancer cell lines including colon cancer, lung cancer, and breast cancer cell lines.
  • Valproate was found to have an IC50 for HDAC2 of about 1300 micromolar and an EC50 in the HCT1 16 assay of about 2000 micromolar.
  • Phenylbutyrate was found to have an IC50 value of about 1400 micromolar for HDAC2 and an EC50 value of about 3500 micromolar in the HCT1 16 assay.
  • the compounds of the invention are surprisingly much more active (generally 1 to 2 orders of magnitude or more) than similar HDAC inhibitors having carboxylic acid zinc chelating groups both in vitro against purified HDAC enzymes and in vivo in cell-based assays.

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Abstract

La présente invention concerne des dérivés de l'acide alcanoïque de formule (IIa) et (IIb). Ces composés de l'invention se sont avérés avoir une activité en tant qu'inhibiteurs de l'HDAC.
PCT/EP2009/067466 2008-12-19 2009-12-17 Dérivés de l'acide alcanoïque et leur utilisation thérapeutique en tant qu'inhibiteurs de l'hdac WO2010070076A1 (fr)

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US8367863B2 (en) 2007-12-20 2013-02-05 Envivo Pharmaceuticals, Inc. Tetrasubstituted benzenes
US8633319B2 (en) 2010-04-29 2014-01-21 Glaxo Group Limited 7-(1H-pyrazol-4-yl)-1,6-naphthyridine compounds as Syk inhibitors
JP2018501269A (ja) * 2014-12-24 2018-01-18 エルジー・ケム・リミテッド Ｇｐｒ１２０アゴニストとしてのビアリール誘導体

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US8367863B2 (en) 2007-12-20 2013-02-05 Envivo Pharmaceuticals, Inc. Tetrasubstituted benzenes
US8664249B2 (en) 2007-12-20 2014-03-04 Envivo Pharmaceuticals, Inc. Tetrasubstituted benzenes
US8633319B2 (en) 2010-04-29 2014-01-21 Glaxo Group Limited 7-(1H-pyrazol-4-yl)-1,6-naphthyridine compounds as Syk inhibitors
JP2018501269A (ja) * 2014-12-24 2018-01-18 エルジー・ケム・リミテッド Ｇｐｒ１２０アゴニストとしてのビアリール誘導体
US11261186B2 (en) 2014-12-24 2022-03-01 Lg Chem. Ltd. Biaryl derivative as GPR120 agonist

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