WO2006012310A2 - Carbazole derivatives for treating polycystic kidney disease - Google Patents

Carbazole derivatives for treating polycystic kidney disease Download PDF

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Publication number
WO2006012310A2
WO2006012310A2 PCT/US2005/022524 US2005022524W WO2006012310A2 WO 2006012310 A2 WO2006012310 A2 WO 2006012310A2 US 2005022524 W US2005022524 W US 2005022524W WO 2006012310 A2 WO2006012310 A2 WO 2006012310A2
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nrr
nrc
halogen
group
ncs
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PCT/US2005/022524
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French (fr)
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WO2006012310A3 (en
Inventor
Scott F. Sneddon
Oxana Beskrovnaya
Jill S. Gregory
Laurie Ann Smith
Herve Husson
Nikolai O. Bukanov
Christopher Yee
Bradford H. Hirth
Lisa M. Cuff
Andrew Janjigian
Thomas H. Jozefiak
Cecilia M. Bastos
Ahmed Hilmy
Jeffrey Skell
Craig Giragossian
Brian Cochran
Monica Serrano
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Genzyme Corporation
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Publication of WO2006012310A3 publication Critical patent/WO2006012310A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles 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 carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • a cyst is an abnormal fluid-filled sac that can form in many parts of the body, such as the kidney, liver, pancreas, spleen and heart.
  • Polycystic disease is a disease that occurs when a large number of cysts cause damage to these organs.
  • PPD polycystic kidney disease
  • the PKD cysts can slowly replace much of the mass of the kidneys, reducing kidney function and leading to kidney failure. About half the people with the most common form of PKD progress to kidney failure and require dialysis or kidney transplantation.
  • PKD can also cause cysts in other organs, most commonly the liver, but also the spleen, pancreas, heart and blood vessels in the brain. About 500,000 people have PKD in this country, and PKD is the fourth leading cause of kidney failure. Autosomal dominant PKD (ADPKD) accounts for about 90% of all PKD cases and about 8-10% of all cases of end stage renal disease. Currently, there is no approved treatment or cure for PKD. Present medical and surgical procedures only reduce the pain resulting from expansion of renal cysts or resolve other symptoms associated with PKD such as infections or high blood pressure. None of these procedures, aside from kidney transplantation, appreciably slows the progression of the disease. Thus, there is a need for agents and methods for preventing the onset of or slowing the progression of PKD.
  • the present invention is a method for treating PKD in a patient comprising administering to the patient an effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof:
  • Ring A is a 5-, 6-, 7- or 8-membered carbocyclic ring optionally substituted at one or more substitutable ring atoms.
  • Ring A is a substituted or unsubstituted aromatic ring, such as a 5- or 6-membered substituted or unsubstituted aromatic ring, for example, a carbocyclic aromatic ring such as a substituted or unsubstituted phenyl ring.
  • Ring A is a substituted or unsubstituted non-aromatic carbocyclic ring.
  • Ring B is optionally substituted at one or more substitutable ring carbon atoms.
  • X is -OR, -SH, -OC(O)R, -OC(O)OR, -OC(O)NRR or -SC(O)OR. In another embodiment, X is also -H. When X is -OC(O)OR or -SC(O)OR, R is preferably not hydrogen.
  • Ri is -R, -C(O)R or -R 5 C(O)R.
  • Each R is independently hydrogen or a substituted or unsubstituted alkyl, alkenyl or aryl group, or NRR forms a substituted or unsubstituted non-aromatic heterocyclic ring.
  • the present invention is a pharmaceutical composition
  • a pharmaceutically acceptable carrier or diluent and a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention also includes novel compounds disclosed herein.
  • One group of the novel compounds includes novel 3-hydroxymethyl-substituted carbazoles.
  • the 3-hydroxymethyl-substituted carbazoles have the substituents described above as suitable for the corresponding position of compounds represented by Structural Formula (I). These compounds are typically also substituted at the 4-position and at one or more of the 5-, 6- and 7-positions of the carbazole ring system.
  • a 3- hydroxymethyl-substituted carbazole of the invention is unsubstituted at the 2- and 8- positions.
  • Another group of novel compounds includes compounds represented by Strucutral Formula (I), where Ring A is a 5-, 6-, 7- or 8-membered non-aromatic carbocyclic ring optionally substituted at one or more substitutable ring atoms.
  • compositions and compounds disclosed herein can be used in therapy, for example, for treating PKD.
  • present invention also provides for the use of the pharmaceutical compositions and compounds disclosed herein for the manufacture of a medicament for the purpose of treating PKD in an individual.
  • the present invention has many advantages.
  • the present invention provides compounds that have been shown to reduce the extent of cyst fo ⁇ nation in mice with a transgenic form of PKD.
  • these compounds provide a treatment for PKD that addresses the underlying disease state, rather than simply ameliorating symptoms that are associated with PKD.
  • Such compounds may reduce the need for kidney dialysis or transplant, which is currently required for the majority of patients suffering from PKD.
  • FIGs. 1A-1Z, IAA- IEE and 1FF-1JJ show the anti-cystogenic activity data for the compounds that were tested according to the procedure described in Example 2, where the compounds are grouped in three different activity classes based on their IC 50 values (A: ⁇ 1 ⁇ M; B: 1-12.5 ⁇ M; and C: > 12.5 ⁇ M).
  • FIG. 2 shows photographic images of cysts grown from human primary renal epithelial cells, as described in Example 3, at 4 days and 8 days.
  • FIG. 3 shows photographic images of cysts that were treated in Example 3 with 0.04 ⁇ M and 1.5 ⁇ M of 9-ethyl-3-hydroxymethyl-9H-carbazole beginning after 4 days of growth. The images were taken at day 4 and day 8, after 4 days of treatment with the carbazole.
  • the present invention is directed to methods of treating polycystic kidney disease (PKD) that involve administering a compound of Structural Formula (I) to a patient.
  • PPD polycystic kidney disease
  • the invention is directed to pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and a compound represented by Structural Formula (I).
  • the invention also includes novel 3-hydroxylmethyl- substituted carbazoles, particularly those represented by Structural Formula (III) where R 3 and at least one Of R 6 -R 8 is a substituent other than hydrogen and novel compounds represented by Structural Formula (I) where Ring A is a non-aromatic carbocyclic ring.
  • compounds for use in the invention are represented by Structural Formula (II):
  • R a and R b are each independently a halogen, -OR, -SR, -C(O)R 3 -C(S)R,
  • Structural Formula (II) examples of compounds encompassed by Structural Formulas (III) and (Ilia):
  • R 6 -R 8 has one of these typical values when R 3 has a value other than hydrogen.
  • Y is -H, -C(O)R, -C(O)OR or -C(O)NRR. Additionally, Y is substituted or unsubstituted alkyl. Typically, Y is -H. Alternatively, Y is unsubstituted lower allcyl, . preferably methyl, ethyl or isopropyl, more preferably ethyl.
  • Preferred compounds of the invention are represented by Structural Fo ⁇ nulas (III) and (Ilia) where at least one of Re-R 8 have one of the typical values disclosed above (i.e., a value other than hydrogen) and R 3 has one of the values described above, other than hydrogen.
  • Particularly preferred compounds of the invention encompassed within this description can be represented by compounds encompassed by Structural Formulas (IV), (V), (VI) and (XIV), more particularly Structural Formula (XIV).
  • Other preferred compounds of the invention can be represented by compounds encompassed by Structural Formulas (XV), (XVI) and (XVII).
  • Additional compounds preferred in the invention can be represented by Structural Fo ⁇ nulas (IVa), (Va), (Via), (XIVa), (IVb), (Vb), (VIb) and (XIVb).
  • Structural Fonriula (I)
  • Ring A is a 5-, 6-, 7- or 8-membered non-aromatic carbocyclic ring optionally substituted at one or more substitutable ring atoms.
  • Variables for Ring A and B are as described above.
  • Particularly preferred compounds of the invention encompassed within this group can be represented by Structural Formulas (X), (XI), (XII) and (XIII), particularly Structural Fo ⁇ nulas (XII) and (XIII).
  • Ri for Structural Formula (IV) is preferably -H, an acyl group or a substituted or unsubstituted alkyl group.
  • Ri is -H or an unsubstituted lower alkyl group such as methyl, ethyl or ⁇ -propyl.
  • Ri is cyclopropylmethyl, para- fluorobenzyl, methoxymethyl, 2-ethoxyethyl, n-pentyl, 3-pyridylmethyl,
  • R 2 is typically -H or an unsubstituted lower alkyl group (e.g., methyl or ethyl), particularly -H.
  • R 2 include -CF 3 and where R 2 and R 3 , taken together with the carbon atoms between R 2 and R 3 , form a 5-membered carbocyclic ring.
  • the remainder of the variables in Structural Fo ⁇ nula (IV) is as described above.
  • R 3 is typically -H or a substituted or unsubstituted lower alkyl or alkoxy group, particularly an alkoxy-substituted, hydroxy-substituted, or carboxy-substituted lower alkyl or alkoxy group or an unsubstituted lower alkyl or alkoxy group.
  • R 3 examples include -H, -CH 3 , -CH 2 CH 3 , -OCH 3 , -O(CH 2 ) 2 OH, -OCH 2 CH 3, -O(CH 2 ) 2 OCH 3 , z-propoxy, n-pr ⁇ poxy and -O(CH 2 ) 2 N(CH 3 ) 2 , particularly -O(CH 2 ) 2 OH and -CH 3 .
  • Additional examples of R 3 include carboxy-substituted lower alkyl or alkoxy, such as -0-CH 2 -C(O)-OCH 3 and -OCH 2 -C(O)-OH, and alkoxy-substituted lower alkyl or
  • Fo ⁇ nula (FV) is as described above.
  • R 1 is -H or an unsubstituted lower alkyl group
  • R 2 is -H or an unsubstituted lower alkyl group, particularly -H
  • R 3 is an alkoxy-substituted, hydroxy-substituted or carboxy-substituted lower alkyl or alkoxy group or an unsubstituted lower alkyl or alkoxy group
  • R 5 -R 8 are as described above for Structural Formulas (HI)-(IIIa).
  • at least one OfR 6 -R 8 is one of the non-hydrogen substituents described above.
  • R 7 is a halogen, -NH 2 or an unsubstituted lower alkyl or alkoxy group.
  • R 7 is -C(O)OR.
  • R 7 is a halogen, NH 2 or an unsubstituted lower alkyl or alkoxy group
  • R 5 is advantageously an unsubstituted lower alkyl (-CH 3 ) or alkoxy (-OCH 3 ) group.
  • R 6 and R 8 are typically each independently a halogen or an unsubsituted lower alkyl or alkoxy group.
  • R 7 is more typically a halogen (-F, - Cl, -Br), an amine (-NH 2 , -N(CH 3 )(C 2 Hs)) or an unsubstituted lower alkyl or alkoxy group (-CH 3 , -OCH 3 ), preferably -Cl or -F.
  • R 7 is -Cl or -F
  • R 2 is typically -H.
  • R 5 is an unsubstituted lower alkyl or alkoxy group, particularly -CH 3 .
  • R 7 is typically a halogen, an amine (-NH 2 ) or an unsubstituted lower alkyl or alkoxy group, particularly an unsubsituted lower alkyl group.
  • R 5 is an unsubstituted lower alkyl group and R 7 is -Cl or -F, especially when R 2 is -H.
  • Structural Formula (IV) Examples of compounds encompassed within Structural Formula (IV) are represented by Structural Formula (VII):
  • R 6 and R 8 are each independently a halogen (-F, -Cl, -Br) or a substituted or unsubstituted alkyl or alkoxy group, particularly a lower alkoxy group (-OCH 3 ).
  • R 6 and R 8 include -CH 3 , -CH 2 CH 3 , benzyl oxy, hexahydropyridyl, tetrahydropyrrolyl, N-morphonyl, (trifluoromethyl)hydroxymethyl, -NH 2 , -NH(C 2 H 5 ), -N(CH 3 ) 2 , -N(CH 3 )(C 2 H 5 ), -N(C 2 Hj) 2 , -NO 2 , -NH(CH 2 ) 2 (CH(CH 3 ))(CH 2 ) 2 (CH)(C(CH 3 ) 2 ), cyclohexylamine, (2 - chlorophenyl)methylamine, (4-tert-butylphenyl)methylamine, (3 -benzoxy-4-methoxy)phenylmethylamine, (4-methoxyphenyl)methyl amide, (4-methoxyphenyl)amide,
  • R 7 is typically a halogen, an amine (-NH 2 ) or an unsubstituted lower alkyl or alkoxy group, particularly -Cl or -F.
  • R 6 and Rg are each independently an unsubstituted lower alkoxy group (-OCH 3 ) and R 2 is -H.
  • R 1 -R 3 , Re and R 8 are as described above for Structural Formula (VII).
  • Typical values OfR 6 and R 8 are as described for Structural Formula (VII).
  • R 6 and R 8 are each independently a halogen or an unsubstituted lower alkyl or alkoxy group, particularly an unsubstituted lower alkoxy group such as -OCH 3 .
  • R 2 is typically -H.
  • Rg and R 8 are each independently a halogen or an unsubstituted lower alkyl or alkoxy group, particularly -CH 3 or -OCH 3 .
  • R 6 and R 8 are a halogen or an unsubstituted lower allcyl or alkoxy group
  • R 5 is advantageously an unsubstituted lower alkyl or alkoxy group, particularly -CH 3
  • R 2 is generally -H.
  • Ri is a substituted or unsubstituted lower allcyl group
  • R 3 is a substituted or unsubstituted lower allcyl or alkoxy group
  • R 5 is -H or a substituted or unsubstituted lower alkyl or alkoxy group
  • R 7 is a halogen, -NH 2 or a substituted or unsubstituted lower alkyl or alkoxy group.
  • Ri is -CH 3 , -CH 2 CH 3 or -CH 2 CH 2 CH 3 .
  • R 7 is typically -F, -Cl, - Br, -CH 3 or -OCH 3 .
  • R 3 is typically -O(CH 2 ) 2 OH or -CH 3 .
  • Ri is one of the unsubstituted lower groups
  • R 3 is -O(CH 2 ) 2 OH or -CH 3
  • R 7 is -F, -Cl, - Br, -CH 3 or -OCH 3
  • R 5 is -H, -CH 3 , -CH 2 CH 3 or -OCH 3
  • Examples of compounds encompassed by Structural Formula (III) are represented by Structual Formulas (Va), (Via), (Vila), (VIIIa) and (IXa), where all of the variables, including preferred values, are as described above for Structural Formulas (V), (VI), (VII), (VIII) and (IX), respectively:
  • Structural Formula (III) Additional examples of compounds encompassed by Structural Formula (III) are represented by Structual Formulas (Vb), (VIb), (VIIb), (VIIIb) and (IXb), where Rj-R 3 and R 5 -R 8 , including preferred values, are as described above for Structural Formulas (V), (VI), (VII), (VIII) and (IX), respectively; and Ri 0 is Ci-C 5 alkyl:
  • X is -H, -OR, -SH, -OC(O)R, -OC(O)OR, -OC(O)NRR or -SC(O)OR; and Ri-R 3 are as described above for Strucural Formulas (IV) and (IVa).
  • X is -H or -OR, where R is a substituted or unsubstituted alkyl. R is preferably an unsubstitued lower alkyl, such as methyl, ethyl and isopropyl.
  • Ri is -H or a substituted or unsubstituted lower alkyl group
  • R 2 is -H or an unsubstituted lower alkyl group, particularly -H
  • R 3 is an alkoxy- substituted, hydroxy-substituted or carboxy-substituted lower alkyl or alkoxy group, or an unsubstituted lower alkyl or alkoxy group.
  • Rj-R 3 have these values
  • X is -H, -OH or -OEt.
  • R 7 and R 8 are each are described above for Structural Formulas (IV) and (IVa).
  • R 7 and R 8 are typically each independently a halogen, an amine, an unsubstituted lower alkyl or alkoxy group, or a carboxyl group, such as -F, -Cl, -Br, -Me, -OMe, -NH 2 , -N(CH 3 )(C 2 H 5 ), or -C(O)OMe. More specific examples of R 7 and R 8 are described above for Structural Formulas (IV)-(IVa).
  • R 6 is typically a halogen (-Br, - Cl, -F), an alkoxy-substituted, hydroxy-substituted or carboxy-substituted lower alkyl or allcoxy group (-O-(CH 2 ) 2 OH, -O-(CH 2 ) 2 C(O)OH, or -O-(CH 2 ) 2 C(O)OMe), an unsubstituted lower alkyl or alkoxy group (-Me or -OMe) , or hydroxy.
  • R 7 is typically a halogen, an amine, an unsubstituted lower alkyl or alkoxy group, or a carboxyl group, such as -Cl, -Br, -Me, -OMe, -NH 2 , -N(CH 3 )(C 2 H 5 ), or -C(O)OMe. More specific examples of R 6 and R 7 are described above for Structural Formulas (IV)-(IVa).
  • R 0 and R d are each independently a halogen, -OR, -SR, -C(O)R, -C(S)R,
  • Suitable values OfRi-R 3 and each R 0 are as described above for Structural Formula (X). Suitable values of R 5 are as described above for Structural Formula (III).
  • Y is -H, -C(O)R, -C(O)OR or -C(O)NRR. Additionally, Y is substituted or unsubstituted alkyl. Preferably, Y is -H. Alternatively, Y is an unsubstituted lower alkyl group, preferably methyl, ethyl or isopropyl, more preferably ethyl.
  • Y is -H and each R 0 is an unsubstituted alkyl group, preferably unsubstituted lower alkyl group.
  • R 0 is an unsubstituted alkyl group, preferably unsubstituted lower alkyl group.
  • n is typically 1 or 2 and p is typically an integer from 0 to 4, more preferably 0 to 2.
  • Structural Formula (XI) Another group of compounds encompassed by Structural Formula (XI) is represented by Structural Formula (XIII): or a pharmaceutically acceptable salt thereof, where R 1 -R 3 and R 5 are as described above for Structural Formula (XI).
  • Ri for Structural Formulas (XII) and (XIII) is preferably -H, an acyl group or a substituted or unsubstituted alkyl group.
  • Ri is -H, an unsubstituted lower alkyl group (methyl, ethyl or n-propyl) or a halobenzyl group (a benzyl group where the phenyl ring is substituted with one or more halogens, for example, fluorobenzyl and para-halobenzyls such asjo ⁇ r ⁇ -fluorobenzyl).
  • the remainder of the variables in each of Structural Formulas (XII) and (XIII) is as described above.
  • R 2 is typically -H or an unsubstituted lower alkyl group (e.g., methyl or ethyl), particularly -H.
  • R 3 and R 5 in each of Structural Formulas (XII) and (XIII) are as described above.
  • R 3 is typically -H or a substituted or unsubstituted lower alkyl or alkoxy group, particularly -H or an alkoxy-substituted, hydroxy-substituted, or carboxy-substituted lower alkyl or alkoxy group or an unsubstituted lower alkyl or alkoxy group.
  • R 3 examples include -H, -CH 3 , -CH 2 CH 3 , -OCH 3 , -O(CH 2 ) 2 OH, -OCH 2 CH 3 , -O(CH 2 ) 2 OCH 3 , z-propoxy, n-propoxy and -O(CH 2 ) 2 N(CH 3 ) 2 , particularly -O(CH 2 ) 2 OH and -OCH 3 .
  • R 5 in each of Structural Formulas (XII) and (XIIi) is as described above.
  • Ri is -H, an unsubstituted lower alkyl group or a halobenzyl group
  • R 2 is -H or an unsubstituted lower alkyl group, particularly -H
  • R 3 is an alkoxy-substituted, hydroxy-substituted or carboxy-substituted lower alkyl or alkoxy group or an unsubstituted lower alkyl or alkoxy group
  • R 5 is -H, a halogen or an unsubstituted lower allcyl or alkoxy group, preferably, -H or a halogen such as -Cl.
  • the invention also includes novel compounds disclosed herein along with salts thereof, which are not limited to pharmaceutically acceptable salts thereof.
  • Carbocyclic rings include carbocyclic aromatic rings (e.g., phenyl) and carbocyclic non-aromatic rings (e.g., cycloalkyl and cycloalkenyl).
  • Heterocyclic rings include heteroaryl groups and non-aromatic heterocyclic groups. The rings can be three- to twelve-membered, but are typically five, six, seven or eight-membered.
  • a "bridgehead" is the region where two rings are fused together.
  • a substitutable ring atom is an atom in a carbocyclic or heterocyclic ring to which a substituent can be attached. In non-aromatic rings, carbon and nitrogen atoms other than quaternary atoms are substitutable.
  • Carbon atoms at non-bridgehead positions can have one or two substituents, but typically have only one substituent. In aromatic rings, typically only carbon atoms that are not at a bridgehead position are substitutable. A ring atom in a structure which is already depicted as having a substitutent is not substitutable. For example, the 3-position of Ring B in Structural Formula (I) already has a substituent, -CH(R 2 )X, so that the carbon atom at the 3- position cannot have another substituent.
  • aryl group may be used interchangeably with “aryl,” “aryl ring,” “aromatic group,” and “aromatic ring.”
  • heteroaryl group may be used interchangeably with “heteroaryl,” “heteroaryl ring,” “heteroaromatic ring” and
  • Carbocyclic aromatic groups include phenyl, naphthyl, and anthracyl groups.
  • heterocyclic aromatic groups include imidazolyl, thienyl, furanyl, pyridyl, pyrimidyl, pyranyl, pyrazolyl, pyrroyl, pyrazinyl, thiazolyl, oxazolyl, and tetrazolyl groups.
  • Aryl groups also include fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings.
  • alkyl refers to a cyclic or acyclic, straight or branched hydrocarbon group of 1-24 carbon atoms, typically 1-12 carbon atoms.
  • Suitable alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, «-butyl, sec- butyl, tert-butyl, pentyl, ⁇ -pentyl, neopentyl, hexyl, heptyl, octyl and the like.
  • An alkyl group may be substituted with one or more substituents independently selected for each position.
  • a C1-C4 straight chained or branched alkyl group or a C3-C6 cyclic alkyl group is also referred to as a "lower alkyl" group.
  • alkenyl refers to a straight or branched hydrocarbon group that contains one or more double bonds between carbon atoms. Suitable alkenyl groups include, e.g., n-butenyl, cyclooctenyl and the like. An alkenyl group may be substituted.
  • An alkoxy group is an alkyl group that is connected to a molecule through an oxygen atom.
  • Alkylene group is a saturated hydrocarbon in a molecule that is bonded to two other groups in the molecule through single covalent bonds.
  • Alkylene groups can be cyclic or acyclic and branched or unbranched. Typically, an alkylene group has one to about six carbon atoms, for example, one to about four carbon atoms.
  • An alkenylene group is an unsaturated hydrocarbon containing one or more double bonds in a molecule that is bonded to two other groups in the molecule through single covalent bonds.
  • Alkenylene groups can be cyclic or acyclic and branched or unbranched. Typically, an alkenylene group has two to about eight carbon atoms, for example, three to about six carbon atoms.
  • Suitable substituents on an alkyl, alkylene, alkenyl, alkenylene and carbocyclic or heterocyclic rings are those which do not substantially interfere with the cystogenesis-inhibiting activity of the disclosed compounds, for example, do not lower the activity by more than a factor of about two.
  • an alkyl, alkylene, alkenyl or alkenylene group can be substituted with substituted or unsubstituted aryl group to form, for example, an aralkyl group such as benzyl.
  • aryl groups can be substituted with a substituted or unsubstituted alkyl or alkenyl group.
  • compounds of the invention do not include perhaloalkyl groups attached directly to a carbazole ring, particularly perfiuoroalkyl groups (e.g., trifluoromethyl groups).
  • R a -R d are each independently an alkyl group, aromatic group, non-aromatic heterocyclic group or -N(R a R b ), taken together, form a substituted or unsubstituted non- aromatic heterocyclic group.
  • the alkyl, aromatic and non-aromatic heterocyclic group represented by R a -R d and the non-aromatic heterocyclic group represented by -N(R a R b ) can optionally be substituted.
  • the compounds of the invention or salts or thereof thereof can be administered by an appropriate route.
  • Suitable routes of administration include, but are not limited to, orally, intraperitoneally, subcutaneously, intramuscularly, intradermally, transdermally, rectally, sublingually, intravenously, buccally or via inhalation.
  • the compounds are administered orally or intravenously.
  • compositions of the invention preferably contain a pharmaceutically acceptable carrier or diluent suitable for rendering the compound or mixture administrable orally, parenterally, intravenously, intradermally, intramuscularly or subcutaneously, rectally, via inhalation or via buccal administration, or transdermally.
  • Suitable pharmaceutically acceptable carriers typically contain inert ingredients which do not inhibit the biological activity of the disclosed compounds.
  • the pharmaceutically acceptable carriers should be biocompatible, i.e., non-toxic, non-inflammatory, non- immunogenic and devoid of other undesired reactions upon administration to a subject.
  • the formulations of the present invention for use in a subject comprise the agent, together with one or more acceptable carriers or diluents therefor and optionally other therapeutic ingredients.
  • the carriers or diluents must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations can conveniently be presented in unit dosage form and can be prepared by methods well known in the art of pharmacy. All methods include the step of bringing into association the agent with the carrier or diluent which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the agent with the carriers and then, if necessary, dividing the product into unit dosages thereof.
  • Formulations suitable for parenteral administration conveniently comprise sterile aqueous preparations of the agents that are preferably isotonic with the blood of the recipient.
  • Suitable carrier solutions often include phosphate buffered saline, saline, water, lactated ringers or dextrose (5% in water), cyclodextrin, cremophor, a mixture of cyclodextrin, cremophor and ethanol (12.7% in water) or a mixture of cremophor (10% in water) and ethanol (10% in water).
  • Such formulations can be conveniently prepared by admixing the agent with water to produce a solution or suspension, which is filled into a sterile container and sealed against bacterial contamination.
  • sterile materials are used under aseptic manufacturing conditions to avoid the need for terminal sterilization.
  • Such formulations can optionally contain one or more additional ingredients, which can include preservatives such as methyl hydroxybenzoate, chlorocresol, metacresol, phenol and benzalkonium chloride.
  • additional ingredients such as methyl hydroxybenzoate, chlorocresol, metacresol, phenol and benzalkonium chloride.
  • Buffers can also be included to provide a suitable pH value for the formulation.
  • Suitable buffer materials include sodium phosphate and acetate.
  • Sodium chloride or glycerin can be used to render a formulation isotonic with the blood.
  • a formulation can be filled into containers under an inert atmosphere such as nitrogen and can be conveniently presented in unit dose or multi-dose form, for example, in a sealed ampoule.
  • compositions of the invention to be administered in accordance with the method of the invention to a subject will depend upon those factors noted above.
  • compositions of the invention when given orally or via buccal administration can be formulated as tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum syrups and lozenges.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier, for example, ethanol, glycerine or water, with a flavoring or coloring agent.
  • a liquid carrier for example, ethanol, glycerine or water
  • a flavoring or coloring agent for example, ethanol, glycerine or water
  • one or more pharmaceutical carriers routinely used for preparing solid formulations can be employed. Examples of such carriers include magnesium stearate, starch, lactose and sucrose.
  • compositions are in the form of a capsule, the use of routine encapsulation is generally suitable, for example, using the aforementioned carriers in a hard gelatin capsule shell.
  • pharmaceutical carriers routinely used for preparing dispersions or suspensions can be considered, for example, aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.
  • a typical suppository formulation a compound that is active when administered in this way, with a binding and/or lubricating agent, for example, polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats.
  • Typical transdermal formulations include a conventional aqueous or non-aqueous vehicle, for example, a cream, ointment, lotion or paste or are in the form of a medicated plastic, patch or membrane.
  • Typical compositions for inhalation are in the form of a solution, suspension or emulsion that can be administered in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
  • the effective amount of a compound or pharmaceutical composition of the invention depends, in each case, upon several factors, e.g., the health, age, gender, size and condition of the subject to be treated, the intended mode of administration, and the capacity of the subject to incorporate the intended dosage form, among others.
  • An effective amount of an active agent is an amount sufficient to have the desired effect for the condition being treated, which can either be treatment of an active disease state or prophylactically inhibiting the active disease state from appearing.
  • an effective amount of a compound for treating a polycystic kidney disease is the quantity of compound that results in a slowing in the progression of the polycystic kideny disease, a reversal of the polycystic kidney disease state, the inhibition of new cyst formation (partial or complete inhibition of cystogenesis), a reduction in cyst mass, a reduction in the size and number of cysts, and/or a reduction in the severity of the symptoms associated with the polycystic kidney disease.
  • Effective amounts of the disclosed compounds typically range between about 0.001 mg/kg per day and 500 mg/kg per day, and preferably between 0.01 mg/kg per day and 50 mg/kg, more preferably between 0.1 mg/kg per day and 10 mg/kg.
  • salts and pharmaceutically acceptable salts of the compounds described herein Compounds disclosed herein that possess a sufficiently acidic functional group, a sufficiently basic functional group or both can react with any of a number of organic or inorganic bases, and inorganic and organic acids, to form a salt. Acidic groups commonly fo ⁇ n salts with alkali and alkaline earth metals (e.g, sodium, potassium, magnesium, calcium). In addition, acidic groups can form salts with amines.
  • Acids commonly employed to form acid addition salts from compounds with basic groups are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such asp- toluenesulfonic acid, methanesulfonic acid, oxalic acid, jo-bromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such asp- toluenesulfonic acid, methanesulfonic acid, oxalic acid, jo-bromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • salts include the hydroxide, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate,
  • the compounds disclosed herein can be prepared in the fo ⁇ n of their hydrates, such as hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate and the like and as solvates. It is to be understood that the compounds depicted herein include hydrates and solvates thereof even though the hydration or solvation state is not specifically indicated, unless otherwise indicated (e.g., as anhydrous or unsolvated).
  • a patient is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, e.g., a companion animal (e.g., dogs, cats, and the like), a farm animal (e.g., cows, sheep, pigs, horses, and the like) and a laboratory animal (e.g., rats, mice, guinea pigs, and the like).
  • a companion animal e.g., dogs, cats, and the like
  • a farm animal e.g., cows, sheep, pigs, horses, and the like
  • laboratory animal e.g., rats, mice, guinea pigs, and the like.
  • the compounds of the invention can be administered alone as a monotherapy or co-administered either simultaneously as a single dosage form or consecutively as separate dosage forms with other agents that ease the symptoms and/or complications associated with PKD.
  • the associated symptoms with PKD include pain, headaches, urinary tract infections and high blood pressure.
  • the agents that can be co ⁇ administered with the compounds of the invention include, but are not limited to, over-the counter pain medications, antibiotics, antimicrobials, thiazide diuretics, angiotensin- converting enzyme inhibitors, angiotensin II antagonists such as losartan, and calcium channel blockers such as diltiazem.
  • Examples of pain medications include acetaminophen, aspirin, naproxen, ibuprofen and COX-2 selective inhibitors such as rofecoxib, celecoxib and valdecoxib.
  • antibiotics and antimicrobials include cephalosporins, penicilin derivatives, aminoglycosidesm ciprofloxacin, erythromycin, chloramphemicol, tetracycline, ampicillin, gentamicin, sulfamethoxazole, trimethoprim and ciprofloxacin, streptomycin, rifamycin, amphotericin B, griseofulvin, cephalothin, cefazolin, fluconazole, clindamycin, erythromycin, bacitracin, vancomycin and fusidic acid
  • thiazide diuretics include bendroflumethiazide, chlorothiazide, chlorthalidone, hydrochlorothiazi
  • angiotensin-converting enzyme inhibitors examples include benazepril, captopril, cilazapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril.
  • Ethyl ⁇ -chloro-l ⁇ S ⁇ -tetrahydro ⁇ H-carbazole-S-carboxylate A suspension of 4- chlorophenylhydrazine hydrochloride (10.3 g, 57.2 mmol) and ethyl 4- oxocyclohexanecarboxylate (9.41 g, 55.3 mmol) in acetic acid (100 mL) was heated at reflux for 16 h. The reaction was allowed to cool to room temperature. The resulting suspension was stirred vigorously while water (400 mL) was added slowly.
  • Ethyl ⁇ -chloro ⁇ -ethyl-l ⁇ -tetrahydro ⁇ H-carbazole-S-carboxylate A solution of ethyl 6-chloro-l,2,3,4-tetrahydro-9H-carbazole-3-carboxylate (14.Og, 50.4 mmol) in dry DMF (80 mL) was slowly added to a cold suspension of sodium hydride (60% dispersion in mineral oil, 2.03 g, 50.4 mmol) in DMF (10 mL). After stirring for 5 min, a solution of iodoethane (7.86 g, 50.4 mmol) in DMF (6 mL) was added via a syringe.
  • the mixture was stirred at room temperature for 16 h.
  • the reaction mixture was diluted with water then extracted three times with ethyl acetate.
  • the ethyl acetate layers were combined, washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate and then concentrated in vacuo to afford a brown syrup.
  • the crude product was purified by silica gel chromatography (eluent gradient of 1 % ethyl acetate-hexane to 15% ethyl acetate-hexane) to afford a golden syrup (13.46 g, 87%).
  • Ethyl ⁇ -chloro-P-ethyl-PH-carbazole-S-carboxylate A mixture of ethyl 6-chloro-9- ethyl-l,2,3,4-tetrahydro-9H-carbazole-3-carboxylate (7.05 g, 23 mmol) and tetrachloro- 1,4-benzoquinone (12.5 g, 50.7 mmol) in toluene (100 mL) was heated at reflux for 17 h. The reaction was cooled to room temperature, diluted with hexane (200 mL) and filtered. The filter cake was washed with another portion of hexane. The filtrates were combined and concentrated in vacuo.
  • P-Ethyl- ⁇ -chloro-S-hydroxymethyl-PH-carbazole A solution of ethyl 6-chloro-9- ethyl-9H-carbazole-3-carboxylate (6.54 g, 21.7 mmol) in T ⁇ F (80 mL) was added via a cannula to stirred suspension of lithium aluminum hydride (1.88 g, 49.5 mmol) in T ⁇ F (10 mL) at 0 0 C. After the addition was completed the reaction mixture was stirred at room temperature for 45 min. The unreacted lithium aluminum hydride was hydrolyzed with water (2 mL) and the reaction mixture diluted with saturated ammonium chloride solution.
  • the aqueous mixture was extracted twice with ethyl acetate.
  • the ethyl acetate layers were combined, washed successively with saturated ammonium chloride solution, saturated sodium chloride solution, dried over magnesium sulfate and then concentrated in vacuo to afford a tan solid.
  • the crude product was purified by silica gel chromatography (neat dichloromethane) to afford a white solid (5.19 g, 92%).
  • Ethyl P-ethyl-S-methyl-ljZjS ⁇ -tetrahydro-PH-carbazole- ⁇ -carboxylate A solution of 3 -methyl- 1,2,3, 4-tetrahydro-9H-carbazole-6-carboxylic acid (3 g, 13.1 mmol) and iodoethane (2.62 mL, 32.7 mmol) in DMF (20 mL) was added to a stirred suspension of sodium hydride (90% sodium hydride, 1.05 g, 39.3 mmol) in DMF (3OmL). The mixture was stirred at room temperature for 16 h. The reaction was diluted with water and the resulting mixture was extracted twice with ethyl acetate.
  • Ethyl 9-ethyl-6-methyl-9H-carbazole-3-carboxylate A mixture of ethyl 9-ethyl-3- methyl-1, 2,3, 4-tetrahydro-9H-carbazole-6-carboxy late and 10% palladium on charcoal (300 mg) was placed in a flask. The reaction flask was purged with nitrogen then heated at 250-300 0 C for 45 minutes. After the flask cooled to room temperature the fused contents was pulverized and stirred with boiling ethanol. After the ethanol cooled the mixture was filtered through Celite filter aid. The Celite was washed with ethanol. The filtrates were combined and concentrated.
  • Ethyl l,2,3,4-tetrahydro-9H-carbazole-3-carboxylate A mixture of phenylhydrazine (3.0 g, 27.7 mmol) and ethyl 4-oxocyclohexanecarboxylate (4.7 g, 27.5 mmol) in acetic acid (30 niL) was heated at reflux for 16 h. The reaction was allowed to cool to room temperature. The resulting suspension was stirred vigorously while water (300 mL) was added slowly. After stirring at room temperature for 1 h, the solid was collected by filtration then washed with water.
  • Ethyl 9-pentyl-9H-carbazole-3-carboxyIate A solution of ethyl 1,2,3,4-tetrahydro- 9H-carbazole-3-carboxylate (5.0 g, 20.5 mmol) and 1-iodopentane (6.1 g, 30.8 mmol) in dry DMF (15 mL) was added to cold suspension of sodium hydride (dry, 95%, 1.2 g, 46.7 mmol in dry DMF). After the addition was completed the reaction was stirred at room temperature and monitored by TLC. After 1.5 Ii the reaction was chilled and carefully diluted with water (500 mL). The aqueous mixture was extracted twice with ethyl acetate.
  • 6-Chloro-l,4-dimethyl-9H-carbazole A mixture of 5-chloroindole (5.0 g, 33.0 mmol), 2,5-hexanedione (4.1 niL, 34.6 mmol), andp-toluenesulfonic acid monohydrate (6.7 g, 35.3 mmol) in ethanol (20 niL) was heated at reflux for 16 h. The reaction was cooled to room temperature, diluted with water and extracted twice with ethyl acetate. The ethyl acetate layers were washed successively with saturated sodium carbonate and saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to afford a brown syrup. The crude product was used without purification.
  • Methyl l-Chloro- ⁇ methoxy-Sj ⁇ S-tetrahydro-PH-carbazole-S-carboxylate A solution of methyl 5-chloro-4-hydrazino-2-methoxybenzoate (11.8 g, 51 mmol) and cyclohexanone (10 g, 102 mmol) in acetic acid (200 mL) was heated at reflux for 20 h. The reaction was cooled to room temperature, diluted with water (0.5 L) and extracted three times with ether.
  • Methyl l-Chloro-P-ethyM-methoxy-S ⁇ -tetrahydro-PH-carbazoIe-S- carboxylate To a stirred solution of methyl l-chloro-4-methoxy-5,6,7,8-tetrahydro-9H- carbazole-3-carboxylate (4.5 g, 15.3 mmol) in DMF (60 mL) was added sodium hydride (60% dispersion in mineral oil, 860 mg, 21.4 mmol). After gas evolution ceased, neat iodoethane (1.5 ml, 18.4 mmol) was added via a syringe and the mixture was stirred at room temperature for 24 h.
  • 9-Cyclopropylmethyl-9H-carbazole A solution of 9H-carbazole (6.8 g, 41 mmol) and cyclopropylmethyl bromide (5.0 g, 37 mmol) in DMF (50 mL) was added to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 1.63 g, 41 mmol) in DMF (50 mL). The reaction was stirred at room temperature for 16 h then carefully diluted with water and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo.
  • Methyl 3-(2,4-DimethoxyphenyI)-4-nitrobenzoate To a deoxygenated mixture of 2,4- dimethoxyphenyl boronic acid (2.24g, 12.3 mmol), 5-(methoxycarbonyl)-2-nitrophenyl trifiuoromethanesulfonate (2.77 g, 8.40 mmol), and potassium phosphate (1.32 g, 6.21 mmol) in ethylene glycol dimethyl ether (70 mL) was added tetrakis (triphenylphosphine)palladium(O) (738 mg, 0.639mmol).
  • the reaction was heated at reflux for 6 hours under inert atmosphere, cooled to ambient temperature, and filtered through a bed of Celite. The bed was rinsed with several volumes of ethyl acetate. The filtrate was washed successively with IM sodium hydroxide solution (2 x 100 niL), IM HCl (2 x 100 mL), water (100 mL), and saturated sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to a brown residue. The crude material was purified by silica gel chromatography (dichloromethane : hexanes (1 : I)) to afford a bright yellow solid (1.60 g, 60%).
  • Methyl ⁇ -Dimethoxy ⁇ H-carbazole-S-carboxylate A solution of methyl 3-(2,4- dimethoxyphenyl)-4-nitrobenzoate (612 mg, 1.92 mmol) and triethyl phosphite (25 mL) was heated at reflux under inert atmosphere until no starting material was evident by TLC. The reaction was cooled to ambient temperature. Vacuum distillation of the excess triethyl phosphite resulted in a yellow residue which was purified by silica gel chromatography (ethyl acetate: hexanes, (1 : 3)) to afford a white solid (370 mg, 68%).
  • Methyl 5,7-dimethoxy-9-ethyI-9H-carbazole-3-carboxylate A solution of methyl 5,7-dimethoxy-9H-carbazole-3-carboxylate (360 mg, 1.25 mmol) and iodoethane (390 mg, 2.50 mmol) in DMF (3.0 mL) was added dropwise to a chilled (0 0 C) suspension of sodium hydride (60 % dispersion in oil, 83.0 mg, 2.08 mmol) in DMF (2 mL). The ice bath was removed once the addition was complete and the reaction was stirred at ambient temperature for several hours.
  • Cyclohexane-l,3-dione mono-(4-chlorophenyl) ⁇ ydrazone 4-Chlorophenyl hydrazine hydrochloride (74.37 g, 0.415 mol) was suspended in water (400 mL) and placed in a 1 L three neck flask equipped with a mechanical stirrer and an addition funnel. A suspension of cyclohexane-l,3-dione (46.604 g, 0.416 mol) in water was added slowly. The mixture was stirred overnight resulting in an aqueous layer and a dark orange oil. The aqueous layer was decanted and hot MeOH (400 mL) was added to the oil.
  • the mixture was poured into water (1.6 L) and vigorously stirred until a solid formed.
  • the mixture was filtered and the solid was washed with water (300 mL).
  • the solid was suspended in hexane (500 niL), stirred for 1 hour then filtered.
  • the solid was dried overnight in the air.
  • 9-Ethyl-6-chloro- 4-hydroxy-9H-carbazole 9-Ethyl-6-chloro- 1,2,3, 4-tetrahydro-4- oxocarbazole (38.84 g, 0.156 mol) was dissolved in a mixture of T ⁇ F (200 mL) and DMF (200 mL). Pyridine hydrobromide perbromide (50.172 g, 0.156 mol) was added and the mixture was heated at 70 0 C for 20 hours. The reaction solvent was removed and the residue was partitioned between ethyl acetate (250 mL) and a solution of NaHSO 3 (20 %, 200 mL).
  • the aqueous layer was extracted again with ethyl acetate (100 mL). The organic layers were combined and washed with brine (200 mL), dried over MgSO 4 , filtered and concentrated in vacuo. The residue was redissolved in DMF (350 mL) and LiBr (31.10 g, 0.357 rnol, 2.3 eq) and Li 2 CO 3 (26.67 g, 0.36 mol, 2.3 eq) were added. The mixture was refluxed for 3 hours then the solvent was removed by distillation. The residue was partitioned between ethyl acetate (700 mL) and water (200 mL).
  • Methyl 9-Ethyl-6-chloro-4-hydroxy-9H-carbazole-3-carboxyIate A solution of 9- ethyl-6-chloro- 4-hydroxy-9H-carbazole (2.79 g, 11.4 mmol) in 1,2-dichloroethane (26 mL) was cooled to 0 0 C and a solution OfBCl 3 (1 M in xylenes, 13 mL) was added slowly. The mixture was slowly warmed to room temperature and methyl chloroformate (6.0 mL, 78 mmol, 7 eq) was added. The mixture was heated to 50 0 C for 15 hours, cooled to 0 0 C and quenched with drop-wise addition of methanol.
  • 9-Ethyl-6-chloro- 4-(2-hydroxyethoxy)-3-hydroxymethyl-9H-carbazole A solution of methyl 9-ethyl-6-chloro-4-(2-methoxy-2-oxoethoxy)-9H-carbazole-3- carboxylate in T ⁇ F (40 mL) was cooled to -2 0 C and LiAlH 4 (1.988 g, 52.6 mmol, 4.6 eq) was added very slowly. Mixture was stirred at 0 0 C for 1 hour and then poured slowly into ice (100 mL).
  • This compound was prepared in a manner analogous to Compound 96, using iodomethane rather than methyl bromoacetate to alkylate methyl 9-ethyl-6-chloro- 4- hydroxy-9H-carbazole-3-carboxylate.
  • Methyl 9-ethyl-6-chloro-4-methoxy-9H-carbazole-3-carboxylate 1 H NMR (DMSO- d 6 ) ⁇ 8.16 (sd, IH), 7.95 (d, IH), 7.75 (d, IH), 7.57 (dd, IH), 7.50 (d, IH), 4.49 (q, 2H), 4.03 (s, 3H), 3.88 (s, 3H), 1.31 (t, 3H).
  • This compound was prepared in a manner analogous to Compound 93, utilizing phenylhydrazine rather than 4-chlorophenylhydrazine in the initial Fischer indole cyclization.
  • Example 2 In Vitro Anti-cvsto genetic Activity of 3-hydroxymethyl carbazoles and 3- methyl carbazoles using Mardin-Darby canine kidney cells
  • Mardin-Darby canine kidney (MDCK) (ATTC CCL-34) cells were grown in a collagen-I matrix.
  • MDCK cells imbedded in collagen-I matrix form small cysts (see, for example, Bukanov et ah, Human Molecular Genetics, 77(8): 923-936 (2002)). After three days' incubation, 0.5 ⁇ l of a 12.5 ⁇ M solution of the test compound containing 0.25% DMSO was added to the MDCK cells. After additional 5 days incubation, anti-cystogenesis activity of the tested compounds was determined.
  • FIGs. IA-I JJ The results are summarized in FIGs. IA-I JJ. Because cytotoxic compounds are expected to produce a false positive in the assay, a cell growth assay using normal kidney epithelial cells was also performed as a comparative test to identify a cytotoxic compound. As can be seen in FIGs. IA-I JJ, the vast majority of compounds tested inhibited cystogenesis.
  • Example 3 In Vitro Anti-cystogenetic Activity of 3-hydroxymethyl carbazoles using human kidney derived cells
  • Human primary renal epithelial cells were grown in REGMTM medium supplemented with hydrocortisone, hEGF, FBS, epinephrine, insulin, triiodothyronine, transferrin and gentamicin/amphorericin B.
  • REGMTM medium supplemented with 2.8 mM NaOH, 1.34 mg/ml NaHCO3 and 0.84 mg/ml rat tail collagen
  • Cysts were grown for 8 days and REGMTM medium was added and refreshed every other day. Pictures were taken under light microscopy using a Zeiss Axiovert25 inverted microscope coupled to QED digital camera (QED Imaging Inc, Pittsburgh, PA) 4 and 8 days post 3D culture inoculation. Images were acquired with QED Camera Plus-In software version 1.3. Photographs showing cysts grown for 4 days and 8 days without a compound of the invention are shown in FIG 2.
  • cysts were grown as described above for four days in REGMTM medium. At day 4 the compound was added at 0.04 ⁇ M or 1.5 ⁇ M concentration and the cysts were incubated for four days. The growth of individual cysts was monitored and photomicrographs were taken at day 4 and day 8. The photographs are shown in FIG 3. 9-ethyl-3-hydroxymethyl-9H-carbazoIe has anti-cystogenesis activity at both 0.04 ⁇ M and 1.5 ⁇ M concentration.
  • Example 4 In Vivo Inhibition of Cysto genesis in Jck Mice
  • Cyst % represents the total cystic area (in pixels) divided by the total kidney section area (in pixels) x 100.
  • Table 2 shows the results of treating jck mice with 10 mg/kg of 9-ethyl-3- hydroxymethyl-9H-carbazole (comp 109), 9-ethyl-3-(l-hydroxy-l-ethyl)-9H-carbazole (comp 110), 9-ethyl-6-chloro-3-hydroxymethyl-9H-carbazole (comp 2) and 9-ethyl-6- fluoro-3-hydroxymethyl-9H-carbazole (comp 4) by daily IP injection for 26-50 days.
  • the compounds were formulated in CE vehicle (saline with 10% cremophor and 10% ethanol). Administration of the CE vehicle was used as a control.
  • Table 3 shows the effectiveness of 9-ethyl-6-methyl-3-hydroxymethyl- 9H-carbazole (comp 5), 9-pentyl-3-hydroxymethyl-9H-carbazole (comp 12), 9-Ethyl-4- methyl-3-hydroxymethyl-9H-carbazole (comp 16) and 9-ethyl-6-chloro-l,4-diniethyl-3- hydroxymethyl-9H-carbazole (comp 45) in inhibiting cystogenesis when 10 mg/kg of the compounds in CE were administered to jck mice by daily IP injection for 26-50 days.
  • Table 4 shows the effectiveness of 9-ethyl-5,7-dimethoxy-3- hydroxymethyl-9H-carbazole (comp 59), in inhibiting cystogenesis when 10 mg/kg of the compound in CE was administered to jck mice by daily IP injection for 26-64 days. Table 4, (26-64d treatment).

Abstract

Compounds represented by Structural Formula (I): where X is -H, -OR, -SH, -OC(O)R, -OC(O)OR,-OC(O)NRR or -SC(O)OR have anti-cystogenic activity, particularly against polycystic kidney disease. Such compounds can be used in pharmaceutical compounds and in methods of treating polycystic kidney diseases. The invention also includes novel 3-hydroxymethyl-substituted carbazoles and compounds of Structural Formula (I) where Ring A is a 5-, 6-, 7- or 8- membered non-aromatic carbocyclic ring optionally substituted at one or more substitutable ring atoms.

Description

1
CARBAZOLE DERIVATIVES FOR TREATING POLYCYSTIC KIDNEY DISEASE
RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No.
60/583,175 filed June 25, 2004, the entire teachings of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION A cyst is an abnormal fluid-filled sac that can form in many parts of the body, such as the kidney, liver, pancreas, spleen and heart. Polycystic disease is a disease that occurs when a large number of cysts cause damage to these organs. For example, polycystic kidney disease (PKD) is a disease characterized by the growth of numerous cysts throughout the kidneys. The PKD cysts can slowly replace much of the mass of the kidneys, reducing kidney function and leading to kidney failure. About half the people with the most common form of PKD progress to kidney failure and require dialysis or kidney transplantation. PKD can also cause cysts in other organs, most commonly the liver, but also the spleen, pancreas, heart and blood vessels in the brain. About 500,000 people have PKD in this country, and PKD is the fourth leading cause of kidney failure. Autosomal dominant PKD (ADPKD) accounts for about 90% of all PKD cases and about 8-10% of all cases of end stage renal disease. Currently, there is no approved treatment or cure for PKD. Present medical and surgical procedures only reduce the pain resulting from expansion of renal cysts or resolve other symptoms associated with PKD such as infections or high blood pressure. None of these procedures, aside from kidney transplantation, appreciably slows the progression of the disease. Thus, there is a need for agents and methods for preventing the onset of or slowing the progression of PKD.
SUMMARY OF THE INVENTION It has now been found that 3-hydroxymethyl-substituted carbazoles and related compounds inhibit cystogenesis in vivo and in vitro. The vast majority of the compounds listed in Figure 1 inhibited cystogenesis in vitro (see Examples 2 and 3). Moreover, 9-ethyl-6-chloro- 1 ,4-dimethyl-3 -hydroxymethyl-ΘH-carbazole, 9-ethyl-6- methyl-3-hydroxymethyl-9H-carbazole, 9-ethyl-3-hydroxymethyl-9H-carbazole, 9- ethyl-6-chloro-3-hydroxymethyl-9H-carbazole, and 9-ethyl-5,7-dimethoxy-3- hydroxymethyl-9H-carbazole significantly inhibited cystogenesis in vivo in a jck mouse model of PKD (see Example 4). Based on these results, pharmaceutical compositions comprising compounds disclosed herein and methods of treatment using these compounds are disclosed. In addition, the present invention includes novel 3- hydroxymethyl-substituted carbazoles and related compounds, disclosed herein.
In one embodiment, the present invention is a method for treating PKD in a patient comprising administering to the patient an effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000003_0001
Ring A is a 5-, 6-, 7- or 8-membered carbocyclic ring optionally substituted at one or more substitutable ring atoms. Typically, Ring A is a substituted or unsubstituted aromatic ring, such as a 5- or 6-membered substituted or unsubstituted aromatic ring, for example, a carbocyclic aromatic ring such as a substituted or unsubstituted phenyl ring. Alternatively, Ring A is a substituted or unsubstituted non-aromatic carbocyclic ring. Ring B is optionally substituted at one or more substitutable ring carbon atoms.
X is -OR, -SH, -OC(O)R, -OC(O)OR, -OC(O)NRR or -SC(O)OR. In another embodiment, X is also -H. When X is -OC(O)OR or -SC(O)OR, R is preferably not hydrogen.
Ri is -R, -C(O)R or -R5C(O)R. R2 is hydrogen, a halogen, -C(O)R, -C(S)R3 -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -C(=NR)-NRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR or R2 and a substiτutable ring atom on Ring B, taken together with the carbon atoms between R2 and the substitutable ring atom, form a substituted or unsubstituted non-aromatic carbocyclic ring.
Each R is independently hydrogen or a substituted or unsubstituted alkyl, alkenyl or aryl group, or NRR forms a substituted or unsubstituted non-aromatic heterocyclic ring.
R' is an alkylene or alkenylene group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR.
In another embodiment, the present invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.
The invention also includes novel compounds disclosed herein. One group of the novel compounds includes novel 3-hydroxymethyl-substituted carbazoles. The 3-hydroxymethyl-substituted carbazoles have the substituents described above as suitable for the corresponding position of compounds represented by Structural Formula (I). These compounds are typically also substituted at the 4-position and at one or more of the 5-, 6- and 7-positions of the carbazole ring system. Preferably, a 3- hydroxymethyl-substituted carbazole of the invention is unsubstituted at the 2- and 8- positions. Another group of novel compounds includes compounds represented by Strucutral Formula (I), where Ring A is a 5-, 6-, 7- or 8-membered non-aromatic carbocyclic ring optionally substituted at one or more substitutable ring atoms.
The pharmaceutical compositions and compounds disclosed herein can be used in therapy, for example, for treating PKD. The present invention also provides for the use of the pharmaceutical compositions and compounds disclosed herein for the manufacture of a medicament for the purpose of treating PKD in an individual.
The present invention has many advantages. In particular, the present invention provides compounds that have been shown to reduce the extent of cyst foπnation in mice with a transgenic form of PKD. Thus, these compounds provide a treatment for PKD that addresses the underlying disease state, rather than simply ameliorating symptoms that are associated with PKD. Such compounds may reduce the need for kidney dialysis or transplant, which is currently required for the majority of patients suffering from PKD.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGs. 1A-1Z, IAA- IEE and 1FF-1JJ show the anti-cystogenic activity data for the compounds that were tested according to the procedure described in Example 2, where the compounds are grouped in three different activity classes based on their IC50 values (A: < 1 μM; B: 1-12.5 μM; and C: > 12.5 μM).
FIG. 2 shows photographic images of cysts grown from human primary renal epithelial cells, as described in Example 3, at 4 days and 8 days.
FIG. 3 shows photographic images of cysts that were treated in Example 3 with 0.04 μM and 1.5 μM of 9-ethyl-3-hydroxymethyl-9H-carbazole beginning after 4 days of growth. The images were taken at day 4 and day 8, after 4 days of treatment with the carbazole.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to methods of treating polycystic kidney disease (PKD) that involve administering a compound of Structural Formula (I) to a patient. In addition, the invention is directed to pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and a compound represented by Structural Formula (I). The invention also includes novel 3-hydroxylmethyl- substituted carbazoles, particularly those represented by Structural Formula (III) where R3 and at least one Of R6-R8 is a substituent other than hydrogen and novel compounds represented by Structural Formula (I) where Ring A is a non-aromatic carbocyclic ring. In a preferred embodiment, compounds for use in the invention are represented by Structural Formula (II):
Figure imgf000006_0001
or a pharmaceutically acceptable salt thereof. Ra and Rb are each independently a halogen, -OR, -SR, -C(O)R3 -C(S)R,
-C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R3 -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR3 -C(O)NRR3 -NRR3 -NRC(O)R3 -NRC(O)NRR3 -OC(O)R3 -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R3 -CN, -NCS3 -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR.
R3 is hydrogen, a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR3 -C(S)OR3 -C(S)SR3 -C(O)NRR, -NRR, -NRC(O)R3 -NRC(O)NRR3 -OC(O)R3 -SO3R3 -S(O)R, -S(O)2R, -SO2NRR3 -NRSO2R3 -CN3 -NCS3 -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR3 -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR3 -C(O)R, -C(S)R3 -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR3 -NRR3 -NRC(O)R, -NRC(O)NRR3 -OC(O)R3 -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR, or R2 and R3, taken together with the carbon atoms between R2 and R3, form a substituted or unsubstituted non-aromatic carbocyclic ring. k is O, 1, 2, 3 or 4. m is 0, 1 or 2.
The remaining values are as described for Structural Formula (I).
Examples of compounds encompassed by Structural Formula (II) are represented by Structural Formulas (III) and (Ilia):
Figure imgf000007_0001
Figure imgf000007_0002
or a pharmaceutically acceptable salt thereof.
Suitable values of R3 are as described above for Structural Formula (II). Typically, R3 is a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR, or R2 and R3, taken together with the carbon atoms between R2 and R3, form a substituted or unsubstituted non-aromatic carbocyclic ring. R4 and R5 are each independently hydrogen, a halogen, -OR, -SR, -C(O)R,
-C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR.
R6-R8 are each independently hydrogen, a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR. Typically, at least one of R6- R8 is a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR. Preferably, R6-R8 has one of these typical values when R3 has a value other than hydrogen. Y is -H, -C(O)R, -C(O)OR or -C(O)NRR. Additionally, Y is substituted or unsubstituted alkyl. Typically, Y is -H. Alternatively, Y is unsubstituted lower allcyl, . preferably methyl, ethyl or isopropyl, more preferably ethyl.
The remaining variables for Structural Foπnulas (HI)-(IIIa) are as described above for Structural Formulas (I) and (II).
Preferred compounds of the invention are represented by Structural Foπnulas (III) and (Ilia) where at least one of Re-R8 have one of the typical values disclosed above (i.e., a value other than hydrogen) and R3 has one of the values described above, other than hydrogen. Particularly preferred compounds of the invention encompassed within this description can be represented by compounds encompassed by Structural Formulas (IV), (V), (VI) and (XIV), more particularly Structural Formula (XIV). Other preferred compounds of the invention can be represented by compounds encompassed by Structural Formulas (XV), (XVI) and (XVII). Additional compounds preferred in the invention can be represented by Structural Foπnulas (IVa), (Va), (Via), (XIVa), (IVb), (Vb), (VIb) and (XIVb).
Additional prefeπed compounds of the invention are represented by Structural Fonriula (I), where Ring A is a 5-, 6-, 7- or 8-membered non-aromatic carbocyclic ring optionally substituted at one or more substitutable ring atoms. Variables for Ring A and B are as described above. Particularly preferred compounds of the invention encompassed within this group can be represented by Structural Formulas (X), (XI), (XII) and (XIII), particularly Structural Foπnulas (XII) and (XIII).
A particular group of compounds encompassed by Structural Foπnula (III) is represented by Structural Formula (IV):
(IV),
Figure imgf000009_0001
or a pharmaceutically acceptable salt thereof, where Ri-R3 and R5-Rs are as described above for Structural Formula (III). Typically, R3 is a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR, or R2 and R3, taken together with the carbon atoms between R2 and R3, foπn an unsubstituted non- aromatic carbocyclic ring.
Ri for Structural Formula (IV) is preferably -H, an acyl group or a substituted or unsubstituted alkyl group. Preferably, Ri is -H or an unsubstituted lower alkyl group such as methyl, ethyl or ^-propyl. Alternatively, Ri is cyclopropylmethyl, para- fluorobenzyl, methoxymethyl, 2-ethoxyethyl, n-pentyl, 3-pyridylmethyl,
2-pyridylmethyl, benzyl, 4-pyridylmethyl, 2-tetrahydropyranylmethyl, 2-acetylethyl, /z-pentyl, z-propyl, /z-propyl, phenyl, 3-(benzyloxy)propyl, 3-phenylpropyl, 2-(N- morpholinyl)ethyl, methylcarbonyl, methoxycarboxymethyl, 2-phenylethyl, zz-butyl or 2-hydroxyethyl. The remainder of the variables in Structural Formula (IV) is as described above.
When Ri has the values disclosed in the previous paragraph, R2 is typically -H or an unsubstituted lower alkyl group (e.g., methyl or ethyl), particularly -H. Other specific examples of R2 include -CF3 and where R2 and R3, taken together with the carbon atoms between R2 and R3, form a 5-membered carbocyclic ring. The remainder of the variables in Structural Foπnula (IV) is as described above.
When Ri and R2 have the values discussed in the previous two paragraphs, R3 is typically -H or a substituted or unsubstituted lower alkyl or alkoxy group, particularly an alkoxy-substituted, hydroxy-substituted, or carboxy-substituted lower alkyl or alkoxy group or an unsubstituted lower alkyl or alkoxy group. Examples of R3 include -H, -CH3, -CH2CH3, -OCH3, -O(CH2)2OH, -OCH2CH3, -O(CH2)2OCH3, z-propoxy, n-prσpoxy and -O(CH2)2N(CH3)2, particularly -O(CH2)2OH and -CH3. Additional examples of R3 include carboxy-substituted lower alkyl or alkoxy, such as -0-CH2-C(O)-OCH3 and -OCH2-C(O)-OH, and alkoxy-substituted lower alkyl or
alkoxy, such as
Figure imgf000011_0001
. The remainder of the variables in Structural
Foπnula (FV) is as described above.
A particular group of compounds encompassed by Structural Formula (Ilia) is represented by Structural Formula (IVa):
Figure imgf000011_0002
or a pharmaceutically acceptable salt thereof. The variables and preferred variables in Structural Formula (FVa) are as described above for Strucrual Formula (IV).
Thus, in a particularly preferred group of compounds of the invention (suitable for use in methods of the invention and in pharmaceutical compounds) represented by Structural Formulas (IV)-(IVa), R1 is -H or an unsubstituted lower alkyl group; R2 is -H or an unsubstituted lower alkyl group, particularly -H; R3 is an alkoxy-substituted, hydroxy-substituted or carboxy-substituted lower alkyl or alkoxy group or an unsubstituted lower alkyl or alkoxy group; and R5-R8 are as described above for Structural Formulas (HI)-(IIIa). Typically for compounds of the invention, at least one OfR6-R8 is one of the non-hydrogen substituents described above.
For certain compounds represented by Structural Formulas (IV) and (IVa), Rs-R8 are each independently a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR. and -NRNRR. Typically, R7 is a halogen, -NH2 or an unsubstituted lower alkyl or alkoxy group. Alternatively, R7 is -C(O)OR. When R7 is a halogen, NH2 or an unsubstituted lower alkyl or alkoxy group, R5 is advantageously an unsubstituted lower alkyl (-CH3) or alkoxy (-OCH3) group. For compounds having these values of R5 and R7, R6 and R8 are typically each independently a halogen or an unsubsituted lower alkyl or alkoxy group.
One commonly used group of compounds encompassed within Structural Formula (IV) is represented by Structural Formula (V):
Figure imgf000012_0001
or a pharmaceutically acceptable salt thereof, where Ri -R3 are as described for
Structural Formula (IV) and R7 is a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -CC=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR. For compounds of Structural Formula (V), R7 is more typically a halogen (-F, - Cl, -Br), an amine (-NH2, -N(CH3)(C2Hs)) or an unsubstituted lower alkyl or alkoxy group (-CH3, -OCH3), preferably -Cl or -F. When R7 is -Cl or -F, R2 is typically -H.
Another commonly used group of compounds encompassed with Structural Formula (IV) are represented by Structural Formula (VI):
Figure imgf000013_0001
or a pharmaceutically acceptable salt thereof, where R5 and R7 are each independently a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR; and Ri-R3 are as described above for Structural Formula (IV).
Typically for compounds represented by Structural Formula (VI), R5 is an unsubstituted lower alkyl or alkoxy group, particularly -CH3.
When R5 has the values described immediately above, R7 is typically a halogen, an amine (-NH2) or an unsubstituted lower alkyl or alkoxy group, particularly an unsubsituted lower alkyl group. Preferably, R5 is an unsubstituted lower alkyl group and R7 is -Cl or -F, especially when R2 is -H.
Examples of compounds encompassed within Structural Formula (IV) are represented by Structural Formula (VII):
Figure imgf000013_0002
or a pharmaceutically acceptable salt thereof, where R6-R8 are each independently a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR; and Ri-R3 are as described above for Structural Formula (IV). Typically, R6 and R8 are each independently a halogen (-F, -Cl, -Br) or a substituted or unsubstituted alkyl or alkoxy group, particularly a lower alkoxy group (-OCH3). Other specific examples of R6 and R8 include -CH3, -CH2CH3, benzyl oxy, hexahydropyridyl, tetrahydropyrrolyl, N-morphonyl, (trifluoromethyl)hydroxymethyl, -NH2, -NH(C2H5), -N(CH3)2, -N(CH3)(C2H5), -N(C2Hj)2, -NO2, -NH(CH2)2(CH(CH3))(CH2)2(CH)(C(CH3)2), cyclohexylamine, (2 - chlorophenyl)methylamine, (4-tert-butylphenyl)methylamine, (3 -benzoxy-4-methoxy)phenylmethylamine, (4-methoxyphenyl)methyl amide, (4-methoxyphenyl)amide,
—
Figure imgf000014_0001
When R6 and R8 have the values discussed immediately above, R7 is typically a halogen, an amine (-NH2) or an unsubstituted lower alkyl or alkoxy group, particularly -Cl or -F. Preferably, when R7 is -Cl or -F, R6 and Rg are each independently an unsubstituted lower alkoxy group (-OCH3) and R2 is -H.
Compounds of Structural Formula (VII) where R7 is -H are represented by Structural Formula (VIII):
Figure imgf000015_0001
or a pharmaceutically acceptable salt thereof, where R1-R3, Re and R8 are as described above for Structural Formula (VII). Typical values OfR6 and R8 are as described for Structural Formula (VII). Preferably, R6 and R8 are each independently a halogen or an unsubstituted lower alkyl or alkoxy group, particularly an unsubstituted lower alkoxy group such as -OCH3. When R6 and R8 are unsubstituted lower alkoxy groups, R2 is typically -H.
Further examples of compounds encompassed within Structural Formula (IV) are represented by Structural Formula (IX):
Figure imgf000015_0002
or a pharmaceutically acceptable salt thereof, where R5, R6 and R8 are each independently a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR5 -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR; and Ri -R3 are as described above for Structural Formula (IV).
Typically, Rg and R8 are each independently a halogen or an unsubstituted lower alkyl or alkoxy group, particularly -CH3 or -OCH3. When R6 and R8 are a halogen or an unsubstituted lower allcyl or alkoxy group, R5 is advantageously an unsubstituted lower alkyl or alkoxy group, particularly -CH3, and R2 is generally -H.
A particular group of compounds of the invention are represented by Structural Formula (XIV):
Figure imgf000016_0001
or a pharmaceutically acceptable salt thereof, where:
Ri is a substituted or unsubstituted lower allcyl group;
R3 is a substituted or unsubstituted lower allcyl or alkoxy group;
R5 is -H or a substituted or unsubstituted lower alkyl or alkoxy group; and
R7 is a halogen, -NH2 or a substituted or unsubstituted lower alkyl or alkoxy group.
Preferably, Ri is -CH3, -CH2CH3 or -CH2CH2CH3. When Ri is one of these unsubstituted lower allcyl groups, R7 is typically -F, -Cl, - Br, -CH3 or -OCH3. For compounds where Ri is one of the unsubstituted lower groups and R7 is -F, -Cl, - Br, -CH3 or -OCH3, R3 is typically -O(CH2)2OH or -CH3. Even more preferably, Ri is one of the unsubstituted lower groups, R3 is -O(CH2)2OH or -CH3, R7 is -F, -Cl, - Br, -CH3 or -OCH3 and R5 is -H, -CH3, -CH2CH3 or -OCH3. Examples of compounds encompassed by Structural Formula (III) are represented by Structual Formulas (Va), (Via), (Vila), (VIIIa) and (IXa), where all of the variables, including preferred values, are as described above for Structural Formulas (V), (VI), (VII), (VIII) and (IX), respectively:
Figure imgf000017_0001
Figure imgf000017_0002
and pharmaceutically acceptable salts thereof. Additional examples of compounds encompassed by Structural Formula (III) are represented by Structual Formulas (Vb), (VIb), (VIIb), (VIIIb) and (IXb), where Rj-R3 and R5-R8, including preferred values, are as described above for Structural Formulas (V), (VI), (VII), (VIII) and (IX), respectively; and Ri0 is Ci-C5 alkyl:
Figure imgf000018_0001
; and or pharmaceutically acceptable salts thereof. Preferably, Rio is ethyl. Additional compounds encompassed by the present invention are represented by
Structural Formulas (XV):
Figure imgf000018_0002
or a pharmaceutically acceptable salt thereof, where X is -H, -OR, -SH, -OC(O)R, -OC(O)OR, -OC(O)NRR or -SC(O)OR; and Ri-R3 are as described above for Strucural Formulas (IV) and (IVa). Preferably, X is -H or -OR, where R is a substituted or unsubstituted alkyl. R is preferably an unsubstitued lower alkyl, such as methyl, ethyl and isopropyl. Preferably, Ri is -H or a substituted or unsubstituted lower alkyl group; R2 is -H or an unsubstituted lower alkyl group, particularly -H; R3 is an alkoxy- substituted, hydroxy-substituted or carboxy-substituted lower alkyl or alkoxy group, or an unsubstituted lower alkyl or alkoxy group. In some preferred embodiments, Rj-R3 have these values; and X is -H, -OH or -OEt. Compounds encompassed by the present invention are also represented by
Structural Formula (XVI):
Figure imgf000019_0001
or a pharmaceutically acceptable salt thereof, where X and Ri-R3 are each as described above for Structural Formula (XV); and R7 and R8 are each are described above for Structural Formulas (IV) and (IVa). R7 and R8 are typically each independently a halogen, an amine, an unsubstituted lower alkyl or alkoxy group, or a carboxyl group, such as -F, -Cl, -Br, -Me, -OMe, -NH2, -N(CH3)(C2H5), or -C(O)OMe. More specific examples of R7 and R8 are described above for Structural Formulas (IV)-(IVa).
Other ompounds encompassed by the present invention are also represented by Structural Formula (XVII):
Figure imgf000019_0002
or a pharmaceutically acceptable salt thereof, where X and Ri-R3 are each independently as described above for Structural Formula (XV); and R6 and R7 are each independently described above for Structural Formulas (IV) and (IVa). R6 is typically a halogen (-Br, - Cl, -F), an alkoxy-substituted, hydroxy-substituted or carboxy-substituted lower alkyl or allcoxy group (-O-(CH2)2OH, -O-(CH2)2C(O)OH, or -O-(CH2)2C(O)OMe), an unsubstituted lower alkyl or alkoxy group (-Me or -OMe) , or hydroxy. R7 is typically a halogen, an amine, an unsubstituted lower alkyl or alkoxy group, or a carboxyl group, such as -Cl, -Br, -Me, -OMe, -NH2, -N(CH3)(C2H5), or -C(O)OMe. More specific examples of R6 and R7 are described above for Structural Formulas (IV)-(IVa).
Certain compounds encompassed by the present invention are also represented by Structural Formulas (XVIIIa), (XIXa) and (XXa):
Figure imgf000020_0001
thereof, whrere Ri-R2 are each independently as described above for Structural Formula (XV), and R6 and R7 are each independently as described above for Structural Formula (XVII).
Other certain compounds encompassed by the present invention are represented by Structural Formulas (XVIIIb), (XIXb) and (XXb): and
Figure imgf000021_0001
, or pharmaceutically acceptable salts thereof, whrere Rj-R2 are each independently as described above for Structural Formula (XV); R6 and R7 are each independently as described above for Structural Formula (XVII); and Ri0 is Ci-C5 alkyl, preferably, ethyl.
In a second preferred embodiment, compounds for use in the invention are represented by Structural Formula (X):
Figure imgf000021_0002
or a pharmaceutically acceptable salt thereof. R0 and Rd are each independently a halogen, -OR, -SR, -C(O)R, -C(S)R,
-C(O)OR, C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR. Preferably, each Rc is independently an unsubstituted alkyl group, such as a lower alkyl group. p is an integer from O to 12, q is O, 1 or 2, and n is O, 1, 2 or 3.
The remaining values are as described above for Structural Formula (II).
Examples of compounds encompassed by Structural Formula (X) are represented by Structural Formula (XI):
Figure imgf000022_0001
or a pharmaceutically acceptable salt thereof.
Suitable values OfRi-R3 and each R0 are as described above for Structural Formula (X). Suitable values of R5 are as described above for Structural Formula (III). Y is -H, -C(O)R, -C(O)OR or -C(O)NRR. Additionally, Y is substituted or unsubstituted alkyl. Preferably, Y is -H. Alternatively, Y is an unsubstituted lower alkyl group, preferably methyl, ethyl or isopropyl, more preferably ethyl.
Further examples of compounds encompassed by Structural Formula (X) are represented by Structural Formula (XIa):
Figure imgf000023_0001
and a pharmaceutically acceptable salt thereof. Suitable values Of Ri-R3 and each Rc are as described above for Structural Formula (X). Suitable values of R5 are as described above for Structural Formula (Ilia).
For one group of preferred compounds of the invention represented by Structural Formula (XI), Y is -H and each R0 is an unsubstituted alkyl group, preferably unsubstituted lower alkyl group. When Y and Rc have these values, n is typically 1 or 2 and p is typically an integer from 0 to 4, more preferably 0 to 2.
A particular group of compounds encompassed by Structural Formula (XI) is represented by Structural Formula (XII):
Figure imgf000023_0002
or a pharmaceutically acceptable salt thereof, where Ri-R3 and R5 are as described above for Structural Formula (XI).
Another group of compounds encompassed by Structural Formula (XI) is represented by Structural Formula (XIII): or a pharmaceutically acceptable salt thereof, where R1-R3 and R5 are as described above for Structural Formula (XI).
Ri for Structural Formulas (XII) and (XIII) is preferably -H, an acyl group or a substituted or unsubstituted alkyl group. In particular, Ri is -H, an unsubstituted lower alkyl group (methyl, ethyl or n-propyl) or a halobenzyl group (a benzyl group where the phenyl ring is substituted with one or more halogens, for example, fluorobenzyl and para-halobenzyls such asjoαrα-fluorobenzyl). The remainder of the variables in each of Structural Formulas (XII) and (XIII) is as described above. When Ri has the values disclosed in the previous paragraph, R2 is typically -H or an unsubstituted lower alkyl group (e.g., methyl or ethyl), particularly -H. R3 and R5 in each of Structural Formulas (XII) and (XIII) are as described above.
When Ri and R2 have the values discussed in the previous two paragraphs, R3 is typically -H or a substituted or unsubstituted lower alkyl or alkoxy group, particularly -H or an alkoxy-substituted, hydroxy-substituted, or carboxy-substituted lower alkyl or alkoxy group or an unsubstituted lower alkyl or alkoxy group. Examples of R3 include -H, -CH3, -CH2CH3, -OCH3, -O(CH2)2OH, -OCH2CH3, -O(CH2)2OCH3, z-propoxy, n-propoxy and -O(CH2)2N(CH3)2, particularly -O(CH2)2OH and -OCH3. R5 in each of Structural Formulas (XII) and (XIIi) is as described above. Thus, in a particularly preferred group of compounds of the invention (suitable for use in methods of the invention and in pharmaceutical compounds) represented by Structural Formula (XII) or Structural Formula (XIII), Ri is -H, an unsubstituted lower alkyl group or a halobenzyl group; R2 is -H or an unsubstituted lower alkyl group, particularly -H; R3 is an alkoxy-substituted, hydroxy-substituted or carboxy-substituted lower alkyl or alkoxy group or an unsubstituted lower alkyl or alkoxy group; and R5 is -H, a halogen or an unsubstituted lower allcyl or alkoxy group, preferably, -H or a halogen such as -Cl.
Specific examples of compounds of the invention are shown below:
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001

Figure imgf000028_0001

Figure imgf000029_0001
Figure imgf000030_0001
30
Figure imgf000031_0001
31
Figure imgf000032_0001
Figure imgf000033_0001
33
Figure imgf000034_0001

Figure imgf000035_0001

Figure imgf000036_0001
36
Figure imgf000037_0001

Figure imgf000038_0001

Figure imgf000039_0001

Figure imgf000040_0001
Figure imgf000040_0002
40
Figure imgf000041_0001
Figure imgf000041_0002
Figure imgf000041_0003
41
Figure imgf000042_0001
42
Figure imgf000043_0001
Figure imgf000043_0002
Figure imgf000044_0001
Figure imgf000044_0002
Figure imgf000045_0001
Figure imgf000045_0002

Figure imgf000046_0001
Figure imgf000046_0002

Figure imgf000047_0001
Figure imgf000047_0002

Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000049_0002

Figure imgf000050_0001
50
Figure imgf000051_0001
Figure imgf000051_0002
Figure imgf000051_0003
51
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000052_0003
52
Figure imgf000053_0001
53
Figure imgf000054_0001
54
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000056_0002
Figure imgf000057_0001
Figure imgf000057_0002

Figure imgf000058_0001
Figure imgf000058_0002

Figure imgf000059_0001
Figure imgf000059_0002

Figure imgf000060_0001
60
Figure imgf000061_0001
Figure imgf000061_0002
61
Figure imgf000062_0001
62
Figure imgf000063_0001
Figure imgf000064_0001
and pharmaceutically acceptable salts thereof. Additional specific examples of compounds of the invention are shown below:
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
, and pharmaceutically acceptable salts thereof. The invention also includes novel compounds disclosed herein along with salts thereof, which are not limited to pharmaceutically acceptable salts thereof.
Carbocyclic rings include carbocyclic aromatic rings (e.g., phenyl) and carbocyclic non-aromatic rings (e.g., cycloalkyl and cycloalkenyl). Heterocyclic rings include heteroaryl groups and non-aromatic heterocyclic groups. The rings can be three- to twelve-membered, but are typically five, six, seven or eight-membered. A "bridgehead" is the region where two rings are fused together. A substitutable ring atom is an atom in a carbocyclic or heterocyclic ring to which a substituent can be attached. In non-aromatic rings, carbon and nitrogen atoms other than quaternary atoms are substitutable. Carbon atoms at non-bridgehead positions can have one or two substituents, but typically have only one substituent. In aromatic rings, typically only carbon atoms that are not at a bridgehead position are substitutable. A ring atom in a structure which is already depicted as having a substitutent is not substitutable. For example, the 3-position of Ring B in Structural Formula (I) already has a substituent, -CH(R2)X, so that the carbon atom at the 3- position cannot have another substituent.
The term "aryl group" may be used interchangeably with "aryl," "aryl ring," "aromatic group," and "aromatic ring." The term "heteroaryl group" may be used interchangeably with "heteroaryl," "heteroaryl ring," "heteroaromatic ring" and
"heteroaromatic group." Carbocyclic aromatic groups include phenyl, naphthyl, and anthracyl groups. Examples of heterocyclic aromatic groups include imidazolyl, thienyl, furanyl, pyridyl, pyrimidyl, pyranyl, pyrazolyl, pyrroyl, pyrazinyl, thiazolyl, oxazolyl, and tetrazolyl groups. Aryl groups also include fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings. Examples include benzothienyl, benzofuranyl, indolyl, quinolinyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl and isoindolyl. As used herein, the term "alkyl" refers to a cyclic or acyclic, straight or branched hydrocarbon group of 1-24 carbon atoms, typically 1-12 carbon atoms. Suitable alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, «-butyl, sec- butyl, tert-butyl, pentyl, ώø-pentyl, neopentyl, hexyl, heptyl, octyl and the like. An alkyl group may be substituted with one or more substituents independently selected for each position. A C1-C4 straight chained or branched alkyl group or a C3-C6 cyclic alkyl group is also referred to as a "lower alkyl" group. As used herein, the tenn "alkenyl" refers to a straight or branched hydrocarbon group that contains one or more double bonds between carbon atoms. Suitable alkenyl groups include, e.g., n-butenyl, cyclooctenyl and the like. An alkenyl group may be substituted.
An alkoxy group is an alkyl group that is connected to a molecule through an oxygen atom.
An alkylene group is a saturated hydrocarbon in a molecule that is bonded to two other groups in the molecule through single covalent bonds. Alkylene groups can be cyclic or acyclic and branched or unbranched. Typically, an alkylene group has one to about six carbon atoms, for example, one to about four carbon atoms. An alkenylene group is an unsaturated hydrocarbon containing one or more double bonds in a molecule that is bonded to two other groups in the molecule through single covalent bonds. Alkenylene groups can be cyclic or acyclic and branched or unbranched. Typically, an alkenylene group has two to about eight carbon atoms, for example, three to about six carbon atoms. Suitable substituents on an alkyl, alkylene, alkenyl, alkenylene and carbocyclic or heterocyclic rings (including aryl groups) are those which do not substantially interfere with the cystogenesis-inhibiting activity of the disclosed compounds, for example, do not lower the activity by more than a factor of about two. Examples of suitable substituents include -OH, halogens (-Br, -Cl, -I, -F), -ORa, -O-CORa, -CORa, -CN, -NCS, -NO2, - COOH, -SO3H, -NH2, -NHRa, -N(RaRb), -COORa, -CHO, -CONH2, -C0NHRa, - CON(RaRb), -NHCORa, -NRbCORa, -NHCONH2, -NHCONRaH, -NHCON(RaRb), - NRbCONH2) -NRbCONRΗ, -NRcCON(RaRb), -C(=NH)-NH2, -C(=NH)-NHRa, - C(=NH)-N(RaRb), -C(=NRC)-NH2, -C(=NRc)-NHRa, -C(=NR°)-N(RaRb), -NH-C(=NH)- NH2, -NH-C(=NH)-NHRa, -NH-C(=NH)-N(RaRb), -NH-C(=NRC)-NH2, -NH-C(=NRC)- NHRa, -NH-C(=NRc)-N(RaRb), -NRdH-C(=NH)-NH2, -NRd-C(=NH)-N(RaRb), -NRd- C(=NR°)-NH2, -NRd-C(=NRc)-NHRa, -NRd-C(=NR°)-N(RaRb), -NHNH2, -NHNHR3, - NHRaRb, -SO2NH2, -SO2NHRa, -SO2NRaRb, -SH, -SRa, -S(O)Ra, and -S(O)2Ra. In addition, an alkyl, alkylene, alkenyl or alkenylene group can be substituted with substituted or unsubstituted aryl group to form, for example, an aralkyl group such as benzyl. Similarly, aryl groups can be substituted with a substituted or unsubstituted alkyl or alkenyl group. Typically, compounds of the invention do not include perhaloalkyl groups attached directly to a carbazole ring, particularly perfiuoroalkyl groups (e.g., trifluoromethyl groups).
Ra-Rd are each independently an alkyl group, aromatic group, non-aromatic heterocyclic group or -N(RaRb), taken together, form a substituted or unsubstituted non- aromatic heterocyclic group. The alkyl, aromatic and non-aromatic heterocyclic group represented by Ra-Rd and the non-aromatic heterocyclic group represented by -N(RaRb) can optionally be substituted.
The compounds of the invention or salts or thereof thereof can be administered by an appropriate route. Suitable routes of administration include, but are not limited to, orally, intraperitoneally, subcutaneously, intramuscularly, intradermally, transdermally, rectally, sublingually, intravenously, buccally or via inhalation. Typically, the compounds are administered orally or intravenously.
The pharmaceutical compositions of the invention preferably contain a pharmaceutically acceptable carrier or diluent suitable for rendering the compound or mixture administrable orally, parenterally, intravenously, intradermally, intramuscularly or subcutaneously, rectally, via inhalation or via buccal administration, or transdermally. Suitable pharmaceutically acceptable carriers typically contain inert ingredients which do not inhibit the biological activity of the disclosed compounds. The pharmaceutically acceptable carriers should be biocompatible, i.e., non-toxic, non-inflammatory, non- immunogenic and devoid of other undesired reactions upon administration to a subject. It will be understood by those skilled in the art that many modes of administration, vehicles or carriers conventionally employed and which are inert with respect to the active agent may be utilized for preparing and administering the pharmaceutical compositions of the present invention. Examples of such methods, vehicles and carriers are those described, for example, in Remington's Pharmaceutical Sciences, 18th ed. (1990), the disclosure of which is incorporated herein by reference.
The formulations of the present invention for use in a subject comprise the agent, together with one or more acceptable carriers or diluents therefor and optionally other therapeutic ingredients. The carriers or diluents must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The formulations can conveniently be presented in unit dosage form and can be prepared by methods well known in the art of pharmacy. All methods include the step of bringing into association the agent with the carrier or diluent which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the agent with the carriers and then, if necessary, dividing the product into unit dosages thereof.
Formulations suitable for parenteral administration conveniently comprise sterile aqueous preparations of the agents that are preferably isotonic with the blood of the recipient. Suitable carrier solutions often include phosphate buffered saline, saline, water, lactated ringers or dextrose (5% in water), cyclodextrin, cremophor, a mixture of cyclodextrin, cremophor and ethanol (12.7% in water) or a mixture of cremophor (10% in water) and ethanol (10% in water). Such formulations can be conveniently prepared by admixing the agent with water to produce a solution or suspension, which is filled into a sterile container and sealed against bacterial contamination. Preferably, sterile materials are used under aseptic manufacturing conditions to avoid the need for terminal sterilization.
Such formulations can optionally contain one or more additional ingredients, which can include preservatives such as methyl hydroxybenzoate, chlorocresol, metacresol, phenol and benzalkonium chloride. Such materials are of special value when the formulations are presented in multidose containers.
Buffers can also be included to provide a suitable pH value for the formulation. Suitable buffer materials include sodium phosphate and acetate. Sodium chloride or glycerin can be used to render a formulation isotonic with the blood.
If desired, a formulation can be filled into containers under an inert atmosphere such as nitrogen and can be conveniently presented in unit dose or multi-dose form, for example, in a sealed ampoule.
Those skilled in the art will be aware that the amounts of the various components of the compositions of the invention to be administered in accordance with the method of the invention to a subject will depend upon those factors noted above.
The compositions of the invention when given orally or via buccal administration can be formulated as tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum syrups and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier, for example, ethanol, glycerine or water, with a flavoring or coloring agent. Where the composition is in the form of a tablet, one or more pharmaceutical carriers routinely used for preparing solid formulations can be employed. Examples of such carriers include magnesium stearate, starch, lactose and sucrose. Where the composition is in the form of a capsule, the use of routine encapsulation is generally suitable, for example, using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the foπii of a soft gelatin shell capsule, pharmaceutical carriers routinely used for preparing dispersions or suspensions can be considered, for example, aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell. A typical suppository formulation a compound that is active when administered in this way, with a binding and/or lubricating agent, for example, polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats.
Typical transdermal formulations include a conventional aqueous or non-aqueous vehicle, for example, a cream, ointment, lotion or paste or are in the form of a medicated plastic, patch or membrane. Typical compositions for inhalation are in the form of a solution, suspension or emulsion that can be administered in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
The effective amount of a compound or pharmaceutical composition of the invention depends, in each case, upon several factors, e.g., the health, age, gender, size and condition of the subject to be treated, the intended mode of administration, and the capacity of the subject to incorporate the intended dosage form, among others. An effective amount of an active agent is an amount sufficient to have the desired effect for the condition being treated, which can either be treatment of an active disease state or prophylactically inhibiting the active disease state from appearing. For example, an effective amount of a compound for treating a polycystic kidney disease is the quantity of compound that results in a slowing in the progression of the polycystic kideny disease, a reversal of the polycystic kidney disease state, the inhibition of new cyst formation (partial or complete inhibition of cystogenesis), a reduction in cyst mass, a reduction in the size and number of cysts, and/or a reduction in the severity of the symptoms associated with the polycystic kidney disease.
Effective amounts of the disclosed compounds typically range between about 0.001 mg/kg per day and 500 mg/kg per day, and preferably between 0.01 mg/kg per day and 50 mg/kg, more preferably between 0.1 mg/kg per day and 10 mg/kg. Also included in the present invention are salts and pharmaceutically acceptable salts of the compounds described herein. Compounds disclosed herein that possess a sufficiently acidic functional group, a sufficiently basic functional group or both can react with any of a number of organic or inorganic bases, and inorganic and organic acids, to form a salt. Acidic groups commonly foπn salts with alkali and alkaline earth metals (e.g, sodium, potassium, magnesium, calcium). In addition, acidic groups can form salts with amines.
Acids commonly employed to form acid addition salts from compounds with basic groups are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such asp- toluenesulfonic acid, methanesulfonic acid, oxalic acid, jo-bromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such salts include the hydroxide, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, mandelate, and the like.
The compounds disclosed herein can be prepared in the foπn of their hydrates, such as hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate and the like and as solvates. It is to be understood that the compounds depicted herein include hydrates and solvates thereof even though the hydration or solvation state is not specifically indicated, unless otherwise indicated (e.g., as anhydrous or unsolvated).
A patient is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, e.g., a companion animal (e.g., dogs, cats, and the like), a farm animal (e.g., cows, sheep, pigs, horses, and the like) and a laboratory animal (e.g., rats, mice, guinea pigs, and the like).
The compounds of the invention can be administered alone as a monotherapy or co-administered either simultaneously as a single dosage form or consecutively as separate dosage forms with other agents that ease the symptoms and/or complications associated with PKD. The associated symptoms with PKD include pain, headaches, urinary tract infections and high blood pressure. Examples of the agents that can be co¬ administered with the compounds of the invention include, but are not limited to, over-the counter pain medications, antibiotics, antimicrobials, thiazide diuretics, angiotensin- converting enzyme inhibitors, angiotensin II antagonists such as losartan, and calcium channel blockers such as diltiazem. Examples of pain medications include acetaminophen, aspirin, naproxen, ibuprofen and COX-2 selective inhibitors such as rofecoxib, celecoxib and valdecoxib. Examples of antibiotics and antimicrobials include cephalosporins, penicilin derivatives, aminoglycosidesm ciprofloxacin, erythromycin, chloramphemicol, tetracycline, ampicillin, gentamicin, sulfamethoxazole, trimethoprim and ciprofloxacin, streptomycin, rifamycin, amphotericin B, griseofulvin, cephalothin, cefazolin, fluconazole, clindamycin, erythromycin, bacitracin, vancomycin and fusidic acid Examples of thiazide diuretics include bendroflumethiazide, chlorothiazide, chlorthalidone, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, metolazone, polythiazide, quinethazone and trichlormethiazide. Examples of angiotensin-converting enzyme inhibitors include benazepril, captopril, cilazapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril.
EXEMPLIFICATION Example 1. Preparation of Compounds Unless otherwise indicated, all reagents and solvents were purchased from
Aldrich and used without further purification. Ethyl 4-oxocyclohexanecarboxylate purchased from TCI America. NMR spectra were recorded using either a Varian Unity 400 or a Varian Inova 400 spectrometer using the solvent indicated.
Synthesis of 9-Ethyl-3-hydroxymethyl-9H-carbazole (Compound 109)
To a cold solution of 9-ethyl-3-formyl-9H-carbazole (20.0 g, 89.6 mmol) in methanol (180 mL) was added solid sodium borohydride (3.4 g, 89.6 mmol) at a rate that kept the reaction mixture below 20 0C. The resulting mixture was stirred in an ice bath and monitored by TLC. After 2 h the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and the resulting solution was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and then concentrated to yield an off-white solid. The crude product was purified by silica gel chromatography (ethyl acetate: hexane (3:7)) to afford a white solid (17.9 g, 88%). 1H NMR (CDCl3) δ 8.13-8.07 (m, 2H), 7.52-7.37 (m, 4H), 7.28-7.20 (m, IH), 4.68 (br s, 2H), 4.38 (q, J= 7.3 Hz, 2H), 1.69 (br s, IH), 1.43 (t, J= 7.3 Hz, 3H). Synthesis of 9-Ethyl-3-(l-hydroxy-l-ethyl)-9H-carbazole (Compound 110)
To a stirred and chilled solution of 9-ethyl-3-formyl-9H-carbazole (3.Og, 13.4 mmol) in dry TΗF (10 mL) was slowly added a solution of methylmagnesium chloride (9 mL, 27 mmol, 3.0 M in TΗF) via a syringe. The reaction was stirred at 0 °C and monitored by TLC. After 2 h the reaction was quenched by slow addition of saturated ammonium chloride solution (20 mL). The aqueous mixture was extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over magnesium sulfate and then concentrated in vacuo to afford a bluish gum. The crude product was purified by silica gel chromatography (ethyl acetate : hexane (15 : 85)) to afford an off-white solid (2.1g, 65%). 1H NMR (CDCl3) δ 8.14-8.09 (m, 2H), 7.53-7.36 (m, 4H), 7.27-7.22 (m, IH), 5.11 (q, J= 6.6 Hz, IH), 4.37 (q, J= 7.3 Hz, 2H), 1.93 (br s, IH), 1.63 (d, J= 6.6 Hz, 3H), 1.43 (t, J= 7.3 Hz, 3H).
Synthesis of 9-Ethyl-6-chIoro-3-hydroxymethyI-9H-carbazoIe (Compound 2)
Ethyl ό-chloro-l^S^-tetrahydro^H-carbazole-S-carboxylate: A suspension of 4- chlorophenylhydrazine hydrochloride (10.3 g, 57.2 mmol) and ethyl 4- oxocyclohexanecarboxylate (9.41 g, 55.3 mmol) in acetic acid (100 mL) was heated at reflux for 16 h. The reaction was allowed to cool to room temperature. The resulting suspension was stirred vigorously while water (400 mL) was added slowly. After stirring at room temperature for 1 h, the solid was collected by filtration, washed three times each with water and hexane then dried in vacuo at 45 0C for 3 h. The tan solid weighed 15.5 g (quantitative yield) and was used without further purification. 1H NMR (CDCl3) δ 7.79 (br s, IH), 7.42 (d, J= 2.1 Hz, IH), 7.18 (d, J= 8.5 Hz, IH), 7.07 (dd, J = 8.5 Hz, 2.1 Hz, IH), 4.20 (q, J= 7.1 Hz, 2H), 3.07-2.93 (m, IH), 2.90-2.73 (m, 4H, 2.35-2.24 (m, IH), 2.08-1.95 (m, IH), 1.3 (t, J= 7.1 Hz).
Ethyl ό-chloro^-ethyl-l^^^-tetrahydro^H-carbazole-S-carboxylate: A solution of ethyl 6-chloro-l,2,3,4-tetrahydro-9H-carbazole-3-carboxylate (14.Og, 50.4 mmol) in dry DMF (80 mL) was slowly added to a cold suspension of sodium hydride (60% dispersion in mineral oil, 2.03 g, 50.4 mmol) in DMF (10 mL). After stirring for 5 min, a solution of iodoethane (7.86 g, 50.4 mmol) in DMF (6 mL) was added via a syringe. The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water then extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate and then concentrated in vacuo to afford a brown syrup. The crude product was purified by silica gel chromatography (eluent gradient of 1 % ethyl acetate-hexane to 15% ethyl acetate-hexane) to afford a golden syrup (13.46 g, 87%). 1H NMR (CDCl3) δ 7.43 (d, J= 2.0 Hz, IH), 7.17 (d, J= 8.6 Hz, IH)3 7.09 ( dd, J= 8.6 Hz, 2.0 Hz, IH), 4.20 (q, J= 7.1 Hz, 2H), 4.07-4.01 (m, 2H), 3.06-3.00 (m, IH), 2.90- 2.73 (m, 4H), 2.38-2.32 (m, IH), 2.06-2.00 (m, IH), 1.32-1.26 (m, 6H).
Ethyl ό-chloro-P-ethyl-PH-carbazole-S-carboxylate: A mixture of ethyl 6-chloro-9- ethyl-l,2,3,4-tetrahydro-9H-carbazole-3-carboxylate (7.05 g, 23 mmol) and tetrachloro- 1,4-benzoquinone (12.5 g, 50.7 mmol) in toluene (100 mL) was heated at reflux for 17 h. The reaction was cooled to room temperature, diluted with hexane (200 mL) and filtered. The filter cake was washed with another portion of hexane. The filtrates were combined and concentrated in vacuo. The dark solid residue was purified by silica gel chromatography (eluent gradient of 25% dichloromethane-hexane to 50% dichloromethane-hexane) to yield a light purple solid (6.54 g, 94%). 1H NMR (CDCl3) δ 8.76 (dd, J= 1.6 Hz, 0.5 Hz, IH), 8.19 (dd, J= 8.7 Hz, 1.7 Hz, IH), 8.10 (dd, J= 2.0 Hz, 0.5 Hz, IH), 7.44 (dd, J= 8.6 Hz, 2.0 Hz, IH), 7.38 (d, J= 8.7 Hz, IH), 7.34 (d, J = 8.6 Hz, IH), 4.44 (q, J= 7.1 Hz, 2H), 4.35 (q, J= 7.1 Hz, 2H), 1.47-1.41 (m, overlapping triplets, 6H).
P-Ethyl-δ-chloro-S-hydroxymethyl-PH-carbazole: A solution of ethyl 6-chloro-9- ethyl-9H-carbazole-3-carboxylate (6.54 g, 21.7 mmol) in TΗF (80 mL) was added via a cannula to stirred suspension of lithium aluminum hydride (1.88 g, 49.5 mmol) in TΗF (10 mL) at 0 0C. After the addition was completed the reaction mixture was stirred at room temperature for 45 min. The unreacted lithium aluminum hydride was hydrolyzed with water (2 mL) and the reaction mixture diluted with saturated ammonium chloride solution. The aqueous mixture was extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed successively with saturated ammonium chloride solution, saturated sodium chloride solution, dried over magnesium sulfate and then concentrated in vacuo to afford a tan solid. The crude product was purified by silica gel chromatography (neat dichloromethane) to afford a white solid (5.19 g, 92%). 1H NMR (CDCl3) δ 8.04-8.00 (m, 2H), 7.50 (dd, J= 8.4 Hz, 1.6 Hz, IH), 7.41 (dd, J= 8.7 Hz, 2.0 Hz, IH), 7.38 (d, J= 8.4 Hz, IH), 7.31 (d, J= 8.7 Hz, IH), 4.84 ( br s, 2H), 4.33 (q, J= 7.2 Hz, 2H), 1.82 (br s, IH), 1.40 (t, J= 7.2 Hz, 3H).
Synthesis of 9-Ethyl-6-fluoro-3-hydroxymethyl-9H-carbazoIe (Compound 4)
Compound 4 was prepared using the procedure described for compound 2 using 4-fluorophenylhydrazine hydrochloride as the starting material. 1H NMR (CDCl3) δ 8.03 (m,lH), 7.73 (dd, JH-F= 8.9 Hz, JH.H = 2.5 Hz, IH), 7.50 (dd, J= 8.4 Hz, 1.6 Hz, IH), 7.38 (d, J= 8.4 Hz, IH), 7.31 (dd, JH-H = 8.9 Hz, JH-F = 4.2 Hz, IH), 7.21 (ddd, JH- H = 8.9 Hz, JH-F = 8.9 Hz, JH-H = 2.5 Hz, IH), 4.85 (s, 2H), 4.34 (q, J= 7.2 Hz, 2H), 1.73 (br s, IH), 1.41 (t, J= 7.2 Hz, 3H).
Synthesis of 9-Ethyl-6-methoxy-3-hydroxymethyI-9H-carbazole (Compound 6)
Compound 6 was prepared using the procedure described for compound 2 using 4-methoxyphenylhydrazine hydrochloride as the starting material. 1H NMR (CDCl3) δ 8.08-8.04 (m, IH), 7.58 (d, J= 2.5 Hz, IH), 7.47 (dd, J= 8.3 Hz, 1.6 Hz, IH), 7.37 (d, J= 8.3 Hz, IH), 7.32 (d, J= 8.8 Hz, IH), 7.12 (dd, J= 8.8 Hz, 2.5 Hz, IH), 4.85 (s, 2H), 4.34 (q, J= 7.3 Hz, 2H) 3.93 (s, 3H), 1.58 (br s, IH) 1.41 (t, J= 7.3 Hz).
Synthesis of 9-Ethyl-6-methyl-3-hydroxymethyl-9H-carbazole (Compound 5)
S-Methyϊ-l^jS^-tetrahydro^H-carbazole-ό-carboxylic Acid: A suspension of 4- hydrazinobenzoic acid (10 g, 66 mmol) and 4-methylcyclohexanone (8.2 mL, 66.7 mmol) in acetic acid (100 mL) was heated at reflux for 48 h. The reaction was cooled to room temperature and diluted with water. The mixture was filtered and the solid residue was washed twice with water and once with hexane. The solid was dried in vacuo at 50 0C for 2 h to yield a tan solid (11.2 g, 73%). The 1H NMR spectrum was consistent with the proposed structure. The crude product was used without further purification.
Ethyl P-ethyl-S-methyl-ljZjS^-tetrahydro-PH-carbazole-β-carboxylate: A solution of 3 -methyl- 1,2,3, 4-tetrahydro-9H-carbazole-6-carboxylic acid (3 g, 13.1 mmol) and iodoethane (2.62 mL, 32.7 mmol) in DMF (20 mL) was added to a stirred suspension of sodium hydride (90% sodium hydride, 1.05 g, 39.3 mmol) in DMF (3OmL). The mixture was stirred at room temperature for 16 h. The reaction was diluted with water and the resulting mixture was extracted twice with ethyl acetate. The ethyl acetate layers were combined, dried over sodium sulfate and concentrated to a red solid. The crude product was triturated with ether to afford a white solid (1.7 g, 45%). The proton NMR was consistent with the proposed structure. This solid was used without further purification.
Ethyl 9-ethyl-6-methyl-9H-carbazole-3-carboxylate: A mixture of ethyl 9-ethyl-3- methyl-1, 2,3, 4-tetrahydro-9H-carbazole-6-carboxy late and 10% palladium on charcoal (300 mg) was placed in a flask. The reaction flask was purged with nitrogen then heated at 250-300 0C for 45 minutes. After the flask cooled to room temperature the fused contents was pulverized and stirred with boiling ethanol. After the ethanol cooled the mixture was filtered through Celite filter aid. The Celite was washed with ethanol. The filtrates were combined and concentrated. The residue was purified by silica gel chromatography (ethyl acetate : hexane (1 : 9)) to afford a yellow oil (1.4 g, 94%). 1H NMR (CDCl3) δ 8.82-8.78 (m, IH), 8.13-8.14 (m, IH), 7.98-7.95 (m, IH), 7.40-7.35 (m, IH), 7.34-7.32 (m, 2H), 4.47-4.33 (m, 4H), 2.55 (s, 3H), 1.49-1.40 (m, 6H).
9-EthyI-3-hydroxymethyl-6-methyl-9H-carbazole: A solution of ethyl 9-ethyl-6- methyl-9H-carbazole-3-carboxylate (1.4 g, 5 mmol) in TΗF (10 mL) was added to a stirred suspension of lithium aluminum hydride (0.28 g, 7.4 mmol) in THF (10 niL). After stirring at room temperature for 1 h the reaction was carefully diluted with water. Ethyl acetate was added and the mixture stirred for several minutes then filtered through a pad of Celite filter aid. The Celite was washed twice with ethyl acetate. The filtrates were combined and the ethyl acetate layer was separated, dried over sodium sulfate and concentrated to afford an off-white solid. 1H NMR (CDCl3) δ 8.09-8.05 (m, IH), 7.91- 7.88 (m, IH), 7.49-7.45 (m, IH), 7.39-7.35 (m, IH), 7.33-7.27 (m, 2H), 4.85 (s, 2H), 4.35 (q, J= 7.2 Hz), 2.54 (s, 3H), 1.6 (br s, IH), 1.43 (t, 3H).
Synthesis of 9-Pentyl-3-hydroxymethyl-9H-carbazole (Compound 12)
Ethyl l,2,3,4-tetrahydro-9H-carbazole-3-carboxylate: A mixture of phenylhydrazine (3.0 g, 27.7 mmol) and ethyl 4-oxocyclohexanecarboxylate (4.7 g, 27.5 mmol) in acetic acid (30 niL) was heated at reflux for 16 h. The reaction was allowed to cool to room temperature. The resulting suspension was stirred vigorously while water (300 mL) was added slowly. After stirring at room temperature for 1 h, the solid was collected by filtration then washed with water. The solid residue was suspended in hexane in a sonicating bath, filtered then dried in vacuo at 55 0C for 5 h to afford an off-white solid (5.5 g, 82%). 1H NMR (CDCl3) δ 7.71. br s, IH), 7.50-7.42 (m, IH), 7.32-7.26 (m, IH), 7.16-7.07 (m, IH), 4.28-4.15 (m, 2H), 3.13-3.04 (m, IH), 2.95-2.75 (m, 4H), 2.37-2.28 (m, IH), 2.20-1.95 (m, IH), 1.31 (t, J= 7.3 Hz, 3H).
Ethyl 9-pentyl-9H-carbazole-3-carboxyIate: A solution of ethyl 1,2,3,4-tetrahydro- 9H-carbazole-3-carboxylate (5.0 g, 20.5 mmol) and 1-iodopentane (6.1 g, 30.8 mmol) in dry DMF (15 mL) was added to cold suspension of sodium hydride (dry, 95%, 1.2 g, 46.7 mmol in dry DMF). After the addition was completed the reaction was stirred at room temperature and monitored by TLC. After 1.5 Ii the reaction was chilled and carefully diluted with water (500 mL). The aqueous mixture was extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to afford ethyl 9-pentyl-l,2,3,4-tetrahydro-9H-carbazole-3-carboχylate as a brown oil (6.65 g). The proton NMR spectrum was consistent with the expected structure. This crude material was used in the next step without further purification. A mixture of crude ethyl 9-pentyl-l,2,3,4-tetrahydro-9H-carbazole-3-carboxylate (6.60 g) and tetrachloro-1,4- benzoquinone (20.9 g, 84.8 mmol) in ethanol (100 mL) was heated at reflux for 16 h. The reaction was cooled to room temperature and concentrated in vacuo. The solid residue was purified by silica gel chromatography (ethyl acetate : hexane (1 : 19)) to afford 4.6 g (72 % for 2 steps) of ethyl 9-pentyl-9H-carbazole-3-carboxylate as a burgundy gum. 1H NMR (CDCl3) δ 8.83-8.82 (m, IH), 8.25-8.15 (m, 2H), 7.55-7.50 (m, IH), 7.49-7.39 (m, 2H), 7.35-7.26 (m, IH), 4.45 (q, J= 7.3 Hz, 2H), 4.42-4.29 (m, 2H), 1.95-1.80 (m, 2H), 1.46 (t, J= 7.3 Hz, 3H), 1.43-1.25 (m, 4H), 0.91-0.80 (m, 3H).
9-Pentyl-3-hydroxymethyl-9H-carbazole: A solution of ethyl 9-pentyl-9H-carbazole- 3-carboxylate (4.57 g, 14.8 mmol) in TΗF (20 mL) was added via a syringe to stirred suspension of lithium aluminum hydride (2.11 g, 55.9 mmol) in TΗF (10 mL) at room temperature. After 1.5 h the reaction was complete (TLC). The excess lithium aluminum hydride was hydrolyzed by careful addition of water (30 mL). The mixture was filtered through a pad of Celite filter aid, and the Celite was washed with ethyl acetate three times. The filtrates were transferred to a separatory funnel and the layers were separated. The organic layer was washed with saturated ammonium chloride solution, dried over magnesium sulfate and concentrated in vacuo to afford a brown oil. The crude oil was purified by silica gel chromatography (ethyl acetate : hexane (2 : 8)) to yield a pale yellow oil (2.76 g, 70%). 1H NMR (CDCl3) δ 8.17-8.07 (m, 2H)5 7.52- 7.45 (m, 2H), 7.44-7.37 (m,2H), 7.28-7.19 (m,lH), 4.86 (s, 2H), 4.34-4.26 (m, 2H), 1.94-1.82 (m, 2H), 1.68 (br s, IH), 1.43-1.29 (m, 4H), 0.94-0.82 (m, 3H). Synthesis of 9-Ethyl-2-methyl-3-hydroxymethyl-9H-carbazole (Compound 123) and 9-Ethyl-4-methyl-3-hydroxymethyl-9H-carbazole (Compound 16)
A mixture of ethyl 2-methyl-4-oxo-2-cyclohexenecarboxylate (3.Og, 16.4 mmol) and phenylhydrazine (1.76 g, 16.3 mmol) in trifluoroacetic acid (15 niL) was heated at reflux for 16 h. After the reaction cooled to room temperature it was diluted with water, stirred for 45 min then extracted twice with ethyl acetate. The extracts were combined, washed with saturated sodium chloride solution, dried (magnesium sulfate) and concentrated in vacuo to afford a brown residue (4.7g). The crude product was subjected to silica gel chromatography (ethyl acetate : hexane (15 : 85)) to afford an orange solid which was triturated with ether to give a yellow solid (386 mg, 9%). The proton NMR showed this solid to be a mixture of ethyl 2-methyl-9H-carbazole-3- carboxylate and ethyl 4-methyl-9H-carbazole-3-carboxylate. A solution of this mixture (380 mg, 1.5 mmol) and iodoethane (180 μL, 2.3 mmol) in DMF (5 mL) was added to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 77 nig, 1.9 mmol) in DMF (5 mL) and the resulting suspension was stirred at room temperature. After 5 h the reaction was diluted with water and the mixture was extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with sodium chloride solution, dried (magnesium sulfate) and concentrated in vacuo to afford a brown oil (380 mg). A solution of this crude product (380 mg) in TΗF (5 mL) was added to a stirred suspension of lithium aluminum hydride (254 mg) in TΗF (10 mL). The reaction was stirred for 1 h at room temperature then carefully diluted with water. The mixture was extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with saturated ammonium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography to afford 9-ethyl-3- hydroxymethyl-2-methyl-9H-carbazole (87 mg) as a yellow oil and 9-ethyl-3- hydroxymethyl-4-methyl-9H-carbazole (130mg) as a yellow solid. 9-Ethyl-2-methyl-3-hydroxymethyl-9H-carbazole: 1H NMR (CDCl3) δ 8.06 (d, J= 8 Hz, IH), 8.04 (s, IH), 7.48-7.36 (m, 2H), 7.25-7.18 (m, 2H), 4.87 (s, H), 4.35 (q, J= 7.2 Hz, 2H), 2.61 (s, 3H), 1.52 (br s, IH), 1.43 (t, J= 7.2 Hz, 3H).
9-Ethyl-4-methyl-3-hydroxymethyl-9H-carbazole: 1H NMR(DMSO-rfό) δ 8.20 (d, J = 8.2 Hz, IH), 7.58 (d, J= 8.4 Hz, IH), 7.47-7.34 (m, 3H), 7.22-7.14 (m, IH), 4.93 (t, J = 5.4 Hz, IH), 4.66 (d, J= 5.4 Hz, 2H), 4.41 (q, J= 7.1 Hz, 2H), 2.78 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).
Synthesis of 9-Ethyl-6-chloro-l,4-dimethyl-3-hydroxymethyl-9H-carbazole (Compound 45)
6-Chloro-l,4-dimethyl-9H-carbazole: A mixture of 5-chloroindole (5.0 g, 33.0 mmol), 2,5-hexanedione (4.1 niL, 34.6 mmol), andp-toluenesulfonic acid monohydrate (6.7 g, 35.3 mmol) in ethanol (20 niL) was heated at reflux for 16 h. The reaction was cooled to room temperature, diluted with water and extracted twice with ethyl acetate. The ethyl acetate layers were washed successively with saturated sodium carbonate and saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to afford a brown syrup. The crude product was used without purification.
9-EthyI-6-chloro-l,4-dimethyl-9H-carbazole: A solution of the crude 6-chloro-l,4- dimethyl-9H-carbazole and iodoethane (7.7 g, 49.5 mmol) in DMF (30 mL) was added to a cold suspension of sodium hydride (60% dispersion in mineral oil, 1.84 g, 46 mmol) in DMF (10 mL). After stirring at room temperature for 2 h the mixture was carefully diluted with water and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to afford a dark syrup. The crude product was used without purification. P-Ethyl-ό-chloro-l^-dimethyl-S-formyl-PH-carbazole: A mixture of the crude 9- ethyl-l,4-dimethyl-6-chloro-9H-carbazole, N-methylformanilide (6.9 g, 51 mmol), and phosphorus oxychloride (14.2 g, 93 mmol) in dichloromethane (30 mL) was heated at reflux for 16 h. The reaction was chilled in an ice bath then diluted with water and made alkaline by adding solid potassium carbonate. The mixture was extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo to afford a brown semi-solid residue. The crude aldehyde was used without purification.
9-EthyI-6-chloro-l,4-dimethyl-3-hydroxymethyl-9H-carbazole: Sodium borohydride (6.24 g, 165 mmol) was added to a cold solution of the crude 9-ethyl-6-chloro-l,4- dimethyl-3-formyl-9H-carbazole in methanol (50 mL). The mixture was stirred at room temperature for 16 h. The reaction was diluted with water and stirred for 1 h. The mixture was extracted three times with ethyl acetate. The ethyl acetate extracts were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo to afford a brown solid. The crude product was purified by silica gel chromatography (ethyl acetate : hexane 15 : 85)) to afford an off-white solid (3.9 g, 13.5 mmol, 41% yield based on 5-chloroindole). 1H NMR (CDCl3) δ 8.20 (d, J= 1.8 Hz, IH), 7.42 (dd, J = 8.8 Hz, 1.8 Hz, IH), 7.34 (d, J= 8.8 Hz, IH), 7.20 (s, IH), 4.85 (br s, 2H), 4.57 (q, J = 7.2 Hz, 2H), 2.83 (s, 3H), 2.79 (s, 3H), 1.49 (br s, IH), 1.39 (t, J= 7.2 Hz, 3H).
Synthesis of 9-Ethyl-6-fluoro-l,4-dimethyI-3-hydroxymethyI-9H-carbazole (Compound 33)
This compound was prepared using the procedure described for compound 45. 1H NMR (CDCl3) δ 7.93 (dd, JH-F= 10.0 Hz, JH-H = 2.5 Hz, IH), 7.34 (dd, JH-H = 9.0 Hz, JH-F = 4.4, IH), 7.19 (dd, J= 9.0, 2.5 Hz, IH), 4.85 (br s, 2H), 4.59 (q, J= 7.2 Hz, 2H), 2.86 (s, 3H), 2.84 (s, 3H), 1.44 (br s, IH), 1.40 (t, J= 7.2 Hz, 3H). Synthesis of 9-EthyI-6-methoxy-l,4-dimethyl-3-hydroxymethyl-9H-carbazole (Compound 55)
This compound was prepared using the procedure described for compound 45. 1H NMR (CDCl3) δ 7.79 (d, J= 2.3 Hz, IH), 7.34 (d, J= 8.8 Hz, IH), 7.17-7.10 (m, 2H), 4.84 (d, J= 4.8 Hz, 2H), 4.57 (q, J= 7.0 Hz, 2H), 3.94 (s, 3H), 2.89 (s, 3H), 2.78 (s, 3H), 1.43-1.40 (m, IH), 1.38 (t, J= 7.0, 3H).
Synthesis of 9-Ethyl-6-methyI-l,4-dimethyl-3-hydroxymethyl-9H-carbazole (Compound 57) This compound was prepared using the procedure described for compound 45.
1H NMR (CDCl3 + D2O) δ 8.06 (s, IH), 7.36-7.27 (m, 2H), 7.15 (s, IH), 4.84 (s, 2H), 4.58 (q, J=7.3 Hz, 2H), 2.90 (s, 3H), 2.79 (s, 3H), 2.56 (s, 3H), 1.39 (t, J= 7.3, 3H).
Synthesis of 9-EthyI-l,4-dimethyl-3-hydroxymethyl-9H-carbazole (Compound 31) This compound was prepared using the procedure described for compound 45.
The intermediates were purified by silica gel chromatography. 1H NMR (CDCl3) δ 8.28 (d, J= 8.3 Hz, IH), 7.52-7.0 (m, 2H), 7.29-7.22 (m, IH), 7.18 (s, IH), 4.86 (s, 2H), 4.61 (q, J= 7.1, 2H), 2.91 (s, 3H), 2.81 (s, 3H), 1.44 (br s, IH), 1.42 (t, J= 7.1 Hz, 3H).
Synthesis of 9-Ethyl-6-bromo-l,4-dimethyl-3-hydroxymethyl-9H-carbazole (Compound 92)
This compound was prepared using the procedure described for compound 45. The intermediates were purified by silica gel chromatography. 1H NMR (DMSOd6) δ 8.27 (d, J=1.7 Hz. IH), 7.63-7.56 (m, 2H), 7.22 (s, IH), 4.97 (t, J=5.34 Hz1 IH), 4.63-4.58 (m, 4 H), 2.75 (s, 3H), 2.71 (s, 3H), 1.27 (t, J=U Hz, 3H). Synthesis of P-Ethyl-l-chloro-^methoxy-Sjθ^jS-tetrahydro-S-hydroxymethyl-ΘH- carbazole (Compound 100)
Methyl l-Chloro-^methoxy-Sjδ^S-tetrahydro-PH-carbazole-S-carboxylate: A solution of methyl 5-chloro-4-hydrazino-2-methoxybenzoate (11.8 g, 51 mmol) and cyclohexanone (10 g, 102 mmol) in acetic acid (200 mL) was heated at reflux for 20 h. The reaction was cooled to room temperature, diluted with water (0.5 L) and extracted three times with ether. The ether layers were combined, washed successively with saturated sodium chloride solution, aqueous potassium carbonate, and saturated sodium chloride solution, then dried over magnesium sulfate and concentrated in vacuo to afford a brown solid. The residue was purified by silica gel chromatography (eluent gradient of dichloromethane : hexane (1 : 1) to neat dichloromethane) to afford a tan solid (4.5 g, 30%). 1H NMR (CDCl3) δ 8.08 (br s, IH), 7.65 (s, IH), 3.93 (s, 3H), 3.92 (s, 3H), 2.96- 2.89 (m, 2H), 2.78-2.70 (m, 2H), 1.95-1.82 (m, 2H).
Methyl l-Chloro-P-ethyM-methoxy-S^^δ-tetrahydro-PH-carbazoIe-S- carboxylate: To a stirred solution of methyl l-chloro-4-methoxy-5,6,7,8-tetrahydro-9H- carbazole-3-carboxylate (4.5 g, 15.3 mmol) in DMF (60 mL) was added sodium hydride (60% dispersion in mineral oil, 860 mg, 21.4 mmol). After gas evolution ceased, neat iodoethane (1.5 ml, 18.4 mmol) was added via a syringe and the mixture was stirred at room temperature for 24 h. The reaction was carefully diluted with water and saturated sodium chloride solution then extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to afford a brown oil. The residue was purified by silica gel chromatography (eluent gradient of 5% ethyl acetate to 30% ethyl acetate in hexane) to afford a yellow syrup (4.7 g, 95%). 1H NMR (CDCl3) δ 7.62 (s, IH), 4.42 (q, J= 7.2 Hz, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 2.98-2.91 (m, 2H), 2.71-2.64 (m, 2H), 1.97-1.79 (m, 4H), 1.35 (t, J= 7.2 Hz, 3H). l-Chloro-9-ethyl-3-hydroxymetliyl-4-methoxy-5,6,7,8-tetrahycIro-9H-carbazole: A solution of diisobutylaluminum hydride (IM in dichloromethane, 2.9 mmol) was added via a syringe to a cold (-78 0C) solution of methyl l-chloro-9-ethyl-4-methoxy-5,6,7,8- tetrahydro-9H-carbazole-3-carboxylate in dichloromethane (20 mL). The stirred reaction was kept cold and monitored by TLC. After 3 h saturated potassium sodium tartrate solution (5 mL) was added and the reaction was removed from the cold bath. After the reaction warmed to room temperature it was further diluted with saturated potassium sodium tartrate solution (25 mL) and extracted twice with dichloromethane. The dichloromethane extracts were combined, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to afford a white solid. The solid was purified by silica gel chromatography (eluent gradient of 6% ethyl acetate to 30% ethyl acetate in hexane) to afford a white solid (315 mg, 78%). 1H NMR (CDCl3) δ 7.03 (s, IH), 4.74 (s, 2H), 4.41 (q, J= 7.2 Hz, 2H), 3.87 (s, 3H), 2.96-2.88 (m, 2H), 2.73-2.65 (m, 2H), 1.99-1.89 (m, 5H), 1.77 (br s, IH), 1.33 (t, J= 7.2 Hz, 3H).
Synthesis of 9-Ethyl-3-hydroxymethyl-4-methoxy-5,6,7,8-tetrahydro-9H-carbazole (Compound 101)
A suspension of methyl l-chloro~4-methoxy-5,6,7,8-tetrahydro-9H-carbazole-3- carboxylate (619 mg, 1.9 mmol) and solid lithium aluminum hydride (109 mg, 2.8 mmol) in TΗF (35 mL) was heated at reflux for 4 h, then stirred at room temperature for 16 h. After aqueous work up the dechlorination was incomplete. The crude residue was subjected to lithium aluminum hydride (329 mg, 8.4 mmol) in refluxing TΗF for 24 h. Aqueous work up afforded a liquid residue which was purified by silica gel chromatography (gradient eluent ethyl acetate : hexane (1 : 9) to ethyl acetate in hexane (2 : 8 )) to yield a clear liquid which solidified on standing (133 mg, 26%). 1H NMR (CD3OD) δ 7.07 (d, J= 8.6 HZ, IH), 7.02 (d, J= 8.6 Hz, IH), 4.70 (s, 2H), 3.98 (q, J= 7.2 Hz, 2H), 3.83 (s, 3H), 2.94-2.84 (m, 2H). 2.70-2.60 (m, 2H), 1.94-1.75 (m, 4H), 1.20 (t, J= 7.2 Hz). Synthesis of 9-cyclopropylmethyl-3-hydroxymethyl-9H-carbazole (Compound 11)
9-Cyclopropylmethyl-9H-carbazole: A solution of 9H-carbazole (6.8 g, 41 mmol) and cyclopropylmethyl bromide (5.0 g, 37 mmol) in DMF (50 mL) was added to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 1.63 g, 41 mmol) in DMF (50 mL). The reaction was stirred at room temperature for 16 h then carefully diluted with water and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent gradient ethyl acetate : hexane (1 : 19) to ethyl acetate : hexane (6 : 4)) to afford a white solid (6.65 g, 73%). 1H NMR (CDCl3) δ 8.11 (d, J = 7.8 Hz, 2H), 7.55-7.40 (m, 4H), 7.30-7.20 (m, 2H), 4.25 (d, J= 6.4 Hz, 2H), 1.40-1.25 (m, IH), 0.58-0.40 (m, 4H).
9-CycIopropyImethyl-3-formyl-9H-carbazole: To a solution of 9-cyclopropylmethyl- 9H-carbazole (4.6 g, 20.8 mmol) in dichloromethane (50 mL) was added DMF (4.83 mL, 62.4 mmol) followed by phosphorus oxychloride (2.9 mL, 31.2 mmol). The resulting mixture was heated at reflux and monitored by TLC. After 48 h the reaction was cooled in an ice bath, diluted with aqueous sodium hydroxide (8.4 g in 100 mL water), then stirred for 1 h. The mixture was brought to room temperature and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to yield a syrup that solidified on standing. The crude solid was purified by silica gel chromatography (eluent gradient ethyl acetate : hexane (1 : 19) to ethyl acetate : hexane (1 : 4)) to afford a pale yellow solid (4.76 g, 91%). 1H NMR (CDCl3) δ 10.10 (s, IH), 8.61 (d, J= 1.6 Hz, IH), 8.20-8.15 (m, IH), 8.05-7.95 (m, IH), 7.60-7.45 (m, 3H), 7.35- 7.30 (m, IH), 4.27 (d, J= 6.8 Hz, 2H), 1.42-1.30 (m, IH), 0.62-0.35 (m, 4H).
9-Cyclopropylmethyl-3-hydroxymethyl-9H-carbazoIe (Compound 11): To a stirred solution of 9-cyclopropylmethyl-3-formyl-9H-carbazole (1.17 g, 4.7 mmol) in (1 : 1) isopropanol : ethyl acetate (150 niL) was added solid sodium borohydride (430 mg, 11.4 mmol). The reaction was stirred at room temperature and monitored by TLC. After 0.5 h the reaction was concentrated to a small volume then diluted with water. The resulting mixture was extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed successively with IN HCl and saturated sodium chloride, dried over magnesium sulfate then concentrated in vacuo. The residue was purified by silica gel chromatography (eluent gradient ethyl acetate : hexane (7 : 93) to ethyl acetate : hexane (3 : 7 )) to afford a white solid (620 mg, 52%). 1H NMR (CDCl3) δ 8.15-8.04 (m, 2H), 7.56-7.42 (m, 3H), 7.41-7.34 (m, IH), 7.31-7.23 (m, IH), 4.83 (s, 3H), 4.19 (d, J = 6.4 Hz, 2H), 2.46 (br s, IH), 1.39-1.26 (m, IH)5 0.62-0.33 (m, 4H).
Synthesis of 9-Benzyl-3-hydroxymethyl-9H-carbazole (Compound 112)
Compound 112 was prepared by the method described for compound 11. 1H NMR (CDCl3) δ 8.16-8.10 (m, 2H), 7.52-7.10 (m, 10H), 5.46 (s, 2H), 4.84 (s, 2H), 2.19 (br s, IH).
Synthesis of 9-PropyI-3-hydroxymethyl-9H-carbazole (Compound 112)
Compound 112 was prepared by the method described for Compound 11. 1H NMR (CDCl3) δ 8.15-8.05 (m,2H), 7.50-7.35 (m,4H), 7.26-7.15 (m, IH), 4.86 (br s, 2H), 4.28 (t, J= 7.2 Hz, 2H), 2.00-1.85 (m, 2H), 1.66 (bs s, IH), 0.97 (t, J= 7.2 Hz, 3H).
Synthesis of 9-Ethyϊ-5,7-dimethoxy-3-hydroxymethyl-9H-carbazole (Compound 59)
Methyl 3-(2,4-DimethoxyphenyI)-4-nitrobenzoate: To a deoxygenated mixture of 2,4- dimethoxyphenyl boronic acid (2.24g, 12.3 mmol), 5-(methoxycarbonyl)-2-nitrophenyl trifiuoromethanesulfonate (2.77 g, 8.40 mmol), and potassium phosphate (1.32 g, 6.21 mmol) in ethylene glycol dimethyl ether (70 mL) was added tetrakis (triphenylphosphine)palladium(O) (738 mg, 0.639mmol). The reaction was heated at reflux for 6 hours under inert atmosphere, cooled to ambient temperature, and filtered through a bed of Celite. The bed was rinsed with several volumes of ethyl acetate. The filtrate was washed successively with IM sodium hydroxide solution (2 x 100 niL), IM HCl (2 x 100 mL), water (100 mL), and saturated sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to a brown residue. The crude material was purified by silica gel chromatography (dichloromethane : hexanes (1 : I)) to afford a bright yellow solid (1.60 g, 60%). 1H NMR (DMSO-d6) δ 8.07 (m, 2H), 7.90 (s, IH), 7.32 (d, J= 8.4 Hz, IH), 6.69 (dd, J= 8.4 Hz, 2.3 Hz, IH), 6.63 (d, J= 2.3 Hz5 IH), 3.90 (S, 3H), 3.82 (S, 3H), 3.62 (S, 3H).
Methyl δ^-Dimethoxy^H-carbazole-S-carboxylate: A solution of methyl 3-(2,4- dimethoxyphenyl)-4-nitrobenzoate (612 mg, 1.92 mmol) and triethyl phosphite (25 mL) was heated at reflux under inert atmosphere until no starting material was evident by TLC. The reaction was cooled to ambient temperature. Vacuum distillation of the excess triethyl phosphite resulted in a yellow residue which was purified by silica gel chromatography (ethyl acetate: hexanes, (1 : 3)) to afford a white solid (370 mg, 68%). 1H NMR (DMSOd6) δ 11.6 (s, IH), 8.63 (d, J= 1.7 Hz, IH), 7.90 (dd, J = 8.5 Hz, 1.7 Hz, IH), 7.46 (d, J= 8.5 Hz, IH), 6.64 (d, J= 1.8 Hz, IH), 6.40 (d, J= 1.8 Hz, IH), 4.02 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H).
Methyl 5,7-dimethoxy-9-ethyI-9H-carbazole-3-carboxylate: A solution of methyl 5,7-dimethoxy-9H-carbazole-3-carboxylate (360 mg, 1.25 mmol) and iodoethane (390 mg, 2.50 mmol) in DMF (3.0 mL) was added dropwise to a chilled (0 0C) suspension of sodium hydride (60 % dispersion in oil, 83.0 mg, 2.08 mmol) in DMF (2 mL). The ice bath was removed once the addition was complete and the reaction was stirred at ambient temperature for several hours. The reaction was cooled to 0 0C, slowly quenched with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water and saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated to an off white solid. The crude material was purified by silica gel chromatography (ethyl acetate : hexanes, (1:10)) to afford a white solid (316 mg, 77% yield). 1H NMR (DMSOd6) δ 8.72-8.62 (m, IH), 7.95 (dd, J =8.7 Hz, 1.8 Hz, IH), 7.6 (d, J= 8.7 Hz, IH), 6.83 (d, J=1.7 Hz, IH), 6.45 (d, J=1.7 Hz, IH), 4.42 ( q, J= 7.1 Hz, 2 H)3 4.03 (s, 3H), 3.90 (s, 3H), 3.87 (s, 3H), 1.3 (t, J =7.1 Hz, 3H).
5,7-Dimethoxy-9-ethyl-3-hydroxymethyl-9H-carbazole: A solution of methyl 5,7- dimethoxy-9-ethylcarbazole-3-carboxylate (316 mg, 1.00 mmol) in TΗF (10 mL) was added dropwise to a chilled (0 0C) suspension of lithium aluminum hydride (LAΗ) (77.8 mg, 2.05 mmol) in TΗF (4 mL) under an inert atmosphere. When the addition was complete, the ice bath was removed and the reaction was stirred at ambient temperature for 3.5 hours. The reaction was cooled to 0 0C and quenched with saturated ammonium chloride solution. The reaction was filtered through a bed of Celite which was rinsed several times with diethyl ether. The organic layer was separated, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated to an off white solid. The crude material was purified by silica gel chromatography (ethyl acetate : hexanes, (1 : 5)) to afford a white solid (250 mg, 87% yield). 1H NMR (DMSOd6) δ 8.05-8.00 (m, IH), 7.43 (d, J= 8.4 Hz, IH), 7.26 (dd, J= 8.4 Hz, 1.2 Hz, IH), 6.73 (d, J= 1.8 Hz, IH)3 6.35 (d, J= 1.8 Hz, IH), 5.09 (t, J = 5.8 Hz, IH), 4.60 (d, J= 5.8 Hz, 2H), 4.36 (q, J= 7.1 Hz, 2H), 3.98 (s, 3H), 3.88(s, 3H), 1.37 (t, J= 7.1 Hz3 3H).
Synthesis of 9-Ethyl-6-chloro-4-(2-hydroxyethoxy)-3-hydroxymethyl-9H-carbazole (Compound 96)
Cyclohexane-l,3-dione mono-(4-chlorophenyl) Ηydrazone: 4-Chlorophenyl hydrazine hydrochloride (74.37 g, 0.415 mol) was suspended in water (400 mL) and placed in a 1 L three neck flask equipped with a mechanical stirrer and an addition funnel. A suspension of cyclohexane-l,3-dione (46.604 g, 0.416 mol) in water was added slowly. The mixture was stirred overnight resulting in an aqueous layer and a dark orange oil. The aqueous layer was decanted and hot MeOH (400 mL) was added to the oil. The mixture was poured into water (1.6 L) and vigorously stirred until a solid formed. The mixture was filtered and the solid was washed with water (300 mL). The solid was suspended in hexane (500 niL), stirred for 1 hour then filtered. The solid was dried overnight in the air.
6-Chloro-l,2,3,4-tetrahydro-4-oxocarbazole: Cyclohexane-1 ,3-dione mono-(6- chlorophenyl) hydrazone was suspended in trifluoroacetic acid (400 niL) and the mixture was heated at reflux for 16 hours. The mixture was concentrated to dryness and the residue was suspended in water (500 mL) then filtered. The filter cake was washed with water (200 mL) and suspended in MeOH (200 mL) for 1 hour. Mixture was filtered and solid resuspended in MeOH (100 mL twice). The solid was dried in the air. Recovery: 34.88 g (38 % yield). 1HNMR (DMSO- d6) δ 12 (br , IH), 7.84 (sd, IH), 7.36 (d, IH), 7.13 (dd, IH), 2.91 (t, 2 H), 2.38 (t, 2H), 2.06 (m, 2H).
9-Ethyl-6-chloro-l,2,3,4-tetrahydro-4-oxocarbazole: 6-Chloro-l ,2,3,4-tetrahydro-4- oxocarbazole (34.88 g, 0.158 mol) was suspended in a mixture of anhydrous THF (425 mL) and anhydrous DMF (100 mL). The mixture was cooled to -40 0C and NaH (15.25 g, 0.381 mol, 60 % in mineral oil) was added slowly to the mixture. Ethyl iodide (15 mL, 0.188 mol) was added to the mixture and allowed to slowly warm to room temperature. The mixture was slowly poured into iced water (IL). A light yellow solid formed and the mixture was filtered. The solid was washed with water (300 mL) then suspended in hexane (700 mL) for 1 hour. Mixture was filtered and dried overnight in the air. Recovery: 38.84 g (98 % yield). 1H NMR (DMSO- d6) δ 7.96 (sd, IH), 7.64 (d, IH), 7.25 (dd, IH), 4.26 (q, 2H), 3.02 (t, 2H), 2.44 (t, 2H), 2.15 (m, 2H), 1.29 (t, 3H). 9-Ethyl-6-chloro- 4-hydroxy-9H-carbazole: 9-Ethyl-6-chloro- 1,2,3, 4-tetrahydro-4- oxocarbazole (38.84 g, 0.156 mol) was dissolved in a mixture of TΗF (200 mL) and DMF (200 mL). Pyridine hydrobromide perbromide (50.172 g, 0.156 mol) was added and the mixture was heated at 70 0C for 20 hours. The reaction solvent was removed and the residue was partitioned between ethyl acetate (250 mL) and a solution of NaHSO3 (20 %, 200 mL). The aqueous layer was extracted again with ethyl acetate (100 mL). The organic layers were combined and washed with brine (200 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was redissolved in DMF (350 mL) and LiBr (31.10 g, 0.357 rnol, 2.3 eq) and Li2CO3 (26.67 g, 0.36 mol, 2.3 eq) were added. The mixture was refluxed for 3 hours then the solvent was removed by distillation. The residue was partitioned between ethyl acetate (700 mL) and water (200 mL). The organic layer was washed with brine (200 mL), dried over MgSO4, filtered and concentrated in vacuo. The mixture was purified by SiO2 column chromatography using a mixture of hexane/CH2Cl2 (7/3). The product was obtained as a white solid after removal of the solvent. Recovery: 26.15 g (68 % yield). 1H NMR (DMSO- d6) δ 10.33 (s, IH), 8.11 (sd, IH), 7.58 (d, IH), 7.40 (m, IH), 2.28 (t, IH), 7.02 (d, IH), 6.63 (d, IH), 4.37 (q, 2H), 1.27 (t, 3H).
Methyl 9-Ethyl-6-chloro-4-hydroxy-9H-carbazole-3-carboxyIate: A solution of 9- ethyl-6-chloro- 4-hydroxy-9H-carbazole (2.79 g, 11.4 mmol) in 1,2-dichloroethane (26 mL) was cooled to 00C and a solution OfBCl3 (1 M in xylenes, 13 mL) was added slowly. The mixture was slowly warmed to room temperature and methyl chloroformate (6.0 mL, 78 mmol, 7 eq) was added. The mixture was heated to 50 0C for 15 hours, cooled to 0 0C and quenched with drop-wise addition of methanol. The reaction was concentrated to dryness and the residue was purified by SiO2 column chromatography using a mixture of hexane/CΗ2Cl2 (10/2). The product was obtained as a white solid after removal of the solvent. Recovery: 3.01 g (87 % yield). 1H NMR (DMSO- d6) δ 11.75 (br , IH), 8.16 (sd, IH), 7.89 (d, IH), 7.74 (d, IH), 7.52 (m, IH), 7.24 (d, IH), 4.45 (q, 2H), 3.94 (s, 3H), 1.31 (t, 3H).
Methyl 9-Ethyl-6-chϊoro-4-(2-methoxy-2-oxoethoxy)-9H-carbazoIe-3-carboxylate:
A solution of methyl 9-ethyl-6-chloro- 4-hydroxy-9Η-carbazole~3-carboxylate (3.42 g, 11.3 mmol) in THF (30 mL)/DMF (5 mL) was cooled to -15 0C and NaH (60 % in mineral oil, 0.699 g, 17.5 mmol, 1.5 eq) was added very slowly. Methyl bromoacetate (1.60 mL, 17 mmol, 1.5 eq) was added and the mixture was allowed to warm slowly to room temperature. The mixture was poured slowly into iced water (100 mL) and filtered. The solid was washed with water (3 X 25 mL), dried in the air and used without purification in the next step. 1H NMR (CDCl3) δ 8.47 (sd, IH), 8.08 (dd, IH), 7.46 (dd, IH), 7.34 (d, IH), 7.19 (d, IH), 4.88 (s, 2H), 4.35 (q, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 1.45 (t, 3H).
9-Ethyl-6-chloro- 4-(2-hydroxyethoxy)-3-hydroxymethyl-9H-carbazole: A solution of methyl 9-ethyl-6-chloro-4-(2-methoxy-2-oxoethoxy)-9H-carbazole-3- carboxylate in TΗF (40 mL) was cooled to -2 0C and LiAlH4 (1.988 g, 52.6 mmol, 4.6 eq) was added very slowly. Mixture was stirred at 0 0C for 1 hour and then poured slowly into ice (100 mL). THF was removed by rotary evaporation and the mixture partitioned between HCl (0.1 M, 125 mL) and ethyl acetate (125 ml). The aqueous layer was extracted with ethyl acetate (25 mL). The organic layers were combined, washed with a solution OfNaHCO3 (10 %, 50 mL) and then with a brine solution (50 mL). Solvent was removed in vacuo and the residue was purified by SiO2 column chromatography using a mixture of hexane/ethyl acetate (1/1). The product was obtained as a white solid after removal of the solvent. Recovery: 2.52 g, 70 % yield. 1H NMR (DMSO- d6) δ 8.43 (sd, IH), 7.63 (d, IH), 7.54 (d, IH), 7.45 (dd, IH), 7.40 (d, IH), 5.23 (t, IH), 5.09 (t, IH), 4.68 (d, 2H), 4.42 (q, 2H), 4.09 (t, 2H), 3.87 (q, 2H), 1.29 (UH).
Synthesis of 9-Ethyl-6-chIoro-4-methoxy-3-hydroxymethyl-9Hr-carbazole (Compound 93)
This compound was prepared in a manner analogous to Compound 96, using iodomethane rather than methyl bromoacetate to alkylate methyl 9-ethyl-6-chloro- 4- hydroxy-9H-carbazole-3-carboxylate.
Methyl 9-ethyl-6-chloro-4-methoxy-9H-carbazole-3-carboxylate: 1H NMR (DMSO- d6) δ 8.16 (sd, IH), 7.95 (d, IH), 7.75 (d, IH), 7.57 (dd, IH), 7.50 (d, IH), 4.49 (q, 2H), 4.03 (s, 3H), 3.88 (s, 3H), 1.31 (t, 3H). 9-Ethyl-6-chloro-4-methoxy-3-hydroxymethyl-9H-carbazole: 1H NMR (CD3OD) δ 8.13 (sd, IH), 7.54 (d, IH), 7.50 (d, IH), 7.43 (dd, IH), 7.32 (d, IH), 4.82 (s, 2H), 4.42 (q, 2H)5 4.04 (t, 3H), 1.38 (t, 3H).
Synthesis of 9-Ethyl-6-fluoro-4-(2-hydroxyethoxy)-3-hydroxymethyl-9H-carbazole (Compound 99)
This compound was prepared in a manner analogous to Compound 96. 9-Ethyl-6-fluoro-4-(2-hydroxyethoxy)-3-hydroxymethyl-9H-carbazole: 1Η NMR (CD3OD) δ 8.02 (dd, IH), 7.48 (d, IH), 7.43 (dd, IH), 7.26 (d, IH), 7.18 (dt, IH), 4.80 (s, 2H), 4.40 (q, 2H), 4.20 (q, 2H), 4.00 (q, 2H), 1.35 (t, 3H).
Synthesis of 9-Ethyl-4-methoxy-3-hydroxymethyl-9H-carbazole (Compound 37)
This compound was prepared in a manner analogous to Compound 93, utilizing phenylhydrazine rather than 4-chlorophenylhydrazine in the initial Fischer indole cyclization.
9-Ethyl-4-methoxy-3-hydroxymethyl-9H-carbazole: 1H NMR (CDCl3) δ 8.25 (d, IH), 7.39-7.52 (m, 3H), 7.28 (d, IH), 7.18 (d, IH), 4.90 (d, 2H), 4.36 (q, 2H), 4.10 (s, 3H), 2.03 (br m, IH), 1.43 (t, 3H).
Synthesis of 9-Ethyl-4-methoxy-3-methyl-9H-carbazole (Compound 220)
9-Ethyl-4-methoxy-3-hydroxymethyl-9H-carbazole (0.160 g, 0.684 mmol) was dissolved in ethyl acetate (50 rnL), treated with 0.200 g 10% Pd/C, and stirred under an H2 atmosphere for 2 hours. The reaction mixture was then filtered over celite and the filtrate was collected. The solvent was removed to yield clear oil (0.136 g, 91%). 9-Ethyl-4-methoxy-3-methyl-9H-carbazole: 1H NMR (CDCl3) δ 8.26 (d, IH), 7.46 (m, IH), 7.38 (d, IH), 7.22-7.28 (m, 3H), 7.10, (d, IH), 4.33 (q, 2H), 4.00 (s, 3H), 2.46, (s, 3H), 1.41 (t, 3H).
Example 2. In Vitro Anti-cvsto genetic Activity of 3-hydroxymethyl carbazoles and 3- methyl carbazoles using Mardin-Darby canine kidney cells Mardin-Darby canine kidney (MDCK) (ATTC CCL-34) cells were grown in a collagen-I matrix. In 3-4 days MDCK cells imbedded in collagen-I matrix form small cysts (see, for example, Bukanov et ah, Human Molecular Genetics, 77(8): 923-936 (2002)). After three days' incubation, 0.5 μl of a 12.5 μM solution of the test compound containing 0.25% DMSO was added to the MDCK cells. After additional 5 days incubation, anti-cystogenesis activity of the tested compounds was determined. The results are summarized in FIGs. IA-I JJ. Because cytotoxic compounds are expected to produce a false positive in the assay, a cell growth assay using normal kidney epithelial cells was also performed as a comparative test to identify a cytotoxic compound. As can be seen in FIGs. IA-I JJ, the vast majority of compounds tested inhibited cystogenesis.
As a comparative test, anti-cystogenesis activity of five carbazole derivatives, which are structurally very similar to the compounds of the invention, but do not contain a hydroxymethyl, methyl or alkoxymethyl group at the 3 -position of the carbazole ring, were tested according to the procedure described above. As shown below in Table 1 , compounds that do not contain a hydroxymethyl, methyl or alkoxymethyl group at the 3- position did not show any measurable anti-cystogenesis activity. For example, 9-ethyl- 9H-carbazole-3-carboxylic acid and 9-ethyl-3-formyl-9H-carbazole, which have a carboxylic acid and a formyl group, respectively, instead of a hydroxymethyl group, did not show any measurable anti-cystogenesis activity. Similarly, 9-ethyl-3-hydroxy-9H- carbazole, a compound that has a hydroxy group instead of a hydroxymethyl group at the 3-position was not active. Also, 9-ethyl-4-hydroxymethyl-9H-carbazole where the hydroxymethyl group is positioned at tlie 4-position instead of 3-position was shown to be inactive. Thus, a change in the functional group or moving, for example, a hydroxymethyl group to a position other than the 3-position generally diminishes the anti- cystogenesis activity of a compound. Table 1. Comparative Test
Compound IC50
9H-carbazole-9-ethanol > 12.5 μM
9-ethyl-3-hydroxy-9H-carbazole > 12.5 μM
9-ethyl-9H-carbazole-3-carboxylic acid > 12.5 μM
9-ethyl-3-formyl-9H-carbazole > 12.5 μM
9-ethyl-4-hydroxymethyl-9H-carbazole > 12.5 μM
Example 3. In Vitro Anti-cystogenetic Activity of 3-hydroxymethyl carbazoles using human kidney derived cells Human primary renal epithelial cells were grown in REGM™ medium supplemented with hydrocortisone, hEGF, FBS, epinephrine, insulin, triiodothyronine, transferrin and gentamicin/amphorericin B. For incorporation into collagen gels for three-dimensional cystic cultures, cells were resuspended at 104 cells/ml in collagen gelling solution (REGM™ medium supplemented with 2.8 mM NaOH, 1.34 mg/ml NaHCO3 and 0.84 mg/ml rat tail collagen) and overlayed on top of a hardened cell-free collagen gelling solution. Cysts were grown for 8 days and REGM™ medium was added and refreshed every other day. Pictures were taken under light microscopy using a Zeiss Axiovert25 inverted microscope coupled to QED digital camera (QED Imaging Inc, Pittsburgh, PA) 4 and 8 days post 3D culture inoculation. Images were acquired with QED Camera Plus-In software version 1.3. Photographs showing cysts grown for 4 days and 8 days without a compound of the invention are shown in FIG 2.
For in vitro anti-cystogenesis assay with 9-ethyl-3-hydroxymethyl-9H-carbazole (Compound 109), cysts were grown as described above for four days in REGM™ medium. At day 4 the compound was added at 0.04 μM or 1.5 μM concentration and the cysts were incubated for four days. The growth of individual cysts was monitored and photomicrographs were taken at day 4 and day 8. The photographs are shown in FIG 3. 9-ethyl-3-hydroxymethyl-9H-carbazoIe has anti-cystogenesis activity at both 0.04 μM and 1.5 μM concentration. Example 4. In Vivo Inhibition of Cysto genesis in Jck Mice
9-Ethyl-4-methyl-34iydroxymethyl-9H-carbazole (Compound 16), 9-ethyl-6- chloro-l,4-dimethyl-3-hydroxymethyl-9H-carbazole (Compound 45), 9-ethyl-6-methyl- 3-hydroxymethyl-9H-carbazole (Compound 5), 9-ethyl-6-fluoro-3-hydroxymethyl-9H- carbazole (Compound 4), 9-ethyl-3-(l-hydroxy-l-ethyl)-9H-carbazole (Compound 110), 9-ethyl-3-hydroxymethyl-9H-carbazole (Compound 109), 9-ethyl-6-chloro-3- hydroxyinethyl-9H-carbazole (Compound 2), 9-pentyl-3-hydroxy1τiethyl-9H-carbazole (Compound 12) and 9-ethyl-5,7-dimethoxy-3-hydroxymethyl-9H-carbazole (Compound 59) were tested in vivo using jck model of PKD. Jck mice develop focal cysts as early as 3 days of age. Cystogenesis progresses slowly such that enlarged kidneys can be palpated around 4-5 weeks of age and animals survive until 20 weeks of age. Administration of compounds started at 26 days of age, when cystic disease was established in the kidney and continued until day 50. Compounds were administered by daily intraperitoneal (IP) injections. At day 50, the mice were sacrificed and 4 end points were measured. 1) The percentage of kidney to body weight ratio (shown in the tables and graphs below as "KW/BW"; 2) cyst percentage (shown as "cyst %); 3) cystic index shown as "cyst index" and 4) renal function by blood urea nitrogen shown as "BUN". To measure "cyst %" and "cyst index", Η&E kidney sections were scanned under 4X magnification using Automated Cellular Imaging System ACIS II (Chromavision). Each image size was reduced by 90% using Adobe Photoshop 7.0 software leading to ~42 pixels/mm resolution. "Cyst %" and "Cyst index" were calculated using Metamorph 6.0 software. Cyst % represents the total cystic area (in pixels) divided by the total kidney section area (in pixels) x 100. Cyst Index represents the number of cysts (size is >10 pixels) per 100 pixels area (lmm = 42 pixels). All compounds were tested in females only, because the response in males was inconsistent.
Table 2 shows the results of treating jck mice with 10 mg/kg of 9-ethyl-3- hydroxymethyl-9H-carbazole (comp 109), 9-ethyl-3-(l-hydroxy-l-ethyl)-9H-carbazole (comp 110), 9-ethyl-6-chloro-3-hydroxymethyl-9H-carbazole (comp 2) and 9-ethyl-6- fluoro-3-hydroxymethyl-9H-carbazole (comp 4) by daily IP injection for 26-50 days. The compounds were formulated in CE vehicle (saline with 10% cremophor and 10% ethanol). Administration of the CE vehicle was used as a control.
Table 2, (26-50d treatment).
Controls comp 110 comp 4 . comp 109 comp 2 (n=4) (n=8) (n=12) (n=10) (n=13)
KW/BW 6.70±0.84 5.82±0.82 5.08±0.92 * 3.39±0.32 * 3. 21±0.42 *
/O/ \
(%) BUN 60.00±12.50 37.10±10.52 * 30.80±6.32 * 28.50±3.7 * 25 .50±5.00 * (mg/dl) Cyst % 28.22±6.38 28.30±6.12 21.47±4.18 10.77±2.78 15.85±4.47 *
Cyst O.53±O.O8 0.57±0.04 0.49±0.07 0.27±0.05* 0. 38±0.07 * index * p<0.05 compared to controls. Number of animals in each group is shown as (n)
Similarly, Table 3 shows the effectiveness of 9-ethyl-6-methyl-3-hydroxymethyl- 9H-carbazole (comp 5), 9-pentyl-3-hydroxymethyl-9H-carbazole (comp 12), 9-Ethyl-4- methyl-3-hydroxymethyl-9H-carbazole (comp 16) and 9-ethyl-6-chloro-l,4-diniethyl-3- hydroxymethyl-9H-carbazole (comp 45) in inhibiting cystogenesis when 10 mg/kg of the compounds in CE were administered to jck mice by daily IP injection for 26-50 days.
Table 3, (26-5Od treatment).
Controls comp 5 comp 12 comp 16 comp 45 (n=12) (n=9) (n=10) (n=10) (n=10)
KW/BW 5.20±1.22 3.04±0.79 * 4.58±0.82 4.23±1.20 3.90±0.71*
BUN 41.75±17.00 23.00±6.67* 32.50±8.50 30.67±13.26 23.56±4.62* (mg/dl) Cyst % 21.72±5.94 18.12±8.59 22.10±4.46 18.83±6.73 14.45±2.84*
Cyst 0.50±0.06 0.40±0.12 0.47±0.05 0.42±0.07* 0.40±0.06* index * p<0.05 compared to controls. Number of animals in each group is shown as (n)
Similarly, Table 4 shows the effectiveness of 9-ethyl-5,7-dimethoxy-3- hydroxymethyl-9H-carbazole (comp 59), in inhibiting cystogenesis when 10 mg/kg of the compound in CE was administered to jck mice by daily IP injection for 26-64 days. Table 4, (26-64d treatment).
Controls comp 59 (n=9) (n=7)
KW/BW 5.72±0.62 4.37±0.42*
Figure imgf000100_0001
BUN 52.67±12.30 35.43±5.63*
(mg/dl) Cyst % 28.21±6.31 21.57±2.88*
Cyst index 0.57±0.05 0.50±0.03*
* p<0.05 compared to controls. Number of animals in each group is shown as (n)
While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

What is claimed is:
1. A method for treating polycystic kidney disease in a patient comprising administering to said patient an effective amount of a compound represented by
Structural Foπnula (I):
Figure imgf000101_0001
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is a 5-, 6-, 7- or 8-membered carbocyclic ring optionally substituted at one or more substitutable ring atoms;
Ring B is optionally substituted at one or more substitutable ring carbon atoms; X is -H, -OR, -SH, -OC(O)R, -OC(O)OR, -OC(O)NRR or -SC(O)OR;
Ri is -R, -C(O)R or -R'C(O)R;
R2 is hydrogen, a halogen, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -C(=NR)-NRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR,
-C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(^NR)-NRR, -NR-C(=NR)-NRR and -NRNRR or R2 and a substitutable ring atom on Ring B, taken together with the carbon atoms between R2 and the substitutable ring atom, form a substituted or unsubstituted non-aromatic carbocyclic ring ; each R is independently hydrogen or a substituted or unsubstituted alkyl, alkenyl or aryl group, or NRR forms a substituted or unsubstituted non- aromatic heterocyclic ring; and
R' is an alkylene or alkenylene group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR3 -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR,
-NR-C(=NR)-NRR and -NRNRR.
2. The method of Claim 1 , wherein X is -OR3 -SH, -OC(O)R, -OC(O)OR, -OC(O)NRR or -SC(O)OR.
3. The method of Claim 1 or 2, wherein Ring A is a substituted or unsubstituted aromatic ring.
4. The method of Claim 3, wherein the compound is represented by Structural Formula (II):
Figure imgf000102_0001
or a pharmaceutically acceptable salt thereof, wherein:
Ra and Rb are each independently a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRJR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN5 -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected fromthe group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R,
-NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C (=NR) -NRR and -NRNRR; R3 is hydrogen, a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS,
-NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R5 -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS,
-NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR, or R2 and R3, taken together with the carbon atoms between R2 and R3, form a substituted or unsubstituted non-aromatic carbocyclic ring; each R is independently chosen to be hydrogen or a substituted or unsubstituted alkyl, alkenyl or aryl group, or NRR forms a substituted or unsubstituted non-aromatic heterocyclic ring; k is O, 1, 2, 3 or 4; and m is O, 1 or 2.
A method for treating polycystic kidney disease in a patient comprising administering to said patient an effective amount of a compound represented by Structural Formula (III):
Figure imgf000104_0001
or a pharmaceutically acceptable salt thereof, wherein:
Y is -H, -C(O)R, -C(O)OR , -C(O)NRR, or substituted or unsubstituted alkyl; 5 Ri is -R, -C(O)R or -R5C(O)R;
R2 is hydrogen, a halogen,-C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -C(=NR)-NRR or an alkyl, allcenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR,
10 -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R,
-S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR;
R3-Rs are each independently hydrogen, a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R,
15 -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R,
-CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R,
20 -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R,
-CN, -NCS, -NO2, -Q=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR, or R2 and R3, taken together with the carbon atoms between R2 and R3, form a substituted or unsubstituted non-aromatic carbocyclic ring; each R is independently hydrogen or a substituted or unsubstituted alkyl, alkenyl or aryl group, or NRR forms a substituted or unsubstituted non- aromatic heterocyclic ring; and
R' is an alkylene or allcenylene group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR,
-C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR
6. The method of Claim 5, wherein Y is -H or substituted or unsubstituted alkyl.
7. The method of Claim 6, wherein Y is -R and R is an unsubstituted lower alkyl group.
8. The method of Claim 6, wherein the compound is represented by Structural Formula (IV):
Figure imgf000105_0001
or a pharmaceutically acceptable salt thereof.
9. The method of Claim 8, wherein R3 is a halogen, -OR3 -SR, -C(O)R, -C(S)R,
-C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR,
-NR-C(=NR)-NRR and -NRNRR, or R2 and R3, taken together with the carbon atoms between R2 and R3, form an unsubstituted non-aromatic carbocyclic ring.
10. The method of Claim 9, wherein: R1 is -H or an unsubstituted lower alkyl group;
R2 is -H or an unsubstituted lower alkyl group; and
R3 is an alkoxy-substituted, hydroxy-substituted or carboxy-substituted lower alkyl or alkoxy group, or an unsubstituted lower alkyl or alkoxy group.
11. The method of Claim 10, wherein the compound is represented by Structural Formula (V):
Figure imgf000106_0001
or a pharmaceutically acceptable salt thereof, wherein R7 is a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R,
-NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR.
12. The method of Claim 11, wherein R7 is a halogen, -NH2 or an unsubstituted lower alkyl or alkoxy group.
13. The method of Claim 12, wherein R2 is -H and R7 is -Cl or -F.
14. The method of Claim 10, wherein the compound is represented by Structural Formula (VI):
Figure imgf000107_0001
or a pharmaceutically acceptable salt thereof, wherein R5 and R7 are each independently a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R,
-S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally • substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R,
-SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR.
15. The method of Claim 14, wherein: R5 is an unsubstituted lower alkyl or alkoxy group; and R7 is a halogen, -NH2 or an unsubstituted lower alkyl group or alkoxy group.
16. The method of Claim 15, wherein: R2 is -H;
R5 is an unsubstituted lower alkyl group; and R7 is -Cl or -F.
17. The method of Claim 10, wherein the compound is represented by Structural Formula (VII):
Figure imgf000108_0001
or a pharmaceutically acceptable salt thereof, wherein Rg-Rs are each independently a halogen, -OR3 -SR, -C(O)R3 -C(S)R3 -C(O)OR3 -C(S)OR3
-C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R3 -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2,-C(=NR)-NRR3 -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR3 -C(S)SR3 -C(O)NRR3
NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R3 -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR. 18. The method of Claim 17, wherein R6 and R8 are each independently a halogen or an unsubstituted lower alkyl or alkoxy group and R7 is a halogen, -NH2 or an unsubstituted lower alkyl or alkoxy group.
19. The method of Claim 18, wherein: R2 is -H;
R6 and R8 are each independently an unsubstituted lower alkoxy group; R7 is -Cl or -F.
20. The method of Claim 10, wherein the compound is represented by Structural Formula (VIII):
Figure imgf000109_0001
or a pharmaceutically acceptable salt thereof, wherein R6 and R8 are each independently a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR,
-C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR5 -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR,
-C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR- C(=NR)-NRR and -NRNRR. 21. The method of Claim 20, wherein R6 and R8 are each independently a halogen or an unsubstituted lower alkyl or alkoxy group.
22. The method of Claim 21, wherein Rg and R8 are each independently an unsubstituted lower alkoxy group; and R2 is -H.
23. The method of Claim 10, wherein the compound is represented by Structural Formula (IX):
Figure imgf000110_0001
or a pharmaceutically acceptable salt thereof, wherein R5, Re and R8 are each independently a halogen, -OR, -SR3 -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR,
-NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR.
24. The method of Claim 23, wherein R6 and R8 are each independently a halogen or an unsubstituted lower alkyl or alkoxy group. 25. The method of Claim 24, wherein:
K-5 is an unsubstituted lower alkyl or alkoxy group; and R2 is -H.
26. The method of Claim 10, wherein Rs-R8 are each independently a halogen,
-OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R,
-C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NElR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR.
27. The method of Claim 26, wherein R7 is a halogen, -NH2 or an unsubstituted lower alkyl or alkoxy group.
28. The method of Claim 27, wherein R5 is an unsubstituted lower alkyl or alkoxy group.
29. The method of Claim 28, wherein R6 and R8 are each independently a halogen or an unsubstituted lower alkyl or alkoxy group.
30. The method of Claim 4, wherein the compound is represented by a structural formula selected from the group consisting of:
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000112_0002
or a pharmaceutically acceptable salt thereof.
31. A method for treating polycystic kidney disease in a patient comprising administering to said patient an effective amount of a compound represented by Structural Formula (Ilia):
Figure imgf000112_0003
or a pharmaceutically acceptable salt thereof, wherein: Ri is -R, -C(O)R or -R5C(O)R; R2 is hydrogen, a halogen,-C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -C(=NR)-NRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R,
-SO3R5 -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR; R3-R8 are each independently hydrogen, a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR,
-NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R,
-SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(==NR)-NRR, -NR-C(=NR)-NRR and -NRNRR, or R2 and R3, taken together with the carbon atoms between R2 and R3, form a substituted or unsubstituted non-aromatic carbocyclic ring; each R is independently hydrogen or a substituted or unsubstituted alkyl, alkenyl or aryl group, or NRR forms a substituted or unsubstituted non- aromatic heterocyclic ring; and
R' is an alkylene or alkenylene group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR,
-NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R5 -S(O)2R, -SO2NRR, -NRSO2R, -CN5 -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR. 32. The method of Claim 31 , wherein the compound is represented by a structural formula selected from the group consisting of:
Figure imgf000114_0001
Figure imgf000115_0001
pharmaceutically acceptable salt thereof.
33. The method of Claim 1 or 2, wherein Ring A is a non-aromatic carbocyclic ring.
34. The method of Claim 33, wherein the compound is represented by Structural Formula (X):
Figure imgf000115_0002
or a pharmaceutically acceptable salt thereof, wherein: each Rc is independently an unsubstituted allcyl group; each Ra is independently a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an allcyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR; R3 is hydrogen, a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR,
-C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R,
-C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -CC=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR, or R2 and R3, taken together with the carbon atoms between R2 and R3, form a substituted or unsubstituted non-aromatic carbocyclic ring; p is an integer from O to 12; q is O, 1 or 2; and n is 0, 1, 2 or 3.
35. The method of Claim 34, wherein the compound is represented by Structural Formula (XI):
Figure imgf000116_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is -H or substituted or unsubstituted alkyl; R5 is hydrogen, a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R,-S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR.
36. The method of Claim 35, wherein the compound is represented by Structural Formula (XII):
Figure imgf000117_0001
or a pharmaceutically acceptable salt thereof.
37. The method of Claim 36, wherein : Ri is -H, an unsubstituted lower alkyl group or a halobenzyl group;
R2 is -H or an unsubstituted lower alkyl group; and R3 is -H, an alkoxy-substituted, hydroxy-substituted or carboxy- substituted lower alkyl or alkoxy group or an unsubstituted lower alky] or alkoxy group. 38. The method of Claim 37, wherein R5 is hydrogen, a halogen or an unsubstituted lower alkyl or alkoxy group.
39. The method of Claim 35, wherein the compound is represented by Structural Formula (XIII):
Figure imgf000118_0001
or a pharmaceutically acceptable salt thereof.
40. The method of Claim 39, wherein:
Ri is -H, an unsubstituted lower alkyl group or a halobenzyl group;
R2 is -H or an unsubstituted lower alkyl group; and R3 is -H, an alkoxy-substituted, hydroxy-substituted or carboxy- substituted lower alkyl or alkoxy group, or an unsubstituted lower alkyl or alkoxy group.
41. The method of Claim 40, wherein R5 is hydrogen, a halogen or an unsubstituted lower alkyl or alkoxy group.
42. The method of Claim 35, wherein the compound is represented by a structural formula selected from the group consisting of:
Figure imgf000119_0001
or a pharmaceutically acceptable salt thereof.
43. A method for treating polycystic kidney disease in a patient comprising administering to said patient an effective amount of a compound represented by Structural Formula (XIII):
Figure imgf000119_0002
or a pharmaceutically acceptable salt thereof, wherein:
R1 is a substituted or unsubstituted lower alkyl group; R3 is a substituted or unsubstituted lower alkyl or alkoxy group; R5 is -H or a substituted or unsubstituted lower alkyl or alkoxy group; and
R7 is a halogen, -NH2 or a substituted or unsubstituted lower alkyl or alkoxy group.
44. The method of Claim 43 , wherein: Ri is -CH3, -CH2CH3 or -CH2CH2CH3;
R3 is -O(CH2)2OH or -CH3; R5 is -H, -CH3, -CH2CH3 or -OCH3; and R7 is -F, -Cl, -Br, -CH3 or -OCH3.
45. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by Structural Formula (I):
Figure imgf000120_0001
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is a 5-, 6-, 7- or 8-membered carbocyclic ring optionally substituted at one or more substitutable ring atoms;
Ring B is optionally substituted at one or more substitutable ring carbon atoms;
X is -H, -OR, -SH, -OC(O)R, -OC(O)OR5 -OC(O)NRR or -SC(O)OR;
R1 is -R, -C(O)R or -R5C(O)R; 005/022524
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R2 is hydrogen, a halogen, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, - C(S)SR,
-C(O)NRR, -C(=NR)-NRR or an alkyl, allcenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR,
-C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)- NRR, -NR-C(=NR)-NRR and -NRNRR or R2 and a substitutable ring atom on Ring B, taken together with the carbon atoms between R2 and the substitutable ring atom, form a substituted or unsubstituted non-aromatic carbocyclic ring; each R is independently chosen to be hydrogen or a substituted or unsubstituted alkyl, allcenyl or aryl group, or NRR forms a substituted or unsubstituted non-aromatic heterocyclic ring; and
R' is an alkylene or alkenylene group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, - SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-
NRR and -NRNRR.
46. The pharmaceutical composition of Claim 45, wherein X is -OR, -SH, -OC(O)R5 -OC(O)OR, -OC(O)NRR or -SC(O)OR.
47. The pharmaceutical composition of Claim 45 or 46, wherein Ring A is a substituted or unsubstituted aromatic ring. 005/022524
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48. The pharmaceutical composition of Claim 47, wherein the compound is represented by Structural Formula (II):
Figure imgf000122_0001
or a pharmaceutically acceptable salt thereof, wherein:
Ra and Rb are each independently a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R3 -S(O)R, -S(O)2R5 -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR,
-NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR,
-NR-C(-NR)-NRR and -NRNRR;
R3 is hydrogen, a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS5 -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR5 -C(O)R, -C(S)R, -C(O)OR5 -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R5 -S(O)R5 -S(O)2R5 -SO2NRR5 -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR5 -NR-C(=NR)-NRR and 2005/022524
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-NRNRR, or R2 and R3, taken together with the carbon atoms between R2 and R3, form a substituted or unsubstituted non-aromatic carbocyclic ring; each R is independently chosen to be hydrogen or a substituted or unsubstituted alkyl, alkenyl or aryl group, or NRR forms a substituted or unsubstituted non-aromatic heterocyclic ring; k is O, 1, 2, 3 or 4; and m is 0, 1 or 2.
49. The pharmaceutical composition of Claim 45 or 46, wherein Ring A is a non- aromatic carbocyclic ring.
50. The pharmaceutical composition of Claim 49, wherein the compound is represented by Structural Formula (X):
Figure imgf000123_0001
or a pharmaceutically acceptable salt thereof, wherein: each R0 is independently an unsubstituted alkyl group; each R<j is independently a halogen, -OR, -SR, -C(O)R, -C(S)R,
-C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, 5 022524
123
-OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR; R3 is hydrogen, a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR,
-C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R,
-C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR5 -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR, or R2 and R3, taken together with the carbon atoms between R2 and R3, form a substituted or unsubstituted non-aromatic carbocyclic ring; p is an integer from O to 12; q is O, 1 or 2; and n is 0, 1, 2 or 3.
51. The pharmaceutical composition of Claim 50, wherein the compound is represented by Structural Formula (XI):
Figure imgf000124_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is -H or -R; R5 is hydrogen, a halogen, -OR, -SR, -C(O)R, -C(S)R, 24
124
-C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen,
-OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R1-S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR.
52. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by Structural Formula (III):
Figure imgf000125_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is -H, -C(O)R, -C(O)OR, -C(O)NRR, or substituted or unsubstituted alkyl;
Ri is -R, -C(O)R or -R5C(O)R;
R2 is hydrogen, a halogen, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -C(=NR)-NRR or an alkyl, alkenyl or aiyl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR; 22524
125
R3-R8 are each independently hydrogen, a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR3 -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR, or R2 and R3, taken together with the carbon atoms between R2 and R3, form a substituted or unsubstituted non-aromatic carbocyclic ring; each R is independently hydrogen or a substituted or unsubstituted alkyl, alkenyl or aryl group, or NRR forms a substituted or unsubstituted non- aromatic heterocyclic ring; and
R' is an alkylene or alkenylene group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR,
-NR-C(=NR)-NRR and -NRNRR.
53. The pharmaceutical composition of Claim 52, wherein Y is -H or substituted or unsubstituted alkyl.
54. The pharmaceutical composition of Claim 53, wherein the compound is represented by Structural Formula (IV): T/US2005/022524
126
Figure imgf000127_0001
or a pharmaceutically acceptable salt thereof.
55. The pharmaceutical composition of Claim 54, wherein R3 a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R,
-NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR5 -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R,
-S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR, or R2 and R3, taken together with the carbon atoms between R2 and R3, form a substituted or unsubstituted non-aromatic carbocyclic ring.
56. The pharmaceutical composition of Claim 55, wherein at least one of R6-Rs is a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR,
-C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRE., -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR.
57. A compound represented by Structural Formula (I):
Figure imgf000128_0001
or a salt thereof, wherein:
Ring A is a 5-, 6-, 7- or 8-membered non-aromatic carbocyclic ring optionally substituted at one or more substitutable ring atoms;
Ring B is optionally substituted at one or more substitutable ring carbon atoms;
X is -H, -OR, -SH, -OC(O)R, -OC(O)OR, -OC(O)NRR or -SC(O)OR;
R1 is -R, -C(O)R or -R5C(O)R; R2 is hydrogen, a halogen, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR,
-C(S)SR, -C(O)NRR, -C(=NR)-NRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2,
-C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR or R2 and a substitutable ring atom on Ring B, taken together with the carbon atoms between R2 and the substitutable ring atom, form a substituted or unsubstituted non-aromatic carbocyclic ring; each R is independently chosen to be hydrogen or a substituted or unsubstituted alkyl, alkenyl or aryl group, or NRR forms a substituted or unsubstituted non-aromatic heterocyclic ring; and R' is an alkylene or alkenylene group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR,
-C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR.
58. A compound represented by Structural Formula (X) :
Figure imgf000129_0001
or a salt thereof, wherein:
X is -OR, -SH, -OC(O)R, -OC(O)OR, -OC(O)NRR or -SC(O)OR; Ri is -R, -C(O)R or -R5C(O)R;
R2 is hydrogen, a halogen, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -
C(S)SR,
-C(O)NRR, -C(=NR)-NRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR,
-C(O)NRR, -NRR, -NRC(O)R5 -NRC(O)NRR, -OC(O)R, -SO3R, -
S(O)R,
-S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR,
-NR-C(=NR)-NRR and -NRNRR; R3 is hydrogen, a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR5 22524
129
-C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from 5 the group consisting of a halogen, -OR, -SR, -C(O)R,-C(S)R, -C(O)OR,
-C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR, or R2 and R3, taken together with the carbon atoms between R2 and R3, form a
10 substituted or unsubstituted non-aromatic carbocyclic ring; each R0 is independently an unsubstituted alkyl group; each Rd is independently a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS,
15 -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS,
20 -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR; each R is independently hydrogen or a substituted or unsubstituted alkyl, alkenyl or aryl group, or NRR forms a substituted or unsubstituted non- aromatic heterocyclic ring; and R' is an alkylene or alkenylene group optionally substituted with one or
25 more groups selected from the group consisting of a halogen, -OR, -SR,
-C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR;
30 p is an integer from O to 12; 22524
130
q is O, I, or 2; and n is 0, 1, 2 or 3.
59. The compound of Claim 58, wherein the compound is represented by Structural Formula (XI):
Figure imgf000131_0001
or a salt thereof, wherein:
Y is -H or substituted or unsubstituted alkyl; and
R5 is hydrogen, a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R,
-SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R,
-S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR.
60. The compound of Claim 59, wherein the compound is represented by Structural Formula (XII): 22524
131
Figure imgf000132_0001
or a salt thereof.
61. The compound of Claim 60, wherein: Ri is -H, an unsubstituted lower alkyl group or a halobenzyl group;
R2 is -H or an unsubstituted lower alkyl group; and R3 is -H, an alkoxy-substituted, hydroxy-substituted or carboxy-substituted lower alkyl or alkoxy group or an unsubstituted lower alkyl or alkoxy group.
62. The compound of Claim 61, wherein R5 is hydrogen, a halogen or an unsubstituted lower alkyl or alkoxy group.
63. The compound of Claim 59, wherein the compound is represented by Structural Formula (XIII):
Figure imgf000132_0002
64. The compound of Claim 63, wherein:
Ri is -H, an unsubstituted lower alkyl group or a halobenzyl group; R2 is -H or an unsubstituted lower alkyl group; and R3 is -H, an alkoxy-substituted, hydroxy-substituted or carboxy-substituted lower alkyl or alkoxy group or an unsubstituted lower alkyl or alkoxy group.
65. The compound of Claim 64, wherein R5 is hydrogen, a halogen or an unsubstituted lower alkyl or alkoxy group.
66. The compound of Claim 59, wherein the compoud is represented by a structural formula selected from the group consisting of:
Figure imgf000133_0001
thereof. 005/022524
133
67. The compound of Claim 59, wherein Y is unsubstituted lower allcyl group.
68. A compound represented by Structural Formula (III):
Figure imgf000134_0001
or a salt thereof, wherein:
Y is -H, -C(O)R, -C(O)OR , -C(O)NRR, or substituted or unsubstituted allcyl;
Ri is -R, -C(O)R or -R9C(O)R;
R2 is hydrogen, a halogen, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -C(=NR)-NRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR;
R3 is a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -CC=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, 005/022524
134
-NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR, or R2 and R3, taken together with the carbon atoms between R2 and R3, form a substituted or unsubstituted non-aromatic carbocyclic ring; R4 and R5 are each independently hydrogen, a halogen, -OR, -SR, 5 -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR,
-NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of
10 a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR,
-C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR; R<5-R8 are each independently hydrogen, a halogen, -OR, -SR, -C(O)R,
15 -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R,
-NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R5 -SO2NRR, -NRSO2R5 -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R,
20 -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R,
-NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR, wherein at least one OfR6-R8 has a value other than hydrogen; each R is independently hydrogen or a substituted or unsubstituted alkyl,
25 alkenyl or aryl group, or NRR forms a substituted or unsubstituted non- aromatic heterocyclic ring; and
R' is an alkylene or alkenylene group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR5 -SR5 -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR,
30 -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, 22524
135
-SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR.
69. The compound of Claim 68, wherein Y is -H, or substituted or unsubstituted alkyl.
70. The compound of Claim 69, wherein:
Ri is -H or an unsubstituted lower alkyl group; R2 is -H or an unsubstituted lower alkyl group; R3 is an alkoxy-substituted, hydroxy-substituted or carboxy-substituted lower alkyl or alkoxy group or an unsubstituted lower alkyl or alkoxy group.
71. The compound of Claim 70, wherein the compound is represented by Structural Formula (V):
Figure imgf000136_0001
or a salt thereof, wherein R7 is a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR,
-C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR,
-C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRRrNRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR.
72. The compound of Claim 71 , wherein R7 is a halogen, -NH2 or an unsubstituted lower alkyl or alkoxy group.
73. The compound of Claim 72, wherein R7 is -Cl or -F and R2 is -H.
74. The compound of Claim 70, wherein the compound is represented by Structural Formula (VI):
Figure imgf000137_0001
or a salt thereof, wherein R5 and R7 are each independently a halogen, -OR, -SR,
-C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR.
75. The compound of Claim 74, wherein:
R5 is an unsubstituted lower alkyl or alkoxy group; and
R7 is a halogen, -NH2 or an unsubstituted lower alkyl or alkoxy group. 5 022524
137
76. The compound of Claim 75, wherein R2 is -H; R5 is an unsubstituted lower alkyl group; and R7 is -Cl or -F.
77. The compound of Claim 70, wherein the compound is represented by Structural Formula (VII):
Figure imgf000138_0001
or a salt thereof, wherein R6 and R8 are each independently a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR.
78. The compound of Claim 77, wherein R6 and R8 are each independently a halogen or an unsubstituted lower alkyl or alkoxy group.
79. The compound of Claim 78, wherein:
R6 and R8 are each independently an unsubstituted lower alkoxy group; and R2 is -H. 80. The compound of Claim 70, wherein the compound is represented by Structural Formula (VIII):
Figure imgf000139_0001
or a salt thereof, wherein R6-R8 are each independently a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R,
-NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR5 -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R,
-S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR.
81. The compound of Claim 80, wherein R6 and R8 are each independently a halogen or an unsubstituted lower alkyl or alkoxy group; and R7 is a halogen, -NH2 or an unsubstituted lower alkyl or alkoxy group.
82. The compound of Claim 70, wherein the compound is represented by Structural Formula (IX):
Figure imgf000140_0001
or a salt thereof, wherein R5, Rg and R8 are a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR5 -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR- C(=NR)-NRR and -NRNRR.
83. The compound of Claim 82, wherein R6 and R8 are each independently a halogen or an unsubstituted lower alkyl or alkoxy group.
84. The compound of Claim 83, wherein R5 is an unsubstituted lower alkyl or alkoxy group.
85. The compound of Claim 70, wherein R5-R8 are each independently a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR,
-NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR.
86. The compound of Claim 85, wherein R7 is a halogen, -NH2 or an unsubstituted lower alkyl or alkoxy group.
87. The composition of Claim 86, wherein R5 is an unsubstituted lower alkyl or alkoxy group.
88. The compound of Claim 87, wherein R6 and R8 are each independently a halogen or an unsubstituted lower alkyl or alkoxy group.
89. The compound of Claim 57, wherein the compound is represented by a structural formula selected from the group consisting of:
Figure imgf000141_0001
Figure imgf000142_0001
or a salt thereof.
compound represented by Structural Formula (Ilia):
Figure imgf000142_0002
or a salt thereof, wherein:
Ri is -R, -C(O)R or -R'C(O)R;
R2 is hydrogen, a halogen, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR,
-C(O)NRR, -C(=NR)-NRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR,
-C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R,
-S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR,
-NR-C(=NR)-NRR and -NRNRR;
R3 is a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR,
-C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R,
-SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR5 -NRC(O)R, -NRC(O)NRR, 5 -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS,
-NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR, or R2 and R3, taken together with the carbon atoms between R2 and R3, form a substituted or unsubstituted non-aromatic carbocyclic ring; R4 and R5 are each independently hydrogen, a halogen, -OR, -SR,
10 -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR,
-NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of
15 a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR,
-C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR; R6-R8 are each independently hydrogen, a halogen, -OR, -SR, -C(O)R,
20 -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R,
-NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R, -S(O)2R, -SO2NRR5 -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR, -NRNRR or an alkyl, alkenyl or aryl group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R,
25 -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R,
-NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R5 -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR, wherein at least one of RO-R8 has a value other than hydrogen; each R is independently hydrogen or a substituted or unsubstituted alkyl, alkenyl or aryl group, or NRR forms a substituted or unsubstituted non- aromatic heterocyclic ring; and
R' is an alkylene or allcenylene group optionally substituted with one or more groups selected from the group consisting of a halogen, -OR, -SR, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -C(S)SR, -C(O)NRR, -NRR, -NRC(O)R, -NRC(O)NRR, -OC(O)R, -SO3R, -S(O)R1 -S(O)2R, -SO2NRR, -NRSO2R, -CN, -NCS, -NO2, -C(=NR)-NRR, -NR-C(=NR)-NRR and -NRNRR.
The compound of Claim 90, wherein the compound is represented by a structural formula selected from the group consisting of:
Figure imgf000144_0001
Figure imgf000145_0001
A compound represented by Structural Formula (XIV):
Figure imgf000145_0002
or a salt thereof, wherein:
Ri is a substituted or unsubstituted lower alkyl group;
R3 is a substituted or unsubstituted lower alkyl or alkoxy group;
R5 is -H or a substituted or unsubstituted lower alkyl or alkoxy group; and R7 is a halogen, -NH2 or a substituted or unsubstituted lower alkyl or alkoxy group.
93. The composition of Claim 90, wherein:
Ri is -CH3, -CH2CH3 or -CH2CH2CH3; R3 is -O(CH2)2OH or -CH3; R5 is -H, -CH3, -CH2CH3 or -OCH3; and R7 is -F, -Cl, -Br, -CH3 or -OCH3.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008051502A1 (en) * 2006-10-19 2008-05-02 Genzyme Corporation Purine derivatives for the treatment of cystic diseases
WO2008092352A1 (en) * 2007-01-26 2008-08-07 Institute Of Medicinal Biotechnology, Chinese Academy Of Medical Sciences Antitumor compounds and their preparation method
JP2016515098A (en) * 2013-02-27 2016-05-26 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Carbazole compounds useful as bromodomain inhibitors
CN110003089A (en) * 2019-03-04 2019-07-12 陕西科技大学 A kind of 3- methylol -9- substituted carbazole and preparation method thereof

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WO2008051502A1 (en) * 2006-10-19 2008-05-02 Genzyme Corporation Purine derivatives for the treatment of cystic diseases
EP2617423A1 (en) * 2006-10-19 2013-07-24 Genzyme Corporation Purine derivatives for the treatment of cystic diseases
WO2008092352A1 (en) * 2007-01-26 2008-08-07 Institute Of Medicinal Biotechnology, Chinese Academy Of Medical Sciences Antitumor compounds and their preparation method
JP2016515098A (en) * 2013-02-27 2016-05-26 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Carbazole compounds useful as bromodomain inhibitors
CN110003089A (en) * 2019-03-04 2019-07-12 陕西科技大学 A kind of 3- methylol -9- substituted carbazole and preparation method thereof
CN110003089B (en) * 2019-03-04 2022-07-01 陕西科技大学 3-hydroxymethyl-9-substituted carbazole and preparation method thereof

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