EP1888544A2 - Hydroxysteroid dehydrogenase inhibitors - Google Patents

Hydroxysteroid dehydrogenase inhibitors

Info

Publication number
EP1888544A2
EP1888544A2 EP05854426A EP05854426A EP1888544A2 EP 1888544 A2 EP1888544 A2 EP 1888544A2 EP 05854426 A EP05854426 A EP 05854426A EP 05854426 A EP05854426 A EP 05854426A EP 1888544 A2 EP1888544 A2 EP 1888544A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
hetero
cycloalkyl
heteroaryl
bicycloaryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05854426A
Other languages
German (de)
French (fr)
Inventor
Nancy K. Brennan
Edcon Chang
Stephen W. Kaldor
Andre A. Kiryanov
Andrew J. Jennings
Jeffrey A. Stafford
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda California Inc
Original Assignee
Takeda San Diego Inc
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Filing date
Publication date
Application filed by Takeda San Diego Inc filed Critical Takeda San Diego Inc
Publication of EP1888544A2 publication Critical patent/EP1888544A2/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/50—Nitrogen atoms bound to hetero atoms
    • C07D277/52—Nitrogen atoms bound to hetero atoms to sulfur atoms, e.g. sulfonamides
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to compounds that may be used to inhibit hydroxysteroid dehydrogenases, as well as compositions of matter and kits comprising these compounds.
  • the invention also relates to methods for inhibiting hydroxysteroid dehydrogenases and treatment methods using compounds according to the present invention.
  • the present invention relates to 1 l ⁇ -Hydroxysteroid Dehydrogenase Type 1 inhibitors, compositions of matter and kits comprising these compounds and methods for inhibiting 1 l ⁇ -Hydroxysteroid Dehydrogenase Type 1.
  • the present invention relates to inhibitors of enzymes that catalyse the interconversion of active and inactive glucocorticoids, compositions comprising the inhibitors, kits and articles of manufacture comprising the inhibitors and compositions, methods of making the inhibitors and compositions, and methods of using the inhibitors and compositions.
  • the inhibitors and compositions comprising them are useful for treating or modulating diseases in which enzymes that catalyse the interconversion of glucocorticoids may be involved, symptoms of such diseases, or the effect of other physiological events mediated by these enzymes. Accordingly, the invention also provides for methods of treating diseases in which one or more enzymes that catalyse the interconversion of glucocorticoids is involved.
  • Short-chain dehydrogenases/reductases are a family of reversible NAD(H)/NADP(H) dependent oxidoreductases that interconvert active and inactive glucocorticoids.
  • 11 ⁇ -Hydroxysteroid Dehydrogenase Type 1 (1 Ib-HSDl) belongs to the short-chain dehydrogenase/reductase family of enzymes.
  • 1 Ib- HSDl catalyses the conversion of inactive and active glucocorticoids in a number of tissues and organs including adipose tissue, liver, bone, pancreas, endothelium, ocular tissue, muscle and parts of the central nervous system (Hosfield et al, J. Biol. Chem., in press).
  • 1 Ib-HSDl has been implicated in the metabolic syndrome and type-2 diabetes in a number of studies.
  • the non-specific 1 Ib-HSDl inhibitor carbenoxolone increases insulin sensitivity in healthy, lean, humans as well as those with the symptoms of type-2 diabetes.
  • 1 Ib- HSDl knockout mice have shown resistance to developing obesity -induced, and stress- induced, insulin resistance as well as displaying decreased HDL-cholesterol and VLDL triglycerides.
  • hydroxysteroid dehydrogenases specifically but not limited to 1 l ⁇ - Hydroxysteroid Dehydrogenase Type 1 , are especially attractive targets for the discovery of new therapeutics due to their important role in the metabolic syndrome, Cushing's disease, hypertension, cognitive function, ocular function and other diseases.
  • the present invention relates to compounds that have activity for inhibiting hydroxysteroid dehydrogenases.
  • the present invention also provides compositions, articles of manufacture and kits comprising these compounds.
  • a pharmaceutical composition that comprises a hydroxysteroid dehydrogenase inhibitor according to the present invention as an active ingredient.
  • Pharmaceutical compositions according to the invention may optionally comprise 0.001%- 100% of one or more hydroxysteroid dehydrogenase inhibitors of this invention.
  • compositions may be administered or coadministered by a wide variety of routes, including for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally.
  • routes including for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally.
  • routes including for example, orally, parenterally, intra
  • the invention is also directed to kits and other articles of manufacture for treating disease states associated with hydroxysteroid dehydrogenases.
  • a kit comprising a composition comprising at least one hydroxysteroid dehydrogenase inhibitor of the present invention in combination with instructions.
  • the instructions may indicate the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
  • the kit may also comprise packaging materials.
  • the packaging material may comprise a container for housing the composition.
  • the kit may also optionally comprise additional components, such as syringes for administration of the composition.
  • the kit may comprise the composition in single or multiple dose forms.
  • an article of manufacture comprises a composition comprising at least one hydroxysteroid dehydrogenase inhibitor of the present invention in combination with packaging materials.
  • the packaging material may comprise a container for housing the composition.
  • the container may optionally comprise a label indicating the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
  • the kit may also optionally comprise additional components, such as syringes for administration of the composition.
  • the kit may comprise the composition in single or multiple dose forms.
  • the compounds, compositions, kits and articles of manufacture are used to inhibit hydroxysteroid dehydrogenases.
  • the compounds, compositions, kits and articles of manufacture can be used to inhibit 11- ⁇
  • Hydroxysteroid Dehydrogenase Type 1 the compounds, compositions, kits and articles of manufacture are used to treat a disease state for which hydroxysteroid dehydrogenases possess activity that contributes to the pathology and/or symptomology of the disease state.
  • a compound is administered to a subject wherein hydroxysteroid dehydrogenase activity within the subject is altered, preferably reduced.
  • a prodrug of a compound is administered to a subject that is converted to the compound in vivo where it inhibits hydroxysteroid dehydrogenase.
  • a method of inhibiting hydroxysteroid dehydrogenases comprises contacting a hydroxysteroid dehydrogenase with a compound according to the present invention.
  • a method of inhibiting hydroxysteroid dehydrogenases comprises causing a compound according to the present invention to be present in a subject in order to inhibit hydroxysteroid dehydrogenase in vivo.
  • a method of inhibiting an hydroxysteroid dehydrogenase comprises administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits hydroxysteroid dehydrogenase in vivo. It is noted that the compounds of the present invention may be the first or second compounds.
  • a therapeutic method comprises administering a compound according to the present invention.
  • a method of treating a condition in a patient which is known to be mediated by hydroxysteroid dehydrogenases, or which is known to be treated by hydroxysteroid dehydrogenase inhibitors comprising administering to the patient a therapeutically effective amount of a compound according to the present invention.
  • a method for treating a disease state for which hydroxysteroid dehydrogenases possess activity that contributes to the pathology and/or symptomology of the disease state comprising: causing a compound according to the present invention to be present in a subject in a therapeutically effective amount for the disease state.
  • a method for treating a disease state for which hydroxysteroid dehydrogenases possess activity that contributes to the pathology and/or symptomology of the disease state comprising: administering a first compound to a subject that is converted in vivo to a second compound such that the second compound is present in the subject in a therapeutically effective amount for the disease state.
  • the compounds of the present invention may be the first or second compounds.
  • a method for treating a disease state for which hydroxysteroid dehydrogenases possess activity that contributes to the pathology and/or symptomology of the disease state comprising: administering a compound according to the present invention to a subject such that the compound is present in the subject in a therapeutically effective amount for the disease state.
  • a method is provided for using a compound according to the present invention in order to manufacture a medicament for use in the treatment of a disease state that is known to be mediated by hydroxysteroid dehydrogenases, or that is known to be treated by hydroxysteroid dehydrogenase inhibitors.
  • the present invention is intended to encompass all pharmaceutically acceptable ionized forms (e.g., salts) and solvates (e.g., hydrates) of the compounds, regardless of whether such ionized forms and solvates are specified since it is well know in the art to administer pharmaceutical agents in an ionized or solvated form. It is also noted that unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all possible stereoisomers (e.g., enantiomers or diastereomers depending on the number of chiral centers), independent of whether the compound is present as an individual isomer or a mixture of isomers.
  • pharmaceutically acceptable ionized forms e.g., salts
  • solvates e.g., hydrates
  • prodrugs may also be administered which are altered in vivo and become a compound according to the present invention.
  • the various methods of using the compounds of the present invention are intended, regardless of whether prodrug delivery is specified, to encompass the administration of a prodrug that is converted in vivo to a compound according to the present invention.
  • certain compounds of the present invention may be altered in vivo prior to inhibiting hydroxysteroid dehydrogenases and thus may themselves be prodrugs for another compound.
  • Such prodrugs of another compound may or may not themselves independently have hydroxysteroid dehydrogenase inhibitory activity.
  • Figure 1 illustrates SEQ. ID Nos. 1, 2, 3 and 4 referred to in this application.
  • Alicyclic means a moiety comprising a non-aromatic ring structure. Alicyclic moieties may be saturated or partially unsaturated with one, two or more double or triple bonds. Alicyclic moieties may also optionally comprise heteroatoms such as nitrogen, oxygen and sulfur. The nitrogen atoms can be optionally quateraerized or oxidized and the sulfur atoms can be optionally oxidized.
  • alicyclic moieties include, but are not limited to moieties with C 3-8 rings such as cyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene, cycloheptadiene, cyclooctane, cyclooctene, and cyclooctadiene.
  • C 3-8 rings such as cyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene, cycloheptadiene, cyclooctane, cyclooctene, and cycloo
  • Aliphatic means a moiety characterized by a straight or branched chain arrangement of constituent carbon atoms and may be saturated or partially unsaturated with one, two or more double or triple bonds.
  • Alkoxy means an oxygen moiety having a further alkyl substituent.
  • the alkoxy groups of the present invention can be optionally substituted.
  • Alkyl represented by itself means a straight or branched, saturated or unsaturated, aliphatic radical having a chain of carbon atoms, optionally with oxygen (See “oxaalkyl”) or nitrogen atoms (See “aminoalkyl”) between the carbon atoms.
  • C x alkyl and C ⁇ . ⁇ alkyl are typically used where X and Y indicate the number of carbon atoms in the chain.
  • Ci -6 alkyl includes alkyls that have a chain of between 1 and 6 carbons (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and the like).
  • 1 and 6 carbons e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-
  • Alkyl represented along with another radical means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when no atoms are indicated means a bond (e.g., (C 6- i 0 )aryl(Ci -3 )alkyl includes, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-thienylmethyl, 2-pyridinylmethyl and the like).
  • alkenyl means a straight or branched, carbon chain that contains at least one carbon— carbon double bond.
  • alkenyl examples include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
  • alkynyl means a straight or branched, carbon chain that contains at least one carbon— carbon triple bond. Examples of alkynyl include ethynyl, propargyl, 3-methyl-l- pentynyl, 2-heptynyl and the like.
  • Alkylene unless indicated otherwise, means a straight or branched, saturated or unsaturated, aliphatic, divalent radical. Cx alkylene and C ⁇ . ⁇ alkylene are typically used where X and Y indicate the number of carbon atoms in the chain.
  • Alkylidene means a straight or branched saturated or unsaturated, aliphatic radical connected to the parent molecule by a double bond.
  • Cx alkylidene and C ⁇ . ⁇ alkylidene are typically used where X and Y indicate the number of carbon atoms in the chain.
  • amino means a nitrogen moiety having two further substituents where, for example, a hydrogen or carbon atom is attached to the nitrogen.
  • representative amino groups include -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHCi -10 -alkyl, -N(C 1- I 0 - alkyl) 2) -NHaryl, -NHheteroaryl, -N(aryl) 2 , -N(heteroaryl) 2 , and the like.
  • the two substituents together with the nitrogen may also form a ring.
  • the compounds of the invention containing amino moieties may include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
  • Aminoalkyl means an alkyl, as defined above, except where one or more substituted or unsubstituted nitrogen atoms (-N-) are positioned between carbon atoms of the alkyl.
  • an (C 2-6 ) aminoalkyl refers to a chain comprising between 2 and 6 carbons and one or more nitrogen atoms positioned between the carbon atoms.
  • Animal includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds, and the like).
  • non-human mammals e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like
  • non-mammals e.g., birds, and the like.
  • Aromatic means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp 2 hybridized and the total number of pi electrons is equal to 4n+2.
  • An aromatic ring may be such that the ring atoms are only carbon atoms or may include carbon and non-carbon atoms (see Heteroaryl).
  • Aryl means a monocyclic or polycyclic ring assembly wherein each ring is aromatic or when fused with one or more rings forms an aromatic ring assembly. If one or more ring atoms is not carbon (e.g., N, S), the aryl is a heteroaryl. Cx aryl and C ⁇ . ⁇ aryl are typically used where X and Y indicate the number of atoms in the ring.
  • Bicycloalkyl means a saturated or partially unsaturated fused bicyclic or bridged polycyclic ring assembly.
  • Bicycloaryl means a bicyclic ring assembly wherein the rings are linked by a single bond or fused and at least one of the rings comprising the assembly is aromatic.
  • Cx bicycloaryl and C ⁇ . ⁇ bicycloaryl are typically used where X and Y indicate the number of carbon atoms in the bicyclic ring assembly and directly attached to the ring.
  • “Bridging ring” as used herein refers to a ring that is bonded to another ring to form a compound having a bicyclic structure where two ring atoms that are common to both rings are not directly bound to each other.
  • Non-exclusive examples of common compounds having a bridging ring include borneol, norbornane, 7- oxabicyclo[2.2.1]heptane, and the like.
  • One or both rings of the bicyclic system may also comprise heteroatoms.
  • Carbamoyl means the radical -OC(O)NR 3 Rb where R 3 and R b are each independently two further substituents where a hydrogen or carbon atom is attached to the nitrogen.
  • Carbocycle means a ring consisting of carbon atoms.
  • Carbocyclic ketone derivative means a carbocyclic derivative wherein the ring contains a -CO- moiety.
  • Carbonyl means the radical -CO-. It is noted that the carbonyl radical may be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, aldehydes, amides, esters, and ketones.
  • Carboxy means the radical -CO 2 -. It is noted that compounds of the invention containing carboxy moieties may include protected derivatives thereof, i.e., where the oxygen is substituted with a protecting group. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like.
  • Cyano means the radical -CN.
  • Cycloalkyl means a non-aromatic, saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly.
  • Cx cycloalkyl and C ⁇ . ⁇ cycloalkyl are typically used where X and Y indicate the number of carbon atoms in the ring assembly.
  • C 3-I0 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl,
  • Cycloalkylene means a divalent saturated or partially unsaturated, monocyclic or polycyclic ring assembly. Cx cycloalkylene and C ⁇ . ⁇ cycloalkylene are typically used where X and Y indicate the number of carbon atoms in the ring assembly.
  • Disease specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the "side effects" of such therapy.
  • fused ring refers to a ring that is bonded to another ring to form a compound having a bicyclic structure when the ring atoms that are common to both rings are directly bound to each other.
  • Non-exclusive examples of common fused rings include decalin, naphthalene, anthracene, phenanthrene, indole, furan, benzofuran, quinoline, and the like.
  • Compounds having fused ring systems may be saturated, partially saturated, carbocyclics, heterocyclics, aromatics, heteroaromatics, and the like.
  • Halo means fluoro, chloro, bromo or iodo.
  • Halo-substituted alkyl as an isolated group or part of a larger group, means
  • alkyl substituted by one or more "halo" atoms, as such terms are defined in this
  • Halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g. halo-substituted (Ci. 3 )alkyl includes chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl,
  • Heteroatom refers to an atom that is not a carbon atom. Particular examples of heteroatoms include, but are not limited to nitrogen, oxygen, and sulfur.
  • Heteroatom moiety includes a moiety where the atom by which the moiety is attached is not a carbon.
  • Heterobicycloalkyl means bicycloalkyl, as defined in this Application, provided that one or more of the atoms within the ring is a heteroatom.
  • hetero(C 9 -i 2 )bicycloalkyl as used in this application includes, but is not limited to, 3-aza- bicyclo[4.1.0]hept-3-yl, 2-aza-bicyclo[3.1.0]hex-2-yl , 3-aza-bicyclo[3.1.0]hex-3-yl, and the like.
  • Heterocycloalkylene means cycloalkylene, as defined in this Application, provided that one or more of the ring member carbon atoms is replaced by a heteroatom.
  • Heteroaryl means a cyclic aromatic group having five or six ring atoms, wherein at least one ring atom is a heteroatom and the remaining ring atoms are carbon.
  • heteroaryl groups of this invention include, but are not limited to, those derived from furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrroline, thiazole, 1,3,4-thiadiazole, triazole and tetrazole.
  • Heteroaryl also includes, but is not limited to, bicyclic or tricyclic rings, wherein the heteroaryl ring is fused to one or two rings independently selected from the group consisting of an aryl ring, a cycloalkyl ring, a cycloalkenyl ring, and another monocyclic heteroaryl or heterocycloalkyl ring.
  • bicyclic or tricyclic heteroaryls include, but are not limited to, those derived from benzo[b]furan, benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridine, quinazoline, thieno[2,3-c]pyridine, thieno[3,2- b]pyridine, thieno[2,3-b]pyridine, indolizine, imidazo[l,2a]pyridine, quinoline, isoquinoline, phthalazine, quinoxaline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, imidazo[l,5-a]pyridine, pyrazolo[ 1 ,5-a]pyridine, imidazo[ 1 ,2-a]pyrimidine, imidazo[ 1 ,2-c]pyrimidine, imidazo[
  • the bicyclic or tricyclic heteroaryl rings can be attached to the parent molecule through either the heteroaryl group itself or the aryl, cycloalkyl, cycloalkenyl or heterocycloalkyl group to which it is fused.
  • the heteroaryl groups of this invention can be substituted or unsubstituted.
  • Heterobicycloaryl means bicycloaryl, as defined in this Application, provided that one or more of the atoms within the ring is a heteroatom.
  • hetero(C4_i 2 )bicycloaryl as used in this Application includes, but is not limited to, 2-amino-4-oxo-3,4-dihydropteridin-6-yl, tetrahydroisoquinolinyl, and the like.
  • Heterocycloalkyl means cycloalkyl, as defined in this Application, provided that one or more of the atoms forming the ring is a heteroatom selected, independently from N, O, or S.
  • heterocycloalkyl examples include piperidyl, 4- morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolizinyl, 1,4-diazaperhydroepinyl, 1,3-dioxanyl, 1,4-dioxanyl and the like.
  • "Hydroxy” means the radical -OH.
  • Iminoketone derivative means a derivative comprising the moiety -C(NR)-, wherein R comprises a hydrogen or carbon atom attached to the nitrogen.
  • “Isomers” mean any compound having an identical molecular formulae but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space.
  • stereoisomers that differ in the arrangement of their atoms in space are termed “stereoisomers.”
  • Stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimposable mirror images are termed “enantiomers” or sometimes "optical isomers.”
  • a carbon atom bonded to four nonidentical substituents is termed a “chiral center.”
  • a compound with one chiral center has two enantiomeric forms of opposite chirality.
  • a mixture of the two enantiomeric forms is termed a “racemic mixture.”
  • a compound that has more than one chiral center has 2" "1 enantiomeric pairs, where n is the number of chiral centers.
  • Compounds with more than one chiral center may exist as ether an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture.”
  • a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
  • Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and 5-sequencing rules of Cahn, Ingold and Prelog.
  • Niro means the radical -NO 2 .
  • Oxaalkyl means an alkyl, as defined above, except where one or more oxygen atoms (-O-) are positioned between carbon atoms of the alkyl.
  • an (C 2- 6 )oxaalkyl refers to a chain comprising between 2 and 6 carbons and one or more oxygen atoms positioned between the carbon atoms.
  • Oxoalkyl means an alkyl, further substituted with a carbonyl group.
  • the carbonyl group may be an aldehyde, ketone, ester, amide, acid or acid chloride.
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” means salts of inhibitors of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity.
  • Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, ⁇ -(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, /7-tolu
  • Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.
  • Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide.
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
  • Prodrug means a compound that is convertible in vivo metabolically into an inhibitor according to the present invention.
  • the prodrug itself may or may not also have hydroxysteroid dehydrogenase inhibitory activity.
  • an inhibitor comprising a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy compound.
  • Suitable esters that may be converted in vivo into hydroxy compounds include acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates, esters of amino acids, and the like.
  • an inhibitor comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine compound.
  • Protected derivatives means derivatives of inhibitors in which a reactive site or sites are blocked with protecting groups. Protected derivatives are useful in the preparation of inhibitors or in themselves may be active as inhibitors. A comprehensive list of suitable protecting groups can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.
  • “Ring” means a carbocyclic or a heterocyclic system.
  • Substituted or unsubstituted means that a given moiety may consist of only hydrogen substituents through available valencies (unsubstituted) or may further comprise one or more non-hydrogen substituents through available valencies (substituted) that are not otherwise specified by the name of the given moiety.
  • isopropyl is an example of an ethylene moiety that is substituted by -CH 3 .
  • a non-hydrogen substituent may be any substituent that may be bound to an atom of the given moiety that is specified to be substituted.
  • substituents include, but are not limited to, aldehyde, alicyclic, aliphatic, (Ci -I o)alkyl, alkylene, alkylidene, amide, amino, aminoalkyl, aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl, carbocyclyl, carboxyl, carbonyl group, cycloalkyl, cycloalkylene, ester, halo, heterobicycloalkyl, heterocycloalkylene, heteroaryl, heterobicycloaryl, heterocycloalkyl, oxo, hydroxy, iminoketone, ketone, nitro, oxaalkyl, and oxoalkyl moieties, each of which may optionally also be substituted or unsubstituted.
  • Sulfinyl means the radical -SO-. It is noted that the sulfinyl radical may be further substituted with a variety of substituents to form different sulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters, and sulfoxides.
  • “Sulfonyl” means the radical -SO 2 -. It is noted that the sulfonyl radical may be further substituted with a variety of substituents to form different sulfonyl groups including sulfonic acids, sulfonamides, sulfonate esters, and sulfones. [0080] “Therapeutically effective amount” means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease. [0081] "Thiocarbonyl” means the radical -CS-.
  • thiocarbonyl radical may be further substituted with a variety of substituents to form different thiocarbonyl groups including thioacids, thioamides, thioesters, and thioketones.
  • "Treatment” or “treating” means any administration of a compound of the present invention and includes:
  • Ci alkyl indicates that there is one carbon atom but does not indicate what are the substituents on the carbon atom.
  • a Ci alkyl comprises methyl (i.e., -CH 3 ) as well as -CR 3 RbRc where R a , R b , and R c may each independently be hydrogen or any other substituent where the atom attached to the carbon is a heteroatom or cyano.
  • CF 3 , CH 2 OH and CH 2 CN for example, are all Ci alkyls.
  • the present invention relates to compounds, compositions, kits and articles of manufacture that may be used to inhibit hydroxysteroid dehydrogenases and, in particular, l l ⁇ -hydroxysteroid dehydrogenase type 1 (referred to herein as 1 Ib-HSDl).
  • 1 Ib-HSDl belongs to the short-chain dehydrogenase/reductase (SDR) family of enzymes, of which over 60 members are found in humans (Oppermann et al., Chem Biol Interact, 143-144, 247-253 (2003); Kallberg et ai, Protein Sci, 11, 636-641 (2002)).
  • SDR short-chain dehydrogenase/reductase
  • SDRs are reversible NAD(H)/NADP(H) dependent oxidoreductases containing a structurally conserved ⁇ / ⁇ nucleotide-binding Rossman fold. Within the core structure, two conserved motifs are shared among all SDR enzymes. A dinucleotide-binding P-loop forms a turn between a ⁇ -strand and an ⁇ -helix and directly contacts the ribose sugar and pyrophosphate. A Tyr-X-X-X-Lys motif, often in concert with a conserved Ser that orients substrate, catalyzes proton transfer to and from reduced and oxidized reaction intermediates. A flexible region in SDR enzymes, that often changes conformation upon substrate binding to shield the active site from bulk solvent, mediates enzyme specificity.
  • Ib-HSDl is a NADPH-dependent enzyme that functions predominantly as a reductase in vivo.
  • a single N-terminal transmembrane helix and associated linker anchors the C-terminal catalytic domain within the lumen of the endoplasmic reticulum
  • Ib-HSDl is important in regulating local concentrations of glucocorticoids in various tissue types, for example, adipose, vascular, brain, testis, ocular and placental.
  • Cushing's disease hypertension, cognitive function, and ocular function.
  • the compounds of the present invention may also possess inhibitory activity for other short chain dehydrogenase family members and thus may be used to address disease states associated with these other family members.
  • a conformationally-variable ⁇ 6- ⁇ 6 insertion that forms one wall of the steroid binding pocket, an additional ⁇ -strand ( ⁇ 7) and two Cterminal ⁇ -helices ( ⁇ E and ⁇ F) are appended to the core structure and complete the 1 Ib-HSDl fold.
  • NADP+ binding to 1 Ib-HSDl is similar to other SDR enzymes, with the molecule binding in an extended conformation in which both ribose sugars adopt a C2- endo conformation.
  • the adenine and nicotinamide rings are both well ordered and bind roughly perpendicular to the plane of the ribose sugars with the adenine adopting an anti configuration and the nicotinamide adopting a syn configuration.
  • the adenosine moiety lies in a cleft formed by 4 loops ( ⁇ l/ ⁇ l, ⁇ 2/ ⁇ 2, ⁇ 3/ ⁇ 3, and ⁇ 4/ ⁇ 4) and an ⁇ -helix ( ⁇ 4).
  • hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
  • J is selected from the group consisting of CR 6 and N, with the proviso that J is CR 6 and R 6 is absent when J forms part of a double bond;
  • K is selected from the group consisting of CR 6 and N, with the proviso that K is CR 6 and R 6 is absent when K forms part of a double bond;
  • L is selected from the group consisting of CR 6 and N, with the proviso that L is CR 6 and R 6 is absent when L forms part of a double bond;
  • M is selected from the group consisting of S, O and NR ⁇ ;
  • Ri is selected from the group consisting of (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 .i 2 )bicycloalkyl, hetero(C 3 .i 2 )bicycloalkyl, aryl, heteroaryl, (C 9 _i 2 )bicycloaryl, hetero(C 4- i 2 )bicycloaryl, each substituted or unsubstituted;
  • R 2 is selected from the group consisting of
  • R 3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci -I o)alkyl, (C 3 _i 2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (Cg-i ⁇ bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(C 1-1 o)alkyl, heteroaryl(Ci -5 )alkyl, (C 3- i 2 )cycloalkyl(C M0 )alkyl, halo(C 1-10 )alkyl, carbonyl(C 1-3 )alkyl, thiocarbonyl(C ]-3 )alkyl, sulfonyl(Ci -3 )alkyl, sulfinyl(C 1-3 )alkyl, imino(C
  • R 4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-1 o)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3 . 12 )cycloalkyl, (C 9 _i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(C 1- io)alkyl, heteroaryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl(C x .
  • R 5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, hetero(C 3 .i 2 )bicycloalkyl, aryl(Ci.
  • R 6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci -I o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9- i 2 )bicycloalkyl, hetero(C 3 .
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1 .io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci -I o)alkyl, (C 3-)2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9 _i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C 1 .
  • R 9 , Ri 0 , Rn and R 12 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C].io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-1 o)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(C 1-1 o)alkyl, heteroaryl(Ci -5 )alkyl, perhalo(Ci.io)alkyl, (C 3 -i 2 )cycloalkyl(C 1- io)alkyl, halo(Ci.i 0 )alkyl, carbonyl
  • Ri 5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (Cg.i ⁇ bicycloalkyl, hetero(C 3 .i 2 )bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci -5 )alkyl, (C 3- i 2 )cycloalkyl(Ci-io)alkyl, halo(C 1-K) )alkyl, carbonyl(Ci_ 3 )alkyl, thiocarbonyl(Ci -3 )alkyl, sulfonyl(Ci.
  • X is selected from the group consisting of unsubstituted and substituted Ci _ 6 alkylenes
  • Y is selected from the group consisting of (C 3 .i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 -i 2 )bicycloalkyl, hetero(C 3 .i 2 )bicycloalkyl, aryl, heteroaryl, (C 9 .i 2 )bicycloaryl, and hetero(C 4- i 2 )bicycloaryl, each substituted or unsubstituted.
  • hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
  • n is selected from the group consisting of 0, 1, 2,3, 4 and 5;
  • J is selected from the group consisting of CR 6 and N, with the proviso that J is CR 6 and R 6 is absent when J forms part of a double bond;
  • K is selected from the group consisting of CR 6 and N, with the proviso that K is CR 6 and R 6 is absent when K forms part of a double bond;
  • L is selected from the group consisting of CR 6 and N, with the proviso that L is CR 6 and R 6 is absent when L forms part of a double bond;
  • M is selected from the group consisting of S, O and NRi 5 ;
  • R 2 is selected from the group consisting of
  • R 3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 _i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci_ 5 )alkyl, (C 3- i 2 )cycloalkyl(Ci_io)alkyl, halo(Ci-io)alkyl, carbonyl(C 1-3 )alkyl, thiocarbonyl(Ci -3 )alkyl, sulfonyl(Ci.
  • R 4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3 .i 2 )cycloalkyl, (C 9 _i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci -1 o)alkyl, heteroaryl(C 1-5 )alkyl, (C 3- 12 )cycloalkyl(C i .1 0 )alkyl, halo(C i .
  • R 5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci_ 1 o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3 .i 2 )cycloalkyl, hetero(C 3 .
  • R 6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci -I o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-1 o)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (Cg.i ⁇ bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(C 1-1 o)alkyl, heteroaryl(C 1 - 5 )alkyl, perhalo(C 1-1 o)alkyl, (C 3-12 )cycloalkyl(Ci -1 o)alkyl, halo(C 1-1 o)alkyl, carbonyl(C 1-3 )alkyl, thiocarbon
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci -I o)alkyl, (C 3 .i 2 )cycloalkyl, hetero(C 3 -i 2 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C3.i 2 )bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci.).
  • R 9 , Rio, Rn and Ri 2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- ] 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci- 5 )alkyl, perhalo(Ci-io)alkyl, (C 3- i 2 )cycloalkyl(Ci-io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci -3 )alkyl, thiocarbonyl(
  • Ri 3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci_io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, hetero(C 3-]2 )bicycloalkyl, aryl(Ci.i O )alkyl, heteroaryl(Ci- 5 )alkyl, perhalo(Ci_io)alkyl, (C 3- i 2 )cycloalkyl(Ci_io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci -3 )alkyl, thiocarbonyl(Ci -3 )alkyl, sulfonyl(Ci -3 )alkyl, sulfinyl(C
  • each Ri 4 is independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3 _i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (Cg.i ⁇ bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci-io)al
  • i o)alkyl halo(C ⁇ . io)alkyl, carbonyl(Ci -3 )alkyl, thiocarbonyl(Ci -3 )alkyl, sulfonyl(Ci. 3 )alkyl, sulfinyl(Ci -3 )alkyl, imino(Ci -3 )alkyl, aryl, heteroaryl, (C 9-12 )bicycloaryl, and hetero(C 4- i 2 )bicycloaryl, each substituted or unsubstituted;
  • X is selected from the group consisting of unsubstituted and substituted C 1-6 alkylenes
  • Y is selected from the group consisting of (C 3 . 12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (Cc 1-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl, heteroaryl, (Cc) -12 )bicycloaryl, and hetero(C 4- i 2 )bicycloaryl, each substituted or unsubstituted.
  • hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
  • J is selected from the group consisting of CR 6 and N, with the proviso that J is CR 6 and R 6 is absent when J forms part of a double bond;
  • K is selected from the group consisting of CR 6 and N, with the proviso that K is CR 6 and R 6 is absent when K forms part of a double bond;
  • L is selected from the group consisting of CR 6 and N, with the proviso that L is CR 6 and R 6 is absent when L forms part of a double bond; M is selected from the group consisting of S, O and NRi 5 ; R 2 is selected from the group consisting of
  • R 3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-1 o)alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9 .i 2 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(C 1- io)alkyl, heteroaryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl(C 1- io)alkyl, halo(Ci.io)alkyl, carbonyl(C 1-3 )alkyl, thiocarbonyl(Ci.
  • R 4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3 .i 2 )cycloalkyl, hetero(C 3 -i 2 )bicycloalkyl, aryl(Ci -10 )alkyl, heteroaryl(Ci_ 5 )alkyl, (C 3-12 )cycloalkyl(Ci -10 )alkyl, halo(C, -1 o)alkyl, carbonyl(C 1-3 )alkyl, thiocarbonyl(C 1-3 )alkyl, sulfonyl(C 1-3 )alkyl, sulfinyl(C 1-3 )al
  • R 5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci -I o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3 _i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9- i 2 )bicycloalkyl, hetero(C 3 .i 2 )bicycloalkyl, aryl(C M0 )alkyl, heteroaryl(C i -5 )alkyl, perhalo(C i .
  • R 6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3- ] 2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(Ci_io)alkyl, heteroaryl(Ci.
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci -10 )alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3 .
  • R 9 , R 10 , Rn and Rj 2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 _i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(C 1-1 o)alkyl, heteroaryl(Ci- 5 )alkyl, perhalo(Ci.io)alkyl, (C 3-12 )cycloalkyl(Ci.io)alkyl, halo(Ci_io)alkyl, carbonyl(
  • Ri 3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci -I o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1 .io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9- i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci_ 10 )alkyl, heteroaryl(Ci- 5 )alkyl, perhalo(Ci -10 )alkyl, (C 3 .
  • Ri 5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, hetero(C 3 .i 2 )bicycloalkyl, aryl(C 1 - 10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 3- i 2 )cycloalkyl(C 1- io)alkyl, halo(Ci.io)alkyl, carbonyl(Ci -3 )alkyl, thiocarbonyl(Ci.
  • X is selected from the group consisting of unsubstituted and substituted C 1-6 alkylenes
  • Y is selected from the group consisting of (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (Cg.i ⁇ bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl, heteroaryl, (C 9 .i 2 )bicycloaryl, and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted.
  • hydroxysteroid dehydrogenase inhibitors of the present invention comprise: wherein:
  • R 2 is selected from the group consisting of
  • R 3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-1O )HIlCyI, (C 3-12 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 -i 2 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(C 1- io)alkyl, heteroaryl(C 1 .
  • R 5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci -I o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3 .i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (Cg-i ⁇ bicycloalkyl, hetero(C 3-]2 )bicycloalkyl, aryl(C 1- io)alkyl, heteroaryl(C i .
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci- ⁇ o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3 .i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 .i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(C 1-10 )alkyl, heteroaryl(Ci.
  • R 9 , Rio, Rn and R 12 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9 -i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci_ 1 o)alkyl, heteroaryl(Ci_ 5 )alkyl, perhalo(Ci.io)alkyl, (C 3- i 2 )cycloalkyl(Ci.
  • R 13 is selected from the group consisting of hydrogen, carbonyl, amino, (C 1 . 1 o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1- io)alkyl, (C 3 .i 2 )cycloalkyl, hetero(C 3 _i 2 )cycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci.
  • Y is selected from the group consisting of (C 3-12 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3 _i 2 )bicycloalkyl, aryl, heteroaryl, (C 9-12 )bicycloaryl, and hetero(C 4- i 2 )bicycloaryl, each substituted or unsubstituted.
  • hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
  • R 2 is selected from the group consisting of
  • R. 5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-1 o)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 .i 2 )bicycloalkyl, hetero(C 3 .
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3 .
  • Rc 1 , R 1O , Rn and Ri 2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3 -i 2 )cycloalkyl, hetero(C 3 .i 2 )cycloalkyl, hetero(C 3 .i 2 )bicycloalkyl, aryl(Ci -1 o)alkyl, heteroaryl(Ci_ 5 )alkyl, perhalo(Ci_io)alkyl, (C 3 _i 2 )cycloalkyl(C i _i o)alkyl, halo(C M o)alkyl, carbonyl(C i
  • hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
  • R 2 is selected from the group consisting of
  • R 5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-1 o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci -I o)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3 _i 2 )cycloalkyl, (C 9 _i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(C 1-1 o)alkyl, heteroaryl(C 1-5 )alkyl, perhalo(Ci_io)alkyl, (C 3- i 2 )cycloalkyl(Ci-i 0 )alkyl, halo(C 1-1 o)alkyl, carbonyl(Ci -3 )
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C 1-5 )alkyl, perhalo(Ci -10 )alkyl, (C 3- ] 2 )cycloalkyl(C , _i 0 )alkyl, halo(C i .
  • R 9 , Rio, Rn and Ri 2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 _i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci-i 0 )alkyl, heteroaryl(Ci -5 )alkyl, perhalo(Ci.io)alkyl, (C 3- 12 )cycloalkyl(C 1-10 )alkyl, halo(C i .
  • hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
  • Ri is selected from the group consisting of (C 1 - I o)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3 -i 2 )cycloalkyl, (Cg.i ⁇ bicycloalkyl, hetero(C 3 - 12 )bicycloalkyl, aryl, heteroaryl, (C 9 .i 2 )bicycloaryl, hetero(C 4- i 2 )bicycloaryl, each substituted or unsubstituted;
  • R 2 is selected from the group consisting of
  • R 3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9- i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(C 1-10 )alkyl, heteroaryl(Ci.
  • R. 5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3 .i 2 )cycloalkyl, hetero(C 3 .
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1- io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3 . 12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3 .
  • R 9 , Rio, Rn and Rj 2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3 _i 2 )cycloalkyl, (C 9 _i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C].
  • Ri 3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci -]0 )alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 _i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(C 1-10 )alkyl, heteroaryl(Ci -5 )alkyl, perhalo(Ci_io)alkyl, (C 3 -i2)cycloalkyl(Ci.io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci.
  • X is selected from the group consisting of unsubstituted and substituted C 1-6 alkylenes
  • Y is selected from the group consisting of (C 3-12 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 -i 2 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl, heteroaryl, (C 9-12 )bicycloaryl, and hetero(C 4 -i 2 )bicycloaryl, each substituted or unsubstituted.
  • hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
  • Ri is selected from the group consisting of (C 1 .io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl, heteroaryl, (C 9 -i 2 )bicycloaryl, hetero(C 4 . ]2 )bicycloaryl, each substituted or unsubstituted;
  • R 2 is selected from the group consisting of
  • R 5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-1 o)alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(C 1 . 1 o)alkyl, heteroaryl(C ] ⁇ alkyl, perhalo(C ] .
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-1 o)alkyl, (C 3-12 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (Cg.i ⁇ bicycloalkyl, hetero(C 3 .i 2 )bicycloalkyl, aryl(C 1-1 o)alkyl, heteroaryl(C 1-5 )alkyl, perhalo(C 1- io)alkyl, (C 3 .
  • R 9 , R 1O , Rn and R 12 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1- io)alkyl, (C 3 .i 2 )cycloalkyl, hetero(C 3 .i 2 )cycloalkyl, (Cg.i ⁇ bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci_ 5 )alkyl, perhalo(Ci.io)alkyl, (C 3 -i 2 )cycloalkyl(Ci -10 )alkyl ) halo(C 1-10 )alkyl,
  • hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
  • Ri is selected from the group consisting of (Ci.io)alkyl, (C 3 -i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl, heteroaryl, (C 9 _i 2 )bicycloaryl, hetero(C 4- i 2 )bicycloaryl, each substituted or unsubstituted;
  • R 2 is selected from the group consisting of
  • R 5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.i O )alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3 .i 2 )cycloalkyl, (C 9 .i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(C 1.s)alkyl, perhalo(C 1 .
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-i 0 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3 .
  • R 9 , R 10 , Rn and Ri 2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3 _i 2 )cycloalkyl, (C 9 .i 2 )bicycloalkyl, hetero(C 3 .i 2 )bicycloalkyl, aryl(Ci.i O )alkyl, heteroaryl (C i -5 )alkyl, perhalo(Ci-io)alkyl, (C 3 .
  • hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
  • J is selected from the group consisting of CR 6 and N, with the proviso that J is CR 6 and R 6 is absent when J forms part of a double bond;
  • K is selected from the group consisting of CR 6 and N, with the proviso that K is CR 6 and R 6 is absent when K forms part of a double bond;
  • L is selected from the group consisting of CR 6 and N, with the proviso that L is CR 6 and R 6 is absent when L forms part of a double bond;
  • M is selected from the group consisting of S, O and NR 1S ;
  • R 1 is selected from the group consisting of (C]_io)alkyl, (C 3 -] 2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (Cg. ⁇ bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl, heteroaryl, (C 9-12 )bicycloaryl, hetero(C 4- ] 2 )bicycloaryl, each substituted or unsubstituted;
  • R 3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3 . 12 )cycloalkyl, (C 9 . ]2 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(C 1-1 o)alkyl, heteroaryl(C 1 .
  • R 4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3 .i 2 )cycloalkyl, hetero(C 3 .
  • R 5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(C 1-10 )alkyl, heteroaryl(C i - 5 )alkyl, perhalo(C y .
  • R 6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci -I o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci -5 )alkyl, perhalo(C 1-1 o)alkyl, (C 3-12 )cycloalkyl(C 1- io)alkyl, halo(C 1-10 )alkyl, carbonyl(Ci_ 3 )alkyl, thiocarbonyl
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Q. ⁇ alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-1 o)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 _i 2 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(C 1-5 )alkyl, perhalo(Ci -1 o)alkyl, (C 3- i 2 )cycloalkyl(C 1-10 )alkyl, halo(Ci -10 )alkyl, carbonyl(Ci -3 )alkyl,
  • Ri 3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3 .i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 -i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(C].io)alkyl, heteroaryl(Ci -5 )alkyl, perhalo(Ci-io)alkyl, (C 3-12 )cycloalkyl(Ci.io)alkyl, halo(C].io)alkyl, carbonyl(Ci_ 3 )alkyl, thiocarbonyl(Ci -3 )alkyl, sulfonyl(Ci.
  • R 15 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 )SIlCyI, (C 3- i 2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9- i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci -10 )alkyl, heteroaryl(Ci -10 )alkyl, heteroaryl(Ci -10 )alkyl(
  • hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
  • J is selected from the group consisting of CR 6 and N, with the proviso that J is CR 6 and R 6 is absent when J forms part of a double bond;
  • K is selected from the group consisting of CR 6 and N, with the proviso that K is CR 6 and R 6 is absent when K forms part of a double bond;
  • L is selected from the group consisting of CR 6 and N, with the proviso that L is CR 6 and R 6 is absent when L forms part of a double bond;
  • M is selected from the group consisting of S, O and NR 1S ;
  • Ri is selected from the group consisting of (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 -i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl, heteroaryl, (C 9 -i 2 )bicycloaryl, hetero(C 4 .i 2 )bicycloaryl, each substituted or unsubstituted;
  • R 3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (d.io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 .
  • R 4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1 _i 0 )alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9- i 2 )bicycloalkyl, hetero(C 3 .
  • R 5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci -I o)alkyl, (C 3-12 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(Ci_ ⁇ o)alkyl, heteroaryl(C]- 5 )alkyl, perhalo(Ci -1 o)alkyl, (C 3-12 )cycloalkyl(C 1- io)alkyl, halo(Ci_io)alkyl, carbonyl(C 1-3 )alkyl, thiocarbonyl(
  • R 6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-1 o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(Ci.
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1 . 10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 )alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9- i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(C 1- io)alkyl, heteroaryl(Ci -5 )alkyl, perhalo(Ci-io)alkyl, (C 3-12 )cycloalkyl(C 1-10 )alkyl, halo(Ci -10 )alkyl, carbonyl(Ci -3 )alkyl,
  • R 13 is selected from the group consisting of hydrogen, carbonyl, amino, (C 1 - I o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci -I o)alkyl, (C 3 . 12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(C 1-5 )alkyl, perhalo(Ci -1 o)alkyl, (C 3 - 12 )cycloalkyl(C 1 .
  • R 15 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1- io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3- ⁇ 2 )bicycloalkyl, aryl(Ci -1 o)alkyl, heteroaryl(Ci -5 )alkyl, (C 3-12 )cycloalkyl(C 1-10 )alkyl, halo(C 1-10 )alkyl, carbonyl(Ci- 3 )alkyl, thiocarbonyl(Ci -3 )alkyl, sulfonyl(C 1-3 )alkyl, sulfinyl(Ci -3 )alkyl, imino(Ci. 3
  • hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
  • J is selected from the group consisting of CR 6 and N, with the proviso that J is CR 6 and R 6 is absent when J forms part of a double bond;
  • K is selected from the group consisting of CR 6 and N, with the proviso that K is CR 6 and R 6 is absent when K forms part of a double bond;
  • L is selected from the group consisting of CR 6 and N, with the proviso that L is CR 6 and R 6 is absent when L forms part of a double bond;
  • M is selected from the group consisting of S, O and NRi 5 ;
  • Ri is selected from the group consisting of (Ci.io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3 _i 2 )cycloalkyl, (C 9 _i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl, heteroaryl, (C 9 _ 12 )bicycloaryl, hetero(C 4 .i 2 )bicycloaryl, each substituted or unsubstituted;
  • R 3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1- io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-)2 )bicycloalkyl, hetero(C 3 .i 2 )bicycloalkyl, aryl(C].io)alkyl, heteroaryl(C 1 . 5 )alkyl, (C 3- i 2 )cycloalkyl(C 1-1 o)alkyl, halo(C 1 .
  • R 4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-1 o)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(Ci_io)alkyl, heteroaryl(Ci -5 )alkyl, (C 3-12 )cycloalkyl(C 1-10 )alkyl, halo(Ci -10 )alkyl, carbonyl(Ci -3 )alkyl, thiocarbonyl(Ci -3 )alkyl, sulfonyl(Ci- 3 )alkyl, sulfinyl(Ci -3 )alkyl
  • R 5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(d -10 )alkyl, heteroaryl(C i - 5 )alkyl, perhalo(C i -10 )alkyl, (C 3 .
  • R 6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci -I o)alkyl, (C 3 .i 2 )cycloalkyl, hetero(C 3 .i 2 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(Ci -1 o)alkyl, heteroaryl(Ci- 5 )alkyl, perhalo(C 1-10 )alkyl, (C 3-12 )cycloalkyl(C 1 .
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci_ 5 )alkyl, perhalo(C 1- io)alkyl, (C 3-12 )cycloalkyl(C 1-10 )alkyl, halo(Ci.
  • R 9 and Rio are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3 .i 2 )cycloalkyl, (C 9 _i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci -5 )alkyl, perhalo(Ci.io)alkyl, (C 3- 12 )cycloalkyl(C i .
  • Ri 3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci- 10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 .
  • R 15 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(Ci -10 )alkyl, heteroaryl(C ⁇ -5 )alkyl, (C 3 . 12 )cycloalkyl(C ⁇ . 1 o)alkyl, halo(C i. 10 )alkyl, carbonyl(Ci.
  • hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
  • J is selected from the group consisting of CR 6 and N, with the proviso that J is CR 6 and R 6 is absent when J forms part of a double bond
  • K is selected from the group consisting of CR 6 and N, with the proviso that K is CR 6 and R 6 is absent when K forms part of a double bond
  • L is selected from the group consisting of CR 6 and N, with the proviso that L is CR 6 and R 6 is absent when L forms part of a double bond;
  • M is selected from the group consisting of S, O and NRi 5 ;
  • Ri is selected from the group consisting of (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3 .i 2 )cycloalkyl, (C 9 .i 2 )bicycloalkyl, hetero(C 3 .i 2 )bicycloalkyl, aryl, heteroaryl, hetero(C 4- i 2 )bicycloaryl, each substituted or unsubstituted;
  • R 3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (Cg.i ⁇ bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci -5 )alkyl, (C 3- i 2 )cycloalkyl(Ci.io)alkyl, halo(Ci.i 0 )alkyl, carbonyl(Ci -3 )alkyl, thiocarbonyl(Ci -3 )alkyl, sulfonyl(Ci -3 )alkyl, sulfinyl(Ci -3 )alkyl, imino(
  • R 4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (Cg.i ⁇ bicycloalkyl, hetero(C 3 -i 2 )bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci- 5 )alkyl, (C 3- i 2 )cycloalkyl(Ci.io)alkyl, halo(Ci.io)alkyl, carbonyl(Ci -3 )alkyl, thiocarbonyl(Ci.
  • R 5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3 -i 2 )cycloalkyl, hetero(C 3 .i 2 )cycloalkyl, (Cg.i ⁇ bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci -5 )alkyl, perhalo(Ci.io)alkyl, (C 3- i 2 )cycloalkyl(Ci-io)alkyl, halo(Ci -10 )alkyl, carbonyl(Ci -3 )alkyl,
  • R 6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-1 o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1 .
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci -10 )alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(C 1-1 o)alkyl, heteroaryl(C 1-5 )alkyl, perhalo(C t _io)alkyl, (C 3- 12 )cycloalkyl(C L 10 )alkyl, halo(C i .
  • R 9 and R 1O are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1- io)alkyl, (C 3 -i 2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (Cg. ⁇ bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(C ⁇ -io)alkyl, heteroaryl(C 1-5 )alkyl, perhalo(Ci-io)alkyl, (C 3- 12 )cycloalkyl(C 1 .
  • Ri 3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 )alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 -i 2 )bicycloalkyl, hetero(C 3 .i 2 )bicycloalkyl, aryl(Ci-i O )alkyl, hetero
  • Ri 5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3 . )2 )cycloalkyl, hetero(C 3 . 12 )cycloalkyl, (C 9 _i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(C 1- io)alkyl, heteroaryl(C 1-5 )alkyl, (C 3- i 2 )cycloalkyl(Ci-io)alkyl, halo(Ci.
  • hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
  • J is selected from the group consisting of CR 6 and N, with the proviso that J is CR 6 and R 6 is absent when J forms part of a double bond;
  • K is selected from the group consisting of CR 6 and N, with the proviso that K is CR 6 and R 6 is absent when K forms part of a double bond
  • L is selected from the group consisting of CR 6 and N, with the proviso that L is CR 6 and R 6 is absent when L forms part of a double bond
  • M is selected from the group consisting of S, O and NRi 5 ;
  • Ri is selected from the group consisting of (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C ⁇ i ⁇ bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl, heteroaryl, (C 9 .i 2 )bicycloaryl, hetero(C 4- i 2 )bicycloaryl, each substituted or unsubstituted;
  • R 3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci -I o)alkyl, (C 3 .i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 _i 2 )bicycloalkyl, hetero(C 3 .i 2 )bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci -5 )alkyl, (C 3-12 )cycloalkyl(Ci.io)alkyl, halo(C 1 .io)alkyl, carbonyl(Ci -3 )alkyl, thiocarbonyl(Ci.
  • R 4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3 .i 2 )cycloalkyl, hetero(C 3 -i 2 )cycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci- 5 )alkyl, (C 3- 12 )cycloalkyl(C i -I o)alkyl, halo(C i .
  • R 5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 _i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci_ 5 )alkyl, perhalo(Ci.io)alkyl, (C 3- i 2 )cycloalkyl(Ci-io)alkyl, halo(Ci.io)alkyl, carbonyl (C i.
  • R 6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1 .
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-1 o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-i O )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9 _ 12 )bicycloalkyl, hetero(C 3 _ 12 )bicycloalkyl, aryl(C 1 . 1 o)alkyl, heteroaryl(Ci.
  • R 9 , R 1O , Rn and Ri 2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci -5 )alkyl, perhalo(Ci-io)alkyl, (C 3-12 )cycloalkyl(Ci-io)alkyl, halo(C 1- io)alkyl, carbonyl(C
  • Ri 3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (Cg.i ⁇ bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(Ci -10 )alkyl, heteroaryl(C 1-5 )alkyl, perhalo(C 1-10 )alkyl, (C 3 .i 2 )cycloalkyl(Ci -10 )alkyl, halo(Ci-i 0 )alkyl, carbonyl(Ci.
  • Ri 5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9- i 2 )bicycloalkyl, hetero(C 3-]2 )bicycloalkyl, aryl(C 1- i 0 )alkyl, heteroaryl(C 1-5 )alkyl, (C 3- i 2 )cycloalkyl(Ci-i 0 )alkyl, halo(Ci.i 0 )alkyl, carbonyl(Ci.
  • hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
  • J is selected from the group consisting of CR 6 and N, with the proviso that J is CR 6 and R 6 is absent when J forms part of a double bond;
  • K is selected from the group consisting of CR 6 and N, with the proviso that K is CR 6 and R 6 is absent when K forms part of a double bond;
  • L is selected from the group consisting of CR 6 and N, with the proviso that L is CR 6 and R 6 is absent when L forms part of a double bond;
  • M is selected from the group consisting of S, O and NR )5 ;
  • Ri is selected from the group consisting of (C 1- Io)OIlCyI, (C 3- i 2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9- i 2 )bicycloalkyl, hetero(C 3 . 12 )bicycloalkyl, aryl, heteroaryl, (C 9 .i 2 )bicycloaryl, hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted;
  • R 3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3 .i 2 )bicycloalkyl, aryl(C 1 .io)alkyl, heteroaryl(Ci.
  • R 4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3 .i 2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9 .i 2 )bicycloalkyl, hetero(C 3 _i 2 )bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci_ 5 )alkyl, (C 3- i 2 )cycloalkyl(Ci-io)alkyl, halo(Ci.io)alkyl, carbonyl(C 1-3 )alkyl, thiocarbonyl(Ci -3 )alkyl, sulfonyl(Ci -3 )al
  • R 5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-1 o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-1 o)alkyl, (C 3 .
  • R 6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3 _i 2 )cycloalkyl, (C 9-12 )bicycloalk:yl, hetero(C 3-12 )bicycloalkyl, OTyI(C 1-10 )BIlCyI, heteroaryl(Ci -5 )alkyl, PCrIIaIo(Ci -I o)OIlCyI, (C 3- i 2 )cycloalkyl(Ci-io)alkyl, halo(Ci-io)alkyl, carbonyl(C
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci -I o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1- io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci -1 o)alkyl, heteroaryl(C].
  • R 9 , Rio, Rn and R 12 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1- io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (Cg.i ⁇ bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci.
  • Ri 3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3 -i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (Cg.i ⁇ bicycloalkyl, hetero(C 3 .i 2 )bicycloalkyl, aryl(C].i O )alkyl, heteroaryl(Ci -5 )alkyl, perhalo(Ci-io)alkyl, (C 3- i 2 )cycloalkyl(Ci.io)alkyl, halo(Ci.io)alkyl, carbonyl(Ci -3 )alkyl, thiocarbonyl(Ci -3 )alkyl, sulfonyl(Ci -3
  • Ri 5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3 .i 2 )cycloalkyl, hetero(C 3 _i 2 )bicycloalkyl, aryl(Ci_io)alkyl, heteroaryl(Ci -5 )alkyl, (C 3- i 2 )cycloalkyl(Ci-io)alkyl, halo(Ci.io)alkyl, carbonyl(Ci_ 3 )alkyl, thiocarbonyl(Ci_ 3 )alkyl, sulfonyl(Ci -3 )alkyl, sulfinyl(Ci_ 3 )alkyl, imino(Ci -3 )alkyl
  • hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
  • J is selected from the group consisting of CR 6 and N, with the proviso that J is CR 6 and R 6 is absent when J forms part of a double bond;
  • K is selected from the group consisting of CR 6 and N, with the proviso that K is CR 6 and R 6 is absent when K forms part of a double bond;
  • L is selected from the group consisting of CR 6 and N, with the proviso that L is CR 6 and R 6 is absent when L forms part of a double bond;
  • M is selected from the group consisting of S, O and NRi 5 ;
  • Ri is selected from the group consisting of (C 1- io)alkyl, (C 3 .] 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 _i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl, heteroaryl, (C 9 -i 2 )bicycloaryl, hetero(C 4- i 2 )bicycloaryl, each substituted or unsubstituted;
  • R 3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3 .i 2 )cycloalkyl, (C 9- i 2 )bicycloalkyl, hetero(C 3 .i 2 )bicycloal
  • R 4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-1 o)alkyl, (C 3 - 12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(C 1- io)alkyl, heteroaryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl(C 1 .
  • R 5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-1 o)alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci -10 )alkyl, heteroaryl(C 1-5 )alkyl, perhalo(Ci -1 o)alkyl, (C 3- i 2 )cycloalkyl(Ci-io)alkyl, halo(C 1-1 o)alkyl, carbonyl(Ci -3 )alkyl, thiocarbonyl(
  • R 6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci -I o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(Ci-i O )alkyl, heteroaryl(Ci.
  • Ri 5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9- i 2 )bicycloalkyl, hetero(C 3 _i 2 )bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci -5 )alkyl, (C 3-12 )cycloalkyl(Ci-io)alkyl, halo(Ci -10 )alkyl, carbonyl(C 1-3 )alkyl, thiocarbonyl(C 1-3 )alkyl, sulfonyl(Ci -3 )alkyl, sulfinyl(Ci -3 )alkyl, imin
  • X is selected from the group consisting of unsubstituted and substituted C 1-6 alkylenes
  • Y is selected from the group consisting of (C 3-12 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3 . 12 )bicycloalkyl, aryl, heteroaryl, (C 9 . 12 )bicycloaryl, and hetero(C 4- i 2 )bicycloaryl, each substituted or unsubstituted.
  • hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
  • n is selected from the group consisting of 0, 1, 2,3, 4 and 5;
  • J is selected from the group consisting of CR 6 and N, with the proviso that J is CR 6 and R 6 is absent when J forms part of a double bond;
  • K is selected from the group consisting of CR 6 and N, with the proviso that
  • K is CR 6 and R 6 is absent when K forms part of a double bond
  • L is selected from the group consisting of CR 6 and N, with the proviso that L is CR 6 and R 6 is absent when L forms part of a double bond
  • M is selected from the group consisting of S, O and NRi 5 ;
  • R 3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(Ci_i O )alkyl, heteroaryl(Ci -5 )alkyl, (C 3- i 2 )cycloalkyl(Ci-io)alkyl, halo(C M o)alkyl, carbonyl(Ci -3 )alkyl, thiocarbonyl(Ci- 3 )alkyl, sulfonyl(Ci -3 )alkyl, sulfinyl(Ci.
  • R 4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1- io)alkyl, (C 3- ⁇ 2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(C 1- i 0 )alkyl, heteroaryl(C 1-5 )alkyl, (C 3 -i 2 )cycloalkyl(Ci-io)alkyl, halo(C 1- io)alkyl, carbonyl(C 1-3 )alkyl, thiocarbonyl(Ci -3 )alkyl, sulfonyl(C 1-3 )alkyl, sulfinyl(Ci -3 )
  • R 5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Q.icOalkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-1 o)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3 .i 2 )cycloalkyl, (C 9 _ 12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C 1-5 )alkyl, perhalo(Ci-io)alkyl, (C 3 .
  • R 6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, hetero(C 3 - 12 )bicycloalkyl, aryl(C 1-10 )alkyl, heteroaryl(Ci -5 )alkyl, perhalo(Ci-i 0 )alkyl, (C 3- i 2 )cycloalkyl(Ci.
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.jo)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, hetero(C 3 _ 12 )bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C 1-5 )alkyl, perhalo(Ci-io)alkyl, (C 3-12 )cycloalkyl(C M o)alkyl, halo(C 1-1 o)alkyl, carbonyl(d.
  • R 13 is selected from the group consisting of hydrogen, carbonyl, amino, (C 1 . 1 o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci -I o)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci -10 )alkyl, heteroaryl(C 1-5 )alkyl, perhalo(C 1- ⁇ o)alkyl, (C 3-]2 )cycloalkyl(C 1 .io)alkyl, halo(C 1-10 )alkyl, carbonyl(Ci -3 )alkyl, thiocarbonyl(Ci.
  • each Ru is independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-1 o)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, amino (C 1- io)alkyl, sulfinyl(Ci -3 )alkyl, amino (C 1- io)alkyl, imino(C ⁇ -3 )alkyl, aryl, heteroaryl, (C 9-12 )bicycloaryl, and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted, or R 13 and R 7 are taken together to form a ring; each Ru is independently selected from the group
  • Ri 5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (Cg.i ⁇ bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci -10 )alkyl, heteroaryl(C i -5 )alkyl, (C 3- 12 )cycloalkyl(C i . i O )alkyl, halo(C i .
  • hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
  • n is selected from the group consisting of 0, 1, 2,3, 4 and 5;
  • J is selected from the group consisting of CR 6 and N, with the proviso that J is CR 6 and R 6 is absent when J forms part of a double bond;
  • K is selected from the group consisting of CR 6 and N, with the proviso that K is CR 6 and R 6 is absent when K forms part of a double bond;
  • L is selected from the group consisting of CR 6 and N, with the proviso that L is CR 6 and R 6 is absent when L forms part of a double bond;
  • M is selected from the group consisting of S, O and NRi 5 ;
  • R 3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-i O )alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9- i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci -5 )alkyl, (C 3-12 )cycloalkyl(Ci-io)alkyl, carbonyl(Ci -3 )alkyl, thiocarbonyl(Ci -3 )alkyl, sulfonyl(Ci -3 )alkyl, sulfinyl(C 1-3
  • R 4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci -I o)alkyl, (C 3- ] 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9- ] 2 )bicycloalkyl, hetero(C 3 _i 2 )bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl (C i. 5 )alkyl, (C 3 .
  • R 5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci -I o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C] -I o)alkyl, (C 3- ] 2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (Cg. ⁇ bicycloalkyl, hetero(C 3 .
  • R 6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9- i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C 1 -s)alkyl, perhalo(C 1 .
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3 _ 12 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (Cg.i ⁇ bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, perhalo(Ci_io)alkyl, (C 3- 12 )cycloalkyl(C i .
  • R 9 and R 10 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1- io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(C 1-1 o)alkyl, heteroaryl(C 1-5 )alkyl, perhalo(C 1- io)alkyl, (C 3-12 )cycloalkyl(C 1-1 o)alkyl, halo(C 1-10 )alkyl, carbonyl(Ci -3 )alkyl, thiocarbonyl(C] -3 )alkyl, sulf
  • R 13 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci -I o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci -5 )alkyl, perhalo(Ci-io)alkyl, (C 3-12 )cycloalkyl(Ci.io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci -3 )alkyl, thiocarbonyl(Ci -3 )alkyl, sulfonyl(Ci -3 )alkyl,
  • each Ri 4 is independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 -i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci.i O )alkyl, heteroaryl(
  • R 15 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (Cc > .i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C i -5 )alkyl, (C 3- 12 )cycloalkyl(C i -io)alkyl, halo(C [ .
  • io)alkyl carbonyl(Ci -3 )alkyl, thiocarbonyl(Ci_ 3 )alkyl, sulfonyl(Ci. 3 )alkyl, sulfinyl(C 1-3 )alkyl, imino(C]. 3 )alkyl, aryl, heteroaryl, (C 9 .i 2 )bicycloaryl, and hetero(C 4 .i 2 )bicycloaryl, each substituted or unsubstituted.
  • hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
  • n is selected from the group consisting of 0, 1, 2,3, 4 and 5;
  • J is selected from the group consisting of CR 6 and N, with the proviso that J is CR 6 and R 6 is absent when J forms part of a double bond
  • K is selected from the group consisting of CR 6 and N, with the proviso that K is CR 6 and R 6 is absent when K forms part of a double bond
  • L is selected from the group consisting of CR 6 and N, with the proviso that L is CR 6 and R 6 is absent when L forms part of a double bond;
  • M is selected from the group consisting of S, O and NRj 5 ;
  • R 3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- ⁇ 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (Cc 1-12 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci -5 )alkyl, (C 3-12 )cycloalkyl(Ci-io)alkyl, halo(Ci -1 o)alkyl, carbonyl(Ci -3 )alkyl, thiocarbonyl(C 1 .
  • R 4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci -I o)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (Cg-i ⁇ bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, ⁇ yI(C 1 .
  • R 5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci -I o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1- io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 _i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci_io)alkyl, heteroaryl(Ci.
  • R 6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C].
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3 .
  • R 9 , R 1O , Ri 1 and R 12 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1- io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3 _i 2 )cycloalkyl, (C 9 _i 2 )bicycloalkyl, hetero(C 3 .
  • R 13 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci. 10 )alkyl, (C 3- 12 )cycloalkyl, hetero(C 3 .
  • each Ri 4 is independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci
  • Ri 5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci -5 )alkyl, (C 3- i 2 )cycloalkyl(Ci.io)alkyl, halo(Ci. 1 o)alkyl, carbonyl(Ci.
  • hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
  • n is selected from the group consisting of 0, 1, 2,3, 4 and 5;
  • J is selected from the group consisting of CR 6 and N, with the proviso that J is CR 6 and R 6 is absent when J forms part of a double bond;
  • K is selected from the group consisting of CR 6 and N, with the proviso that K is CR 6 and R 6 is absent when K forms part of a double bond;
  • L is selected from the group consisting of CR 6 and N, with the proviso that L is CR 6 and R 6 is absent when L forms part of a double bond;
  • M is selected from the group consisting of S, O and NRi 5 ;
  • R 3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamide, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (Cg.i ⁇ bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1 .
  • R 4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-iojalkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 .i 2 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci -5 )alkyl, (C 3- 12 )cycloalkyl(C i .
  • R 5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci -10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3 .i 2 )cycloalkyl, (C 9-)2 )bicycloalkyl, hetero(C 3 _i 2 )bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(C 1 _ 5 )alkyl, perhalo(Ci-io)alkyl, (C 3 _i 2 )cycloalkyl(C 1 .
  • R 6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci ⁇ alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3-12 )cycloalkyl, hetero(C 3 .
  • each R H is independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1 -io)alkylamino, sulfonamido, imino, sulfonyl,
  • Ri 5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 .i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl(Ci.i O )alkyl, heteroaryl(C 1-5 )alkyl, (C 3- i 2 )cycloalkyl(C M0 )alkyl, halo(C 1- io)alkyl, carbonyl(Ci.
  • X is selected from the group consisting of unsubstituted and substituted Ci -6 alkylenes
  • Y is selected from the group consisting of (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (C 9 .i 2 )bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl, heteroaryl, (C 9 _i 2 )bicycloaryl, and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted.
  • M is S. In another variation, M is O. In yet another variation, M is NR 15 and R 15 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C 3 .i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl(Ci_i O )alkyl, heteroaryl(Ci -5 )alkyl,
  • Ri is selected from the group consisting of (C 3- i 2 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, (Cg.i ⁇ bicycloalkyl, hetero(C 3- i 2 )bicycloalkyl, aryl, heteroaryl, (C 9 -i 2 )bicycloaryl, hetero(C 4 -] 2 )bicycloaryl, each substituted or unsubstituted.
  • Ri is selected from the group consisting of (C 3-6 )alkyl, aryl, (C 3-9 )cycloalkyl, bicycloalkyl and adamantanyl, each unsubstituted or substituted.
  • Ri is selected from the group consisting of alkylphenyl, halophenyl, alkylhalophenyl, alkoxyphenyl, alkylaminoalkoxyphenyl, heterocycloalkylalkoxyphenyl, alkylaminoalkylphenyl, heterocycloalkylalkylphenyl, cycloalkyl, bicycloalkyl and adamantanyl, each unsubstituted or substituted.
  • Ri is substituted with a substituent selected from the group consisting of cyano, carboxamido, aminoalkyl, aminoalkoxy, heterocycloalkyl, heterocycloalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aryloxy, heteroaryloxy, bicycloaryl, heterobicycloaryl, bicycloaryloxy, and heterobicycloaryloxy, each unbsubstituted or substituted.
  • a substituent selected from the group consisting of cyano, carboxamido, aminoalkyl, aminoalkoxy, heterocycloalkyl, heterocycloalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aryloxy, heteroaryloxy, bicycloaryl, heterobicycloaryl, bicycloaryloxy, and heterobicycloaryloxy, each unbsubstituted or substituted.
  • R 3 is H.
  • R 7 is
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heteroaryl, each unsubstituted or substituted.
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, alkylaminoalkyl, dialkylaminoalkyl, benzyl, halobenzyl, dihalobenzyl, phenylethyl, pyrimidinylalkyl, pyrazolylalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methylphenyl, dimethylphenyl, ethylphenyl, halophenyl, dihalophenyl, methoxyphenyl, cyanophenyl, haloalkylphenyl, pyridinyl, halopyridinyl, alkoxypyridinyl, tetrahydropyranyl, pyrazolyl and pyrimidinyl, each unsubstit
  • R 7 and R 8 are taken together to form a ring selected from the group consisting of a (C 3-12 )cycloalkyl, hetero(C 3- i 2 )cycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl, heteroaryl, (C 9-12 )bicycloaryl, and hetero(C 4- i 2 )bicycloaryl, each substituted or unsubstituted.
  • R 13 is
  • Ri 4 is selected from the group consisting of cyano, carboxamido, aminoalkyl, aminoalkoxy, heterocycloalkyl, heterocycloalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aryloxy, heteroaryloxy, bicycloaryl, heterobicycloaryl, bicycloaryloxy, and heterobicycloaryloxy, each unsubstituted or substituted.
  • n 0, 1 or 2.
  • X is methylene.
  • Y is selected from the group consisting of aryl and heteroaryl, each unsubstituted or substituted. In still another variation, Y is selected from the group consisting of phenyl and pyridinyl, each unsubstituted or substituted.
  • Y is selected from the group consisting of phenyl, halophenyl, dihalophenyl, methylphenyl, dimethylphenyl, cyanophenyl, aminocarboxyphenyl, haloalkylphenyl, alkoxyphenyl and oxopyridinyl.
  • hydroxysteroid dehydrogenase inhibitors include, but are not limited to:
  • hydroxysteroid dehydrogenase inhibitors include, but are not limited to:
  • hydroxysteroid dehydrogenase inhibitors include, but are not limited to: 3-Chloro-N-(4-(2-hydroxypentyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-(2-hydroxy-3-methylbutyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-(2-cyclopentyl-2-hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-(2-hydroxy-2-phenylethyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(2-hydroxy-3,3-diniethylbutyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(2-hydroxy-3,3-
  • hydroxysteroid dehydrogenase inhibitors include, but are not limited to: 3-chloro-N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-(2-hydroxy-2-propyl ⁇ entyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(( 1 -hydroxycyclobutyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(( 1 -hydroxycyclopentyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; N-[4-(2-Ethyl-2-hydroxy-butyl)-thiazol-2-yl]-4-fluoro-2-methyl- benzenesulf
  • hydroxysteroid dehydrogenase inhibitors include, but are not limited to:
  • hydroxysteroid dehydrogenase inhibitors include, but are not limited to:
  • the compounds of the present invention may be in the form of a pharmaceutically acceptable salt, biohydrolyzable ester, biohydrolyzable amide, biohydrolyzable carbamate, solvate, hydrate or prodrug thereof.
  • the compound optionally comprises a substituent that is convertible in vivo to a different substituent such as a hydrogen.
  • the compound may be present in a mixture of stereoisomers, or the compound comprises a single stereoisomer.
  • the present invention also provides a pharmaceutical composition comprising as an active ingredient a compound according to any one of the above embodiments and variations.
  • the composition is a solid formulation adapted for oral administration.
  • the composition is a liquid formulation adapted for oral administration.
  • the composition is a tablet.
  • the composition is a liquid formulation adapted for parenteral administration.
  • compositions comprising a compound according to any one of the above embodiments and variations, wherein the composition is adapted for administration by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, and intrathecally.
  • kits comprising a compound of any one of the above embodiments and variations; and instructions which comprise one or more forms of information selected from the group consisting of indicating a disease state for which the composition is to be administered, storage information for the composition, dosing information and instructions regarding how to administer the composition.
  • the kit comprises the compound in a multiple dose form.
  • an article of manufacture comprising a compound of any one of the above embodiments and variations; and packaging materials.
  • the packaging material comprises a container for housing the compound.
  • the container comprises a label indicating one or more members of the group consisting of a disease state for which the compound is to be administered, storage information, dosing information and/or instructions regarding how to administer the compound.
  • the article of manufacture comprises the compound in a multiple dose form.
  • a therapeutic method comprising administering a compound of any one of the above embodiments and variations to a subject.
  • a method of inhibiting HSD comprising causing a compound of any one of the above embodiments and variations to be present in a subject in order to inhibit HSD in vivo.
  • a method of inhibiting HSD comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits HSD in vivo, the second compound being a compound according to any one of the abive embodiments and variations.
  • a method of treating a disease state for which HSD possesses activity that contributes to the pathology and/or symptomology of the disease state comprising causing a compound of any one of the above embodiments and variations to be present in a subject in a therapeutically effective amount for the disease state.
  • a method of treating a disease state for which HSD possesses activity that contributes to the pathology and/or symptomology of the disease state comprising administering a compound of any one of the above embodiments and variations to a subject, wherein the compound is present in the subject in a therapeutically effective amount for the disease state.
  • a method of treating a disease state for which HSD possesses activity that contributes to the pathology and/or symptomology of the disease state comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits
  • the second compound being a compound according to any one of the above embodiments and variations.
  • the disease state is selected from the group consisting of the metabolic syndrome, Cushing's disease, hypertension, cognitive function, and ocular function.
  • the HSD is an 1 Ib-HSD 1.
  • the compounds of the present invention may be present and optionally administered in the form of salts, hydrates and prodrugs that are converted in vivo into the compounds of the present invention.
  • the compounds of the present invention possess a free base form
  • the compounds can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide; other mineral acids and their corresponding salts such as sulfate, nitrate, phosphate, etc.; and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate; and other organic acids and their corresponding salts such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate.
  • a pharmaceutically acceptable inorganic or organic acid e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide
  • other mineral acids and their corresponding salts such as sulfate, n
  • Further acid addition salts of the present invention include, but are not limited to: adipate, alginate, arginate, aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptaoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate, lactobionate, malate, malonate, man
  • a pharmaceutically acceptable base addition salt can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
  • bases include alkali metal hydroxides including potassium, sodium and lithium hydroxides; alkaline earth metal hydroxides such as barium and calcium hydroxides; alkali metal alkoxides, e.g. potassium ethanolate and sodium propanolate; and various organic bases such as ammonium hydroxide, piperidine, diethanolamine and N- methylglutamine.
  • aluminum salts of the compounds of the present invention are alkali metal hydroxides including potassium, sodium and lithium hydroxides; alkaline earth metal hydroxides such as barium and calcium hydroxides; alkali metal alkoxides, e.g. potassium ethanolate and sodium propanolate; and various organic bases such as ammonium hydroxide, piperidine, diethanolamine and N- methylglutamine.
  • aluminum salts of the compounds of the present invention are also included.
  • Organic base salts of the present invention include, but are not limited to: copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium and zinc salts.
  • Organic base salts include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, e.g., arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N-methyl
  • N-oxides of compounds according to the present invention can be prepared by methods known to those of ordinary skill in the art.
  • N-oxides can be prepared by treating an unoxidized form of the compound with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meto-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 0 C.
  • an oxidizing agent e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meto-chloroperoxybenzoic acid, or the like
  • a suitable inert organic solvent e.g., a halogenated hydrocarbon such as dichloromethane
  • Prodrug derivatives of compounds according to the present invention can be prepared by modifying substituents of compounds of the present invention that are then converted in vivo to a different substituent. It is noted that in many instances, the prodrugs themselves also fall within the scope of the range of compounds according to the present invention.
  • prodrugs can be prepared by reacting a compound with a carbamylating agent (e.g., l.l-acyloxyalkylcarbonochloridate. p ⁇ ra-nitrophenyl carbonate, or the like) or an acylating agent. Further examples of methods of making prodrugs are described in Saulnier et ⁇ /.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985.
  • Protected derivatives of compounds of the present invention can also be made. Examples of techniques applicable to the creation of protecting groups and their removal can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3 r edition, John Wiley & Sons, Inc. 1999.
  • Compounds of the present invention may also be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
  • a "pharmaceutically acceptable salt”, as used herein, is intended to encompass any compound according to the present invention that is utilized in the form of a salt thereof, especially where the salt confers on the compound improved pharmacokinetic properties as compared to the free form of compound or a different salt form of the compound.
  • the pharmaceutically acceptable salt form may also initially confer desirable pharmacokinetic properties on the compound that it did not previously possess, and may even positively affect the pharmacodynamics of the compound with respect to its therapeutic activity in the body.
  • An example of a pharmacokinetic property that may be favorably affected is the manner in which the compound is transported across cell membranes, which in turn may directly and positively affect the absorption, distribution, biotransformation and excretion of the compound.
  • the solubility of the compound is usually dependent upon the character of the particular salt form thereof, which it utilized.
  • an aqueous solution of the compound will provide the most rapid absorption of the compound into the body of a subject being treated, while lipid solutions and suspensions, as well as solid dosage forms, will result in less rapid absorption of the compound.
  • a racemic mixture of a compound may be reacted with an optically active resolving agent to form a pair of diastereoisomeric compounds.
  • the diastereomers may then be separated in order to recover the optically pure enantiomers.
  • Dissociable complexes may also be used to resolve enantiomers (e.g., crystalline diastereoisomeric salts).
  • Diastereomers typically have sufficiently distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) that they can be readily separated by taking advantage of these dissimilarities.
  • diastereomers can typically be separated by chromatography or by separation/resolution techniques based upon differences in solubility.
  • separation/resolution techniques A more detailed description of techniques that can be used to resolve stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
  • compositions Comprising Hydroxysteroid Dehydrogenase Inhibitors
  • compositions and administration methods may be used in conjunction with the hydroxysteroid dehydrogenase inhibitors of the present invention.
  • Such compositions may include, in addition to the hydroxysteroid dehydrogenase inhibitors of the present invention, conventional pharmaceutical excipients, and other conventional, pharmaceutically inactive agents.
  • the compositions may include active agents in addition to the hydroxysteroid dehydrogenase inhibitors of the present invention. These additional active agents may include additional compounds according to the invention, and/or one or more other pharmaceutically active agents.
  • the compositions may be in gaseous, liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration to be used. For oral administration, capsules and tablets are typically used.
  • compositions comprising hydroxysteroid dehydrogenase inhibitors of the present invention may be administered or coadministered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally.
  • the compounds and/or compositions according to the invention may also be administered or coadministered in slow release dosage forms.
  • hydroxysteroid dehydrogenase inhibitors and compositions comprising them may be administered or coadministered in any conventional dosage form.
  • Coadministration in the context of this invention is intended to mean the administration of more than one therapeutic agent, one of which includes a hydroxysteroid dehydrogenase inhibitor, in the course of a coordinated treatment to achieve an improved clinical outcome.
  • Such co-administration may also be coextensive, that is, occurring during overlapping periods of time.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may optionally include one or more of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; agents for the adjustment of tonicity such as sodium chloride or dextrose, and agents for adjusting the acidity or alkalinity of the composition, such as alkaline or acidifying agents or buffers like carbonates, bicarbonates, phosphates, hydrochloric acid, and organic acids like acetic and citric acid.
  • Parenteral preparations may optionally be enclosed in ampules
  • hydroxysteroid dehydrogenase inhibitors according to the present invention exhibit insufficient solubility
  • methods for solubilizing the compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN, or dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions.
  • cosolvents such as dimethylsulfoxide (DMSO)
  • surfactants such as TWEEN
  • dissolution in aqueous sodium bicarbonate such as sodium bicarbonate
  • Derivatives of the compounds, such as prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions.
  • a solution, suspension, emulsion or the like may be formed.
  • the form of the resulting composition will depend upon a number of factors, including the intended mode of administration, and the solubility of the compound in the selected carrier or vehicle.
  • the effective concentration needed to ameliorate the disease being treated may be empirically determined.
  • compositions according to the present invention are optionally provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, dry powders for inhalers, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds, particularly the pharmaceutically acceptable salts, preferably the sodium salts, thereof.
  • the pharmaceutically therapeutically active compounds and derivatives thereof are typically formulated and administered in unit-dosage forms or multiple-dosage forms.
  • Unit-dose forms refers to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art.
  • Each unit- dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent.
  • unit-dose forms include ampoules and syringes individually packaged tablet or capsule.
  • Unit-dose forms may be administered in fractions or multiples thereof.
  • a multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form.
  • Examples of multiple-dose forms include vials, bottles of tablets or capsules or bottles of pint or gallons.
  • multiple dose form is a multiple of unit-doses that are not segregated in packaging.
  • the composition may comprise: a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose; a lubricant, such as magnesium stearate, calcium stearate and talc; and a binder such as starch, natural gums, such as gum acaciagelatin, glucose, molasses, polvinylpyrrolidine, celluloses and derivatives thereof, povidone, crospovidones and other such binders known to those of skill in the art.
  • a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose
  • a lubricant such as magnesium stearate, calcium stearate and talc
  • a binder such as starch, natural gums, such as gum acaciagelatin, glucose, molasses, polvinylpyrrolidine, celluloses and derivatives thereof, povidone, crospovidones and other such binders
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, or otherwise mixing an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to form a solution or suspension.
  • a carrier such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like
  • the pharmaceutical composition to be administered may also contain minor amounts of auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.
  • composition or formulation to be administered will, in any event, contain a sufficient quantity of a hydroxysteroid dehydrogenase inhibitor of the present invention to reduce hydroxysteroid dehydrogenase activity in vivo, thereby treating the disease state of the subject.
  • Dosage forms or compositions may optionally comprise one or more hydroxysteroid dehydrogenase inhibitors according to the present invention in the range of 0.005% to 100% (weight/weight) with the balance comprising additional substances such as those described herein.
  • a pharmaceutically acceptable composition may optionally comprise any one or more commonly employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate, sodium saccharin, talcum.
  • compositions include solutions, suspensions, tablets, capsules, powders, dry powders for inhalers and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparing these formulations are known to those skilled in the art.
  • the compositions may optionally contain 0.01%- 100% (weight/weight) of one or more hydroxysteroid dehydrogenase inhibitors, optionally 0.1-95%, and optionally 1-95%.
  • Salts, preferably sodium salts, of the hydroxysteroid dehydrogenase inhibitors may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings.
  • the formulations may further include other active compounds to obtain desired combinations of properties.
  • Oral pharmaceutical dosage forms may be as a solid, gel or liquid.
  • solid dosage forms include, but are not limited to tablets, capsules, granules, and bulk powders. More specific examples of oral tablets include compressed, chewable lozenges and tablets that may be enteric-coated, sugar-coated or film-coated.
  • capsules include hard or soft gelatin capsules. Granules and powders may be provided in non- effervescent or effervescent forms. Each may be combined with other ingredients known to those skilled in the art.
  • hydroxysteroid dehydrogenase inhibitors are provided as solid dosage forms, preferably capsules or tablets.
  • the tablets, pills, capsules, troches and the like may optionally contain one or more of the following ingredients, or compounds of a similar nature: a binder; a diluent; a disintegrating agent; a lubricant; a glidant; a sweetening agent; and a flavoring agent.
  • binders include, but are not limited to, microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste.
  • lubricants examples include, but are not limited to, talc, starch, magnesium or calcium stearate, lycopodium and stearic acid.
  • diluents examples include, but are not limited to, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.
  • glidants examples include, but are not limited to, colloidal silicon dioxide.
  • disintegrating agents examples include, but are not limited to, crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose.
  • coloring agents examples include, but are not limited to, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate.
  • sweetening agents examples include, but are not limited to, sucrose, lactose, mannitol and artificial sweetening agents such as sodium cyclamate and saccharin, and any number of spray-dried flavors.
  • flavoring agents examples include, but are not limited to, natural flavors extracted from plants such as fruits and synthetic blends of compounds that produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate.
  • wetting agents examples include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
  • anti-emetic coatings examples include, but are not limited to, fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates.
  • film coatings examples include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.
  • the salt of the compound may optionally be provided in a composition that protects it from the acidic environment of the stomach.
  • the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine.
  • the composition may also be formulated in combination with an antacid or other such ingredient.
  • dosage unit form When the dosage unit form is a capsule, it may optionally additionally comprise a liquid carrier such as a fatty oil. In addition, dosage unit forms may optionally additionally comprise various other materials that modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents.
  • Compounds according to the present invention may also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like.
  • a syrup may optionally comprise, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the hydroxysteroid dehydrogenase inhibitors of the present invention may also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. For example, if a compound is used for treating asthma or hypertension, it may be used with other bronchodilators and antihypertensive agents, respectively.
  • Examples of pharmaceutically acceptable carriers that may be included in tablets comprising hydroxysteroid dehydrogenase inhibitors of the present invention include, but are not limited to binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents.
  • Enteric-coated tablets because of the enteric-coating, resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines.
  • Sugar-coated tablets may be compressed tablets to which different layers of pharmaceutically acceptable substances are applied.
  • Film-coated tablets may be compressed tablets that have been coated with polymers or other suitable coating. Multiple compressed tablets may be compressed tablets made by more than one compression cycle utilizing the pharmaceutically acceptable substances previously mentioned.
  • Coloring agents may also be used in tablets. Flavoring and sweetening agents may be used in tablets, and are especially useful in the formation of chewable tablets and lozenges.
  • liquid oral dosage forms examples include, but are not limited to, aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • aqueous solutions examples include, but are not limited to, elixirs and syrups.
  • elixirs refer to clear, sweetened, hydroalcoholic preparations.
  • pharmaceutically acceptable carriers examples include, but are not limited to solvents.
  • solvents include glycerin, sorbitol, ethyl alcohol and syrup.
  • syrups refer to concentrated aqueous solutions of a sugar, for example, sucrose. Syrups may optionally further comprise a preservative.
  • Emulsions refer to two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid. Emulsions may optionally be oil-in- water or water-in-oil emulsions. Examples of pharmaceutically acceptable carriers that may be used in emulsions include, but are not limited to non-aqueous liquids, emulsifying agents and preservatives.
  • Examples of pharmaceutically acceptable substances that may be used in non- effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents.
  • Examples of pharmaceutically acceptable substances that may be used in effervescent granules, to be reconstituted into a liquid oral dosage form, include organic acids and a source of carbon dioxide.
  • Coloring and flavoring agents may optionally be used in all of the above dosage forms.
  • preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.
  • non-aqueous liquids that may be used in emulsions include mineral oil and cottonseed oil.
  • emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate.
  • suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia.
  • Diluents include lactose and sucrose.
  • Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as sodium cyclamate and saccharin.
  • wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
  • organic acids that may be used include citric and tartaric acid.
  • Sources of carbon dioxide that may be used in effervescent compositions include sodium bicarbonate and sodium carbonate.
  • Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof.
  • flavoring agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds that produce a pleasant taste sensation.
  • the solution or suspension in for example propylene carbonate, vegetable oils or triglycerides, is preferably encapsulated in a gelatin capsule.
  • the solution e.g., for example, in a polyethylene glycol
  • a pharmaceutically acceptable liquid carrier e.g. water
  • liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g. propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
  • vegetable oils glycols, triglycerides, propylene glycol esters (e.g. propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
  • propylene glycol esters e.g. propylene carbonate
  • compositions designed to administer the hydroxysteroid dehydrogenase inhibitors of the present invention by parenteral administration, generally characterized by injection, either subcutaneously, intramuscularly or intravenously.
  • injectables may be prepared in any conventional form, for example as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • excipients examples include, but are not limited to water, saline, dextrose, glycerol or ethanol.
  • the injectable compositions may also optionally comprise minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
  • Implantation of a slow-release or sustained-release system such that a constant level of dosage is maintained (see, e.g., U.S. Pat. No. 3,710,795) is also contemplated herein.
  • the percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.
  • Parenteral administration of the formulations includes intravenous, subcutaneous and intramuscular administrations.
  • Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as the lyophilized powders described herein, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions.
  • the solutions may be either aqueous or nonaqueous.
  • suitable carriers include, but are not limited to physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
  • PBS physiological saline or phosphate buffered saline
  • Examples of pharmaceutically acceptable carriers that may optionally be used in parenteral preparations include, but are not limited to aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
  • aqueous vehicles examples include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection.
  • nonaqueous parenteral vehicles examples include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil.
  • Antimicrobial agents in bacteriostatic or fungistatic concentrations may be added to parenteral preparations, particularly when the preparations are packaged in multiple-dose containers and thus designed to be stored and multiple aliquots to be removed. Examples of antimicrobial agents that may be used include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride.
  • Examples of isotonic agents that may be used include sodium chloride and dextrose.
  • Examples of buffers that may be used include phosphate and citrate.
  • antioxidants that may be used include sodium bisulfate.
  • Examples of local anesthetics that may be used include procaine hydrochloride.
  • Examples of suspending and dispersing agents that may be used include sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.
  • Examples of emulsifying agents that may be used include Polysorbate 80 (TWEEN 80).
  • a sequestering or chelating agent of metal ions include EDTA.
  • Pharmaceutical carriers may also optionally include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.
  • the concentration of a hydroxysteroid dehydrogenase inhibitor in the parenteral formulation may be adjusted so that an injection administers a pharmaceutically effective amount sufficient to produce the desired pharmacological effect.
  • concentration of a hydroxysteroid dehydrogenase inhibitor and/or dosage to be used will ultimately depend on the age, weight and condition of the patient or animal as is known in the art.
  • Unit-dose parenteral preparations may be packaged in an ampoule, a vial or a syringe with a needle. All preparations for parenteral administration should be sterile, as is know and practiced in the art.
  • Injectables may be designed for local and systemic administration.
  • a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1% w/w up to about 90% w/w or more, preferably more than 1% w/w of the hydroxysteroid dehydrogenase inhibitor to the treated tissue(s).
  • the hydroxysteroid dehydrogenase inhibitor may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment will be a function of the location of where the composition is parenterally administered, the carrier and other variables that may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data.
  • concentrations and dosage values may also vary with the age of the individual treated. It is to be further understood that for any particular subject, specific dosage regimens may need to be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations. Hence, the concentration ranges set forth herein are intended to be exemplary and are not intended to limit the scope or practice of the claimed formulations.
  • the hydroxysteroid dehydrogenase inhibitor may optionally be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug.
  • the form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle.
  • the effective concentration is sufficient for ameliorating the symptoms of the disease state and may be empirically determined.
  • the hydroxysteroid dehydrogenase inhibitors of the present invention may also be prepared as lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures.
  • the lyophilized powders may also be formulated as solids or gels.
  • Sterile, lyophilized powder may be prepared by dissolving the compound in a sodium phosphate buffer solution containing dextrose or other suitable excipient. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. Briefly, the lyophilized powder may optionally be prepared by dissolving dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agent, about 1-20%, preferably about 5 to 15%, in a suitable buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, typically, about neutral pH.
  • a suitable buffer such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, typically, about neutral pH.
  • a hydroxysteroid dehydrogenase inhibitor is added to the resulting mixture, preferably above room temperature, more preferably at about 30-35 0 C, and stirred until it dissolves.
  • the resulting mixture is diluted by adding more buffer to a desired concentration.
  • the resulting mixture is sterile filtered or treated to remove particulates and to insure sterility, and apportioned into vials for lyophilization.
  • Each vial may contain a single dosage or multiple dosages of the hydroxysteroid dehydrogenase inhibitor.
  • the hydroxysteroid dehydrogenase inhibitors of the present invention may also be administered as topical mixtures.
  • Topical mixtures may be used for local and systemic administration.
  • the resulting mixture may be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration.
  • the hydroxysteroid dehydrogenase inhibitors may be formulated as aerosols for topical application, such as by inhalation (see, U.S. Pat.
  • the hydroxysteroid dehydrogenase inhibitors may also be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the hydroxysteroid dehydrogenase inhibitor alone or in combination with other pharmaceutically acceptable excipients can also be administered.
  • rectal administration may also be used.
  • pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect.
  • Rectal suppositories are used herein mean solid bodies for insertion into the rectum that melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients.
  • Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point.
  • bases examples include cocoa butter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases may be used.
  • Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. The typical weight of a rectal suppository is about 2 to 3 gm. Tablets and capsules for rectal administration may be manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration.
  • Citric Acid Monohydrate 1.05 mg
  • kits and other articles of manufacture for treating diseases associated with hydroxysteroid dehydrogenases. It is noted that diseases are intended to cover all conditions for which the hydroxysteroid dehydrogenases possess activity that contributes to the pathology and/or symptomology of the condition.
  • a kit is provided that comprises a composition comprising at least one hydroxysteroid dehydrogenase inhibitor of the present invention in combination with instructions.
  • the instructions may indicate the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
  • the kit may also comprise packaging materials.
  • the packaging material may comprise a container for housing the composition.
  • the kit may also optionally comprise additional components, such as syringes for administration of the composition.
  • the kit may comprise the composition in single or multiple dose forms.
  • an article of manufacture comprises a composition comprising at least one hydroxysteroid dehydrogenase inhibitor of the present invention in combination with packaging materials.
  • the packaging material may comprise a container for housing the composition.
  • the container may optionally comprise a label indicating the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
  • the kit may also optionally comprise additional components, such as syringes for administration of the composition.
  • the kit may comprise the composition in single or multiple dose forms.
  • the packaging material used in kits and articles of manufacture according to the present invention may form a plurality of divided containers such as a divided bottle or a divided foil packet.
  • the container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule.
  • the container that is employed will depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension.
  • kits can be used together in a single package to market a single dosage form.
  • tablets may be contained in a bottle that is in turn contained within a box.
  • the kit includes directions for the administration of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral, topical, transdermal and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • kits are a dispenser designed to dispense the daily doses one at a time in the order of their intended use.
  • the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen.
  • a memory-aid is a mechanical counter that indicates the number of daily doses that has been dispensed.
  • a memory-aid is a battery- powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
  • a racemic mixture of a compound may be reacted with an optically active resolving agent to form a pair of diastereoisomeric compounds.
  • the diastereomers may then be separated in order to recover the optically pure enantiomers.
  • Dissociable complexes may also be used to resolve enantiomers (e.g., crystalline diastereoisomeric salts).
  • Diastereomers typically have sufficiently distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) that they can be readily separated by taking advantage of these dissimilarities.
  • diastereomers can typically be separated by chromatography or by separation/resolution techniques based upon differences in solubility.
  • separation/resolution techniques A more detailed description of techniques that can be used to resolve stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
  • Compounds according to the present invention can also be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid.
  • a pharmaceutically acceptable base addition salt of a compound can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
  • Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds are set forth in the definitions section of this Application.
  • the salt forms of the compounds can be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds can be prepared from the corresponding base addition salt or acid addition salt form.
  • a compound in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like).
  • a compound in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc).
  • the iV-oxides of compounds according to the present invention can be prepared by methods known to those of ordinary skill in the art.
  • N-oxides can be prepared by treating an unoxidized form of the compound with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, met ⁇ -chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 0 C.
  • an oxidizing agent e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, met ⁇ -chloroperoxybenzoic acid, or the like
  • a suitable inert organic solvent e.g., a halogenated hydrocarbon such as dichloromethane
  • the ⁇ f-oxides of the compounds can be prepared from the ⁇ f-oxide of an appropriate starting
  • Compounds in an unoxidized form can be prepared from ⁇ f-oxides of compounds by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 0 C.
  • a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like
  • an inert organic solvent e.g., acetonitrile, ethanol, aqueous dioxane, or the like
  • Prodrug derivatives of the compounds can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et «/.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).
  • appropriate prodrugs can be prepared by reacting a non-derivatized compound with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate, p ⁇ ra-nitrophenyl carbonate, or the like).
  • Protected derivatives of the compounds can be made by methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons, Inc. 1999.
  • Compounds according to the present invention may be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
  • Compounds according to the present invention can also be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of compounds, dissociable complexes are preferred (e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities.
  • the diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
  • M molar
  • mM millimolar
  • i.v. intravenous
  • Hz Hertz
  • Tr retention time
  • RP reverse phase
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • TFAA trifluoroacetic anhydride
  • THF tetrahydrofuran
  • DME (1,2-dimethoxyethane); DCM (dichloromethane);
  • DCE dichloroethane
  • DMF N,N-dimethylformamide
  • DMPU N,N'-dimethylpropyleneurea
  • CDI 1,1-carbonyldiimidazole
  • IBCF isobutyl chloroformate
  • HOAc acetic acid
  • HOSu N-hydroxysuccinimide
  • HOBT 1-hydroxybenzotriazole
  • Et 2 O diethyl ether
  • EDCI ethylcarbodiimide hydrochloride
  • BOC tert-butyloxycarbonyl
  • FMOC 9-fluorenylmethoxycarbonyl
  • DCC (dicyclohexylcarbodiimide); CBZ (benzyl oxycarbonyl);
  • TIPS triisopropylsilyl
  • TBS t-butyldimethylsilyl
  • BOP bis(2-oxo-3-oxazolidinyl)phosphinic chloride
  • TBAF tetra-n-butylammonium fluoride
  • mCPBA metal-chloroperbenzoic acid
  • AU references to ether or Et 2 O are to diethyl ether; brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in 0 C (degrees Centigrade). All reactions conducted under an inert atmosphere at RT unless otherwise noted.
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as the Aldrich Chemical Company (Milwaukee, WI), Bachem (Torrance, CA), Sigma (St. Louis, MO), or may be prepared by methods well known to a person of ordinary skill in the art, following procedures described in such standard references as Fieser and Fieser's Reagents for Organic Synthesis, vols. 1-17, John Wiley and Sons, New York, NY, 1991; Rodd's Chemistry of Carbon Compounds, vols. 1-5 and supps., Elsevier Science Publishers, 1989; Organic Reactions, vols.
  • Hydroxysteroid dehydrogenase inhibitors according to the present invention may be synthesized according to the reaction schemes shown below. Other reaction schemes could be readily devised by those skilled in the art. It should also be appreciated that a variety of different solvents, temperatures and other reaction conditions can be varied to optimize the yields of the reactions.
  • the key ester can be prepared by coupling a carboxy-substituted aminothiazole and various sulfonyl chlorides in pyridine with DMAP. The key ester can then be reduced to the alcohol with LAH and oxidized to the corresponding aldehyde using MnO 2 . The resulting aldehyde can then be treated with a variety of nucleophiles, such as Grignard reagents, to give the desired product.
  • nucleophiles such as Grignard reagents
  • the tertiary ⁇ -alcohols of Scheme 2 can be prepared by reacting the key ester (see Scheme 1) with a variety of Grignard reagents.
  • Cyclic alcohols such as those in Scheme 3, can be synthesized by the addition of bis-organomagnesium species, or by Kulinkovich cyclopropanation.
  • the key ester can be prepared by coupling a carboxymethyl-substituted aminothiazole and various sulfonyl chlorides in pyridine with DMAP. The key ester can then be reacted with a variety of Grignard reagents to give the desired product.
  • tertiary ⁇ -alcohols such as those in Scheme 5 can be prepared from a samarium(II) mediated Barbier reaction of cyclic ketones and chloromethyl- substituted N-sulfonylaminothiazoles, which can be obtained from sulfonylation of the known chloromethyl-substituted aminothiazole HCl salt by various sulfonyl chlorides.
  • the key ester can be reacted with various nucleophiles such as Grignard reagents, followed by reduction of the resulting ketone with LAH or NaBH 4 .
  • the alcohols can be derivatized with the R or S enantiomer of O-methoxyphenylacetic acid. Separation of the resulting diastereomeric products can be accomplished chromatographically or by other means. Separated diastereomers can then be reduced to the corresponding alcohols.
  • Secondary ⁇ -alcohols such as those in Scheme 9 can be obtained via aldol condensation of the key aldehyde with a methyl ketone, followed by the hydrogenation of the resulting double bond using PtO 2 as a catalyst and asymmetric reduction of the ketone functionality with either (+) or (-)-DIPCl.
  • PtO 2 as a catalyst
  • asymmetric reduction of the ketone functionality with either (+) or (-)-DIPCl.
  • other methods for asymmetric reduction known to those skilled in the art can be used.
  • the intermediate epoxide can be prepared from trimethylsulfonium iodide and a key aldehyde according to the procedure described in Corey, E.J., Chaykovsky, M.; J. Am. Chem. Soc. 1965, 87, 1353-1364. Exposure of the epoxide to commercially available amines in the presence of activated alumina can provide the desired products in a regioselective manner, as described in Posner, G.H., Rogers, D.Z.; J. Am. Chem. Soc, 1977, 99, 8214-8218.
  • the key ester can be prepared by coupling a carboxymethyl-substituted aminothiazole and various fluorine substituted arylsulfonyl chlorides in pyridine with DMAP. The key ester can then be reacted with Grignard reagents to give the desired intermediate alcohol. Aromatic nucleophilic substitution with a variety of nucleophiles provides the desired product.
  • R b and R c may b ⁇ taken together to form a ⁇ ng
  • Tertiary ⁇ -alcohols such as those in Scheme 13 can also be obtained from Boc- protected 4-(chloromethyl)thiazol-2-amine via samarium(H) mediated Barbier reaction with various cyclic or acyclic ketones. Acidolysis of the Boc protecting group of the resulting intermediate, followed by sulfonylation by various sulfonyl chlorides, gives the desired tertiary ⁇ -alcohols.
  • Tertiary ⁇ -alcohols such as those in Scheme 14 can also be prepared from ethyl 2-aminothiazole-4-carboxylate.
  • ethyl 2-aminothiazole-4-carboxylate can be reacted with ethylmagnesium chloride to provide the corresponding diethylhydroxy derivative.
  • the amine functionality was then coupled with a variety of sulfonyl chlorides to afford the desired sulfonamides.
  • Chiral components can be separated and purified using any of a variety of techniques known to those skilled in the art.
  • chiral components can be purified using supercritical fluid chromatography (SFC).
  • SFC supercritical fluid chromatography
  • chiral analytical SFC/MS analyses are conducted using a Berger analytical SFC system (AutoChem, Newark, DE) which consists of a Berger SFC dual pump fluid control module with a Berger FCM 1100/1200 supercritical fluid pump and FCM 1200 modifier fluid pump, a Berger TCM 2000 oven, and an Alcott 718 autosampler.
  • the integrated system can be controlled by BI-SFC Chemstation software version 3.4.
  • Detection can be accomplished with a Watrers ZQ 2000 detector operated in positive mode with an ESI interface and a scan range from 200-800 Da with 0.5 second per scan.
  • Chromatographic separations can be performed on a ChiralPak AD-H, ChiralPak AS-H, ChiralCel OD-H, or ChiralCel OJ-H column (5 ⁇ , 4.6 x 250 mm; Chiral Technologies, Inc. West Chester, PA) with 10 to 40% methanol as the modifier and with or without ammonium acetate (10 mM).
  • Any of a variety of flow rates can be utilized including, for example, 1.5 or 3.5 rnL/min with an inlet pressure set at 100 bar.
  • sample injection conditions can be used including, for example, sample injections of either 5 or lO ⁇ L in methanol at 0.1 mg/mL in concentration.
  • preparative chiral separations are performed using a Berger MultiGram II SFC purification system.
  • samples can be loaded onto a ChiralPak AD column (21 x 250 mm, 10 ⁇ ).
  • the flow rate for separation can be 70 mL/min, the injection volume up to 2 mL, and the inlet pressure set at 130 bar. Stacked injections can be applied to increase the efficiency.
  • the above reaction schemes, and variations thereof, can be used to prepare the following:
  • Example 1-1 3-Chloro-N-(4-(l-hydroxyethyl)thiazol-2-yl)-2-methylbenzenesulfonamide
  • Step A Ethyl 2-(3-chloro-2-methylphenylsulfonamido)thiazole-4-carboxylate
  • Step B 3-Chloro-N-(4-(hydroxymethyl)thiazol-2-yl)-2-methylbenzenesulfonamide
  • Step D 3-Chloro-N-(4-(l-hydroxyethyl)thiazol-2-yl)-2-methylbenzenesulfonamide
  • 3-Chloro-N-(4-formylthiazol-2-yl)-2-methylbenzenesulfonamide 64 mg, 0.202 mmol was suspended in THF and treated with a solution of methylmagnesium chloride (3.0M in THF, 0.33 mL, 1.0 mmol) at room temperature.
  • the reaction mixture was stirred for 15 min, quenched with NH 4 Cl (sat. aq) - ice mixture (1: 1, 5 mL), stirred vigorously for 5 min and extracted with ethyl acetate (5 mL).
  • Example 1-7 3-Chloro-N-(4-(cyclohexyl(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
  • Example 1-12 3-chloro-N-(4-((3-fluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
  • Example 1-13 3-chloro-N-(4-((3,4-difluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
  • Example 1-14 3-chloro-N-(4-((4-chloro-3-fluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
  • Example 1-16 3-chloro-N-(4-((4-fluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
  • the title compound was prepared from commercially available 2- iodobenzonitrile and 3-chloro-N-(4-formylthiazol-2-yl)-2-methylbenzenesulfonamide according to the procedure described in Example 1-31.
  • the crude product was purified by column chromatography on SiO 2 eluted with EtOAc/hexanes (3:1) to yield 0.10 g (50 %) of the title compound.
  • Step A Ethyl 2-(2-(3-chloro-2-methylphenylsulfonamido)thiazol-4-yl)acetate
  • Step B 3-Chloro-2-methyl-N-(4-(2-oxoethyl)thiazol-2-yl)benzenesulfonamide
  • Step C 3-Chloro-N-(4-(2-hydroxypentyl)thiazol-2-yl)-2-methylbenzenesulfonamide
  • 3-Chloro-2-methyl-N-(4-(2-oxoethyl)thiazol-2-yl)benzenesulfonamide (0.190 g, 0.534 mmol) was dissolved in THF and cooled to -10 0 C in nitrogen atmosphere, n- Propylmagnesium chloride (2M solution in ethyl ether, 0.600 mL, 1.20 mmol) was added dropwise and the reaction mixture was stirred for 40 min. It was quenched with a cooled NH 4 Cl (sat.
  • Example 2-6 3-chloro-N-(4-(2-(3-fluorophenyl)-2-hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulfonamide
  • Step A 3-chloro-N-(4-(3-(2,5-difluorophenyl)-2-oxopropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
  • Example 2-8 3-chloro-N-(4-(3-(4-fluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
  • Step A (R)-((S)-l-(2-(3-chloro-2-methylphenylsulfonamido)thiazol-4-yl)-3-(2- fluorophenyl)propan-2-yl) 2-methoxy-2-phenylacetate
  • Step B (S)-3-chloro-N-(4-(3-(2-fluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
  • Example 2-10-B The title compound was obtained as described for Example 2-10-B, starting from the other diastereomer isolated by preparative TLC in Example 2-10-A, except that the following quantities were used: (R)-((R)-l-(2-(3-chloro-2- methylphenylsulfonamido)thiazol-4-yl)-3-(2-fluorophenyl)propan-2-yl) 2-methoxy-2- phenylacetate (63.0 mg, 0.107 mmol), DIBAL-H (1.00 mL, 1.00 mmol), dichloromethane (5 mL). The title compound was obtained as a white solid (38.4 mg, 81%). Stereo- configuration was assigned based on NMR analysis of the methoxyphenylacetic acid derivatized diastereomers of Example 2-9 and Example 2-13 with known configurations.
  • Example 2-14 3-chloro-N-(4-(3-(2,4-difluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
  • Example 2-15 3-chloro-N-(4-(3-(2,6-difluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
  • Example 2-16 3-chloro-N-(4-(3-(3-chlorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide

Abstract

Compounds, pharmaceutical compositions, kits and methods are provided for use with hydroxysteroid dehydrogenases that comprise a compound selected from the group consisting of: Formula (I) wherein the variables are as defined herein.

Description

HYDROXYSTEROID DEHYDROGENASE INHIBITORS
FIELD OF THE INVENTION
[0001] The present invention relates to compounds that may be used to inhibit hydroxysteroid dehydrogenases, as well as compositions of matter and kits comprising these compounds. The invention also relates to methods for inhibiting hydroxysteroid dehydrogenases and treatment methods using compounds according to the present invention. In particular, the present invention relates to 1 lβ-Hydroxysteroid Dehydrogenase Type 1 inhibitors, compositions of matter and kits comprising these compounds and methods for inhibiting 1 lβ-Hydroxysteroid Dehydrogenase Type 1.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to inhibitors of enzymes that catalyse the interconversion of active and inactive glucocorticoids, compositions comprising the inhibitors, kits and articles of manufacture comprising the inhibitors and compositions, methods of making the inhibitors and compositions, and methods of using the inhibitors and compositions. The inhibitors and compositions comprising them are useful for treating or modulating diseases in which enzymes that catalyse the interconversion of glucocorticoids may be involved, symptoms of such diseases, or the effect of other physiological events mediated by these enzymes. Accordingly, the invention also provides for methods of treating diseases in which one or more enzymes that catalyse the interconversion of glucocorticoids is involved.
[0003] Short-chain dehydrogenases/reductases are a family of reversible NAD(H)/NADP(H) dependent oxidoreductases that interconvert active and inactive glucocorticoids. For example, 11 β-Hydroxysteroid Dehydrogenase Type 1 (1 Ib-HSDl) belongs to the short-chain dehydrogenase/reductase family of enzymes. Specifically, 1 Ib- HSDl catalyses the conversion of inactive and active glucocorticoids in a number of tissues and organs including adipose tissue, liver, bone, pancreas, endothelium, ocular tissue, muscle and parts of the central nervous system (Hosfield et al, J. Biol. Chem., in press). [0004] 1 Ib-HSDl has been implicated in the metabolic syndrome and type-2 diabetes in a number of studies. The non-specific 1 Ib-HSDl inhibitor carbenoxolone increases insulin sensitivity in healthy, lean, humans as well as those with the symptoms of type-2 diabetes. Mice that overexpress 1 Ib-HSDl in adipocytes develop hyderlipidemia, insulin resistance and visceral obesity. This phenotype has been shown to resemble the human metabolic syndrome (Andrews et al, J. CHn. Endocrinol. Metab., 88, 285 (2003)). 1 Ib- HSDl knockout mice have shown resistance to developing obesity -induced, and stress- induced, insulin resistance as well as displaying decreased HDL-cholesterol and VLDL triglycerides. These findings have stimulated interest in inhibitors of 1 Ib-HSDl as potential drugs for the treatment of disorders where a decreased level of active intracellular glucocorticoid is desired.
[0005] There is a continued need to find new therapeutic agents to treat human diseases. The hydroxysteroid dehydrogenases, specifically but not limited to 1 lβ- Hydroxysteroid Dehydrogenase Type 1 , are especially attractive targets for the discovery of new therapeutics due to their important role in the metabolic syndrome, Cushing's disease, hypertension, cognitive function, ocular function and other diseases.
SUMMARY OF THE INVENTION
[0006] The present invention relates to compounds that have activity for inhibiting hydroxysteroid dehydrogenases. The present invention also provides compositions, articles of manufacture and kits comprising these compounds.
[0007] In one embodiment, a pharmaceutical composition is provided that comprises a hydroxysteroid dehydrogenase inhibitor according to the present invention as an active ingredient. Pharmaceutical compositions according to the invention may optionally comprise 0.001%- 100% of one or more hydroxysteroid dehydrogenase inhibitors of this invention. These pharmaceutical compositions may be administered or coadministered by a wide variety of routes, including for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally. The compositions may also be administered or coadministered in slow release dosage forms.
[0008] The invention is also directed to kits and other articles of manufacture for treating disease states associated with hydroxysteroid dehydrogenases.
[0009] In one embodiment, a kit is provided that comprises a composition comprising at least one hydroxysteroid dehydrogenase inhibitor of the present invention in combination with instructions. The instructions may indicate the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition. The kit may also comprise packaging materials. The packaging material may comprise a container for housing the composition. The kit may also optionally comprise additional components, such as syringes for administration of the composition. The kit may comprise the composition in single or multiple dose forms.
[0010] In another embodiment, an article of manufacture is provided that comprises a composition comprising at least one hydroxysteroid dehydrogenase inhibitor of the present invention in combination with packaging materials. The packaging material may comprise a container for housing the composition. The container may optionally comprise a label indicating the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition. The kit may also optionally comprise additional components, such as syringes for administration of the composition. The kit may comprise the composition in single or multiple dose forms.
[0011] Also provided are methods for preparing compounds, compositions and kits according to the present invention. For example, several synthetic schemes are provided herein for synthesizing compounds according to the present invention.
[0012] Also provided are methods for using compounds, compositions, kits and articles of manufacture according to the present invention.
[0013] In one embodiment, the compounds, compositions, kits and articles of manufacture are used to inhibit hydroxysteroid dehydrogenases. In particular, the compounds, compositions, kits and articles of manufacture can be used to inhibit 11-β
Hydroxysteroid Dehydrogenase Type 1. [0014] In another embodiment, the compounds, compositions, kits and articles of manufacture are used to treat a disease state for which hydroxysteroid dehydrogenases possess activity that contributes to the pathology and/or symptomology of the disease state.
[0015] In another embodiment, a compound is administered to a subject wherein hydroxysteroid dehydrogenase activity within the subject is altered, preferably reduced. [0016] In another embodiment, a prodrug of a compound is administered to a subject that is converted to the compound in vivo where it inhibits hydroxysteroid dehydrogenase. [0017] In another embodiment, a method of inhibiting hydroxysteroid dehydrogenases is provided that comprises contacting a hydroxysteroid dehydrogenase with a compound according to the present invention.
[0018] In another embodiment, a method of inhibiting hydroxysteroid dehydrogenases is provided that comprises causing a compound according to the present invention to be present in a subject in order to inhibit hydroxysteroid dehydrogenase in vivo. [0019] In another embodiment, a method of inhibiting an hydroxysteroid dehydrogenase is provided that comprises administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits hydroxysteroid dehydrogenase in vivo. It is noted that the compounds of the present invention may be the first or second compounds.
[0020] In another embodiment, a therapeutic method is provided that comprises administering a compound according to the present invention.
[0021] In another embodiment, a method of treating a condition in a patient which is known to be mediated by hydroxysteroid dehydrogenases, or which is known to be treated by hydroxysteroid dehydrogenase inhibitors, comprising administering to the patient a therapeutically effective amount of a compound according to the present invention. [0022] In another embodiment, a method is provided for treating a disease state for which hydroxysteroid dehydrogenases possess activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: causing a compound according to the present invention to be present in a subject in a therapeutically effective amount for the disease state. [0023] In another embodiment, a method is provided for treating a disease state for which hydroxysteroid dehydrogenases possess activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a first compound to a subject that is converted in vivo to a second compound such that the second compound is present in the subject in a therapeutically effective amount for the disease state. It is noted that the compounds of the present invention may be the first or second compounds.
[0024] In another embodiment, a method is provided for treating a disease state for which hydroxysteroid dehydrogenases possess activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a compound according to the present invention to a subject such that the compound is present in the subject in a therapeutically effective amount for the disease state. [0025] In another embodiment, a method is provided for using a compound according to the present invention in order to manufacture a medicament for use in the treatment of a disease state that is known to be mediated by hydroxysteroid dehydrogenases, or that is known to be treated by hydroxysteroid dehydrogenase inhibitors. [0026] It is noted in regard to all of the above embodiments that the present invention is intended to encompass all pharmaceutically acceptable ionized forms (e.g., salts) and solvates (e.g., hydrates) of the compounds, regardless of whether such ionized forms and solvates are specified since it is well know in the art to administer pharmaceutical agents in an ionized or solvated form. It is also noted that unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all possible stereoisomers (e.g., enantiomers or diastereomers depending on the number of chiral centers), independent of whether the compound is present as an individual isomer or a mixture of isomers. Further, unless otherwise specified, recitation of a compound is intended to encompass all possible resonance forms and tautomers. With regard to the claims, the language "compound comprising the formula" is intended to encompass the compound and all pharmaceutically acceptable ionized forms and solvates, all possible stereoisomers, and all possible resonance forms and tautomers unless otherwise specifically specified in the particular claim. [0027] It is further noted that prodrugs may also be administered which are altered in vivo and become a compound according to the present invention. The various methods of using the compounds of the present invention are intended, regardless of whether prodrug delivery is specified, to encompass the administration of a prodrug that is converted in vivo to a compound according to the present invention. It is also noted that certain compounds of the present invention may be altered in vivo prior to inhibiting hydroxysteroid dehydrogenases and thus may themselves be prodrugs for another compound. Such prodrugs of another compound may or may not themselves independently have hydroxysteroid dehydrogenase inhibitory activity.
BRIEF DESCRIPTION OF THE FIGURES
[0028] Figure 1 illustrates SEQ. ID Nos. 1, 2, 3 and 4 referred to in this application.
DEFINITIONS
[0029] Unless otherwise stated, the following terms used in the specification and claims shall have the following meanings for the purposes of this Application.
[0030] "Alicyclic" means a moiety comprising a non-aromatic ring structure. Alicyclic moieties may be saturated or partially unsaturated with one, two or more double or triple bonds. Alicyclic moieties may also optionally comprise heteroatoms such as nitrogen, oxygen and sulfur. The nitrogen atoms can be optionally quateraerized or oxidized and the sulfur atoms can be optionally oxidized. Examples of alicyclic moieties include, but are not limited to moieties with C3-8 rings such as cyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene, cycloheptadiene, cyclooctane, cyclooctene, and cyclooctadiene.
[0031] "Aliphatic" means a moiety characterized by a straight or branched chain arrangement of constituent carbon atoms and may be saturated or partially unsaturated with one, two or more double or triple bonds.
[0032] "Alkoxy" means an oxygen moiety having a further alkyl substituent. The alkoxy groups of the present invention can be optionally substituted.
[0033] "Alkyl" represented by itself means a straight or branched, saturated or unsaturated, aliphatic radical having a chain of carbon atoms, optionally with oxygen (See "oxaalkyl") or nitrogen atoms (See "aminoalkyl") between the carbon atoms. Cx alkyl and Cχ.γ alkyl are typically used where X and Y indicate the number of carbon atoms in the chain. For example, Ci-6 alkyl includes alkyls that have a chain of between 1 and 6 carbons (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and the like). Alkyl represented along with another radical (e.g., as in arylalkyl, heteroarylalkyl) means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when no atoms are indicated means a bond (e.g., (C6-i0)aryl(Ci-3)alkyl includes, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-thienylmethyl, 2-pyridinylmethyl and the like). [0034] "Alkenyl" means a straight or branched, carbon chain that contains at least one carbon— carbon double bond. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. [0035] "Alkynyl" means a straight or branched, carbon chain that contains at least one carbon— carbon triple bond. Examples of alkynyl include ethynyl, propargyl, 3-methyl-l- pentynyl, 2-heptynyl and the like.
[0036] "Alkylene", unless indicated otherwise, means a straight or branched, saturated or unsaturated, aliphatic, divalent radical. Cx alkylene and Cχ.γ alkylene are typically used where X and Y indicate the number of carbon atoms in the chain. For example, Ci-6 alkylene includes methylene (-CH2-), ethylene (-CH2CH2-), trimethylene (-CH2CH2CH2-), tetramethylene (-CH2CH2CH2CH2-) 2-butenylene (-CH2CH=CHCH2-), 2-methyltetramethylene (-CH2CH(CH3)CH2CH2-), pentamethylene (-CH2CH2CH2CH2CH2-) and the like).
[0037] "Alkylidene" means a straight or branched saturated or unsaturated, aliphatic radical connected to the parent molecule by a double bond. Cx alkylidene and Cχ.γ alkylidene are typically used where X and Y indicate the number of carbon atoms in the chain. For example, Ci-6 alkylidene includes methylene (=CH2), ethylidene (=CHCH3), isopropylidene (=C(CH3)2), propylidene (=CHCH2CH3), allylidene (=CH-CH=CH2), and the like).
[0038] "Amino" means a nitrogen moiety having two further substituents where, for example, a hydrogen or carbon atom is attached to the nitrogen. For example, representative amino groups include -NH2, -NHCH3, -N(CH3)2, -NHCi-10-alkyl, -N(C1-I0- alkyl)2) -NHaryl, -NHheteroaryl, -N(aryl)2, -N(heteroaryl)2, and the like. Optionally, the two substituents together with the nitrogen may also form a ring. Unless indicated otherwise, the compounds of the invention containing amino moieties may include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
[0039] "Aminoalkyl" means an alkyl, as defined above, except where one or more substituted or unsubstituted nitrogen atoms (-N-) are positioned between carbon atoms of the alkyl. For example, an (C2-6) aminoalkyl refers to a chain comprising between 2 and 6 carbons and one or more nitrogen atoms positioned between the carbon atoms.
[0040] "Animal" includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds, and the like).
[0041] "Aromatic" means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp2 hybridized and the total number of pi electrons is equal to 4n+2. An aromatic ring may be such that the ring atoms are only carbon atoms or may include carbon and non-carbon atoms (see Heteroaryl).
[0042] "Aryl" means a monocyclic or polycyclic ring assembly wherein each ring is aromatic or when fused with one or more rings forms an aromatic ring assembly. If one or more ring atoms is not carbon (e.g., N, S), the aryl is a heteroaryl. Cx aryl and Cχ.γ aryl are typically used where X and Y indicate the number of atoms in the ring.
[0043] "Bicycloalkyl" means a saturated or partially unsaturated fused bicyclic or bridged polycyclic ring assembly.
[0044] "Bicycloaryl" means a bicyclic ring assembly wherein the rings are linked by a single bond or fused and at least one of the rings comprising the assembly is aromatic. Cx bicycloaryl and Cχ.γ bicycloaryl are typically used where X and Y indicate the number of carbon atoms in the bicyclic ring assembly and directly attached to the ring.
[0045] "Bridging ring" as used herein refers to a ring that is bonded to another ring to form a compound having a bicyclic structure where two ring atoms that are common to both rings are not directly bound to each other. Non-exclusive examples of common compounds having a bridging ring include borneol, norbornane, 7- oxabicyclo[2.2.1]heptane, and the like. One or both rings of the bicyclic system may also comprise heteroatoms.
[0046] "Carbamoyl" means the radical -OC(O)NR3Rb where R3 and Rb are each independently two further substituents where a hydrogen or carbon atom is attached to the nitrogen.
[0047] "Carbocycle" means a ring consisting of carbon atoms.
[0048] "Carbocyclic ketone derivative" means a carbocyclic derivative wherein the ring contains a -CO- moiety.
[0049] "Carbonyl" means the radical -CO-. It is noted that the carbonyl radical may be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, aldehydes, amides, esters, and ketones.
[0050] "Carboxy" means the radical -CO2-. It is noted that compounds of the invention containing carboxy moieties may include protected derivatives thereof, i.e., where the oxygen is substituted with a protecting group. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like.
[0051] "Cyano" means the radical -CN.
[0052] "Cycloalkyl" means a non-aromatic, saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly. Cx cycloalkyl and Cχ.γ cycloalkyl are typically used where X and Y indicate the number of carbon atoms in the ring assembly. For example, C3-I0 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl,
2-oxobicyclo[2.2.1]hept-l-yl, and the like.
[0053] "Cycloalkylene" means a divalent saturated or partially unsaturated, monocyclic or polycyclic ring assembly. Cx cycloalkylene and Cχ.γ cycloalkylene are typically used where X and Y indicate the number of carbon atoms in the ring assembly.
[0054] "Disease" specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the "side effects" of such therapy.
[0055] "Fused ring" as used herein refers to a ring that is bonded to another ring to form a compound having a bicyclic structure when the ring atoms that are common to both rings are directly bound to each other. Non-exclusive examples of common fused rings include decalin, naphthalene, anthracene, phenanthrene, indole, furan, benzofuran, quinoline, and the like. Compounds having fused ring systems may be saturated, partially saturated, carbocyclics, heterocyclics, aromatics, heteroaromatics, and the like.
[0056] "Halo" means fluoro, chloro, bromo or iodo.
[0057] "Halo-substituted alkyl", as an isolated group or part of a larger group, means
"alkyl" substituted by one or more "halo" atoms, as such terms are defined in this
Application. Halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g. halo-substituted (Ci.3)alkyl includes chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl,
2,2,2-trifluoro-l,l-dichloroethyl, and the like).
[0058] "Heteroatom" refers to an atom that is not a carbon atom. Particular examples of heteroatoms include, but are not limited to nitrogen, oxygen, and sulfur.
[0059] "Heteroatom moiety" includes a moiety where the atom by which the moiety is attached is not a carbon. Examples of heteroatom moieties include -N=, -NRc-, -N+(O")=,
-O-, -S- or -S(O)2-, wherein Rc is further substituent.
[0060] "Heterobicycloalkyl" means bicycloalkyl, as defined in this Application, provided that one or more of the atoms within the ring is a heteroatom. For example hetero(C9-i2)bicycloalkyl as used in this application includes, but is not limited to, 3-aza- bicyclo[4.1.0]hept-3-yl, 2-aza-bicyclo[3.1.0]hex-2-yl , 3-aza-bicyclo[3.1.0]hex-3-yl, and the like.
[0061] "Heterocycloalkylene" means cycloalkylene, as defined in this Application, provided that one or more of the ring member carbon atoms is replaced by a heteroatom.
[0062] "Heteroaryl" means a cyclic aromatic group having five or six ring atoms, wherein at least one ring atom is a heteroatom and the remaining ring atoms are carbon.
The nitrogen atoms can be optionally quaternerized and the sulfur atoms can be optionally oxidized. Heteroaryl groups of this invention include, but are not limited to, those derived from furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrroline, thiazole, 1,3,4-thiadiazole, triazole and tetrazole. "Heteroaryl" also includes, but is not limited to, bicyclic or tricyclic rings, wherein the heteroaryl ring is fused to one or two rings independently selected from the group consisting of an aryl ring, a cycloalkyl ring, a cycloalkenyl ring, and another monocyclic heteroaryl or heterocycloalkyl ring. These bicyclic or tricyclic heteroaryls include, but are not limited to, those derived from benzo[b]furan, benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridine, quinazoline, thieno[2,3-c]pyridine, thieno[3,2- b]pyridine, thieno[2,3-b]pyridine, indolizine, imidazo[l,2a]pyridine, quinoline, isoquinoline, phthalazine, quinoxaline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, imidazo[l,5-a]pyridine, pyrazolo[ 1 ,5-a]pyridine, imidazo[ 1 ,2-a]pyrimidine, imidazo[ 1 ,2-c]pyrimidine, imidazo[l,5-a]pyrimidine, imidazo[l,5-c]pyrimidine, pyrrolo[2,3-b]pyridine, pyrrolo[2,3- c]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b]pyridine, pyrrolo[2,3-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-b]pyrazine, pyrazolo[l,5-a]pyridine, pyrrolo[l,2- bjpyridazine, pyrrolo[l,2-c]pyrimidine, pyrrolo[l,2-a]pyrimidine, pyrrolo[l,2-a]pyrazine, triazo[l,5-a]pyridine, pteridine, purine, carbazole, acridine, phenazine, phenothiazene, phenoxazine, l,2-dihydropyrrolo[3,2,l-/i/]indole, indolizine, pyrido[l,2-a]indole and 2(lH)-pyridinone. The bicyclic or tricyclic heteroaryl rings can be attached to the parent molecule through either the heteroaryl group itself or the aryl, cycloalkyl, cycloalkenyl or heterocycloalkyl group to which it is fused. The heteroaryl groups of this invention can be substituted or unsubstituted.
[0063] "Heterobicycloaryl" means bicycloaryl, as defined in this Application, provided that one or more of the atoms within the ring is a heteroatom. For example, hetero(C4_i2)bicycloaryl as used in this Application includes, but is not limited to, 2-amino-4-oxo-3,4-dihydropteridin-6-yl, tetrahydroisoquinolinyl, and the like. [0064] "Heterocycloalkyl" means cycloalkyl, as defined in this Application, provided that one or more of the atoms forming the ring is a heteroatom selected, independently from N, O, or S. Non-exclusive examples of heterocycloalkyl include piperidyl, 4- morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolizinyl, 1,4-diazaperhydroepinyl, 1,3-dioxanyl, 1,4-dioxanyl and the like. [0065] "Hydroxy" means the radical -OH.
[0066] "Iminoketone derivative" means a derivative comprising the moiety -C(NR)-, wherein R comprises a hydrogen or carbon atom attached to the nitrogen. [0067] "Isomers" mean any compound having an identical molecular formulae but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereomers" and stereoisomers that are nonsuperimposable mirror images are termed "enantiomers" or sometimes "optical isomers." A carbon atom bonded to four nonidentical substituents is termed a "chiral center." A compound with one chiral center has two enantiomeric forms of opposite chirality. A mixture of the two enantiomeric forms is termed a "racemic mixture." A compound that has more than one chiral center has 2""1 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as ether an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture." When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and 5-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g., see "Advanced Organic Chemistry", 4th edition, March, Jerry, John Wiley & Sons, New York, 1992).
[0068] "Nitro" means the radical -NO2.
[0069] "Oxaalkyl" means an alkyl, as defined above, except where one or more oxygen atoms (-O-) are positioned between carbon atoms of the alkyl. For example, an (C2- 6)oxaalkyl refers to a chain comprising between 2 and 6 carbons and one or more oxygen atoms positioned between the carbon atoms.
[0070] "Oxoalkyl" means an alkyl, further substituted with a carbonyl group. The carbonyl group may be an aldehyde, ketone, ester, amide, acid or acid chloride. [0071] "Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use. [0072] "Pharmaceutically acceptable salts" means salts of inhibitors of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, ø-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, /7-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like. [0073] Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
[0074] "Prodrug" means a compound that is convertible in vivo metabolically into an inhibitor according to the present invention. The prodrug itself may or may not also have hydroxysteroid dehydrogenase inhibitory activity. For example, an inhibitor comprising a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy compound. Suitable esters that may be converted in vivo into hydroxy compounds include acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates, esters of amino acids, and the like. Similarly, an inhibitor comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine compound. [0075] "Protected derivatives" means derivatives of inhibitors in which a reactive site or sites are blocked with protecting groups. Protected derivatives are useful in the preparation of inhibitors or in themselves may be active as inhibitors. A comprehensive list of suitable protecting groups can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999. [0076] "Ring" means a carbocyclic or a heterocyclic system.
[0077] "Substituted or unsubstituted" means that a given moiety may consist of only hydrogen substituents through available valencies (unsubstituted) or may further comprise one or more non-hydrogen substituents through available valencies (substituted) that are not otherwise specified by the name of the given moiety. For example, isopropyl is an example of an ethylene moiety that is substituted by -CH3. In general, a non-hydrogen substituent may be any substituent that may be bound to an atom of the given moiety that is specified to be substituted. Examples of substituents include, but are not limited to, aldehyde, alicyclic, aliphatic, (Ci-Io)alkyl, alkylene, alkylidene, amide, amino, aminoalkyl, aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl, carbocyclyl, carboxyl, carbonyl group, cycloalkyl, cycloalkylene, ester, halo, heterobicycloalkyl, heterocycloalkylene, heteroaryl, heterobicycloaryl, heterocycloalkyl, oxo, hydroxy, iminoketone, ketone, nitro, oxaalkyl, and oxoalkyl moieties, each of which may optionally also be substituted or unsubstituted.
[0078] "Sulfinyl" means the radical -SO-. It is noted that the sulfinyl radical may be further substituted with a variety of substituents to form different sulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters, and sulfoxides.
[0079] "Sulfonyl" means the radical -SO2-. It is noted that the sulfonyl radical may be further substituted with a variety of substituents to form different sulfonyl groups including sulfonic acids, sulfonamides, sulfonate esters, and sulfones. [0080] "Therapeutically effective amount" means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease. [0081] "Thiocarbonyl" means the radical -CS-. It is noted that the thiocarbonyl radical may be further substituted with a variety of substituents to form different thiocarbonyl groups including thioacids, thioamides, thioesters, and thioketones. [0082] "Treatment" or "treating" means any administration of a compound of the present invention and includes:
(1) preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease,
(2) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or
(3) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology) .
[0083] It is noted in regard to all of the definitions provided herein that the definitions should be interpreted as being open ended in the sense that further substituents beyond those specified may be included. Hence, a Ci alkyl indicates that there is one carbon atom but does not indicate what are the substituents on the carbon atom. Hence, a Ci alkyl comprises methyl (i.e., -CH3) as well as -CR3RbRc where Ra, Rb, and Rc may each independently be hydrogen or any other substituent where the atom attached to the carbon is a heteroatom or cyano. Hence, CF3, CH2OH and CH2CN, for example, are all Ci alkyls.
DETAILED DESCRIPTION OF THE INVENTION
[0084] The present invention relates to compounds, compositions, kits and articles of manufacture that may be used to inhibit hydroxysteroid dehydrogenases and, in particular, l lβ-hydroxysteroid dehydrogenase type 1 (referred to herein as 1 Ib-HSDl). [0085] 1 Ib-HSDl belongs to the short-chain dehydrogenase/reductase (SDR) family of enzymes, of which over 60 members are found in humans (Oppermann et al., Chem Biol Interact, 143-144, 247-253 (2003); Kallberg et ai, Protein Sci, 11, 636-641 (2002)). SDRs are reversible NAD(H)/NADP(H) dependent oxidoreductases containing a structurally conserved α/β nucleotide-binding Rossman fold. Within the core structure, two conserved motifs are shared among all SDR enzymes. A dinucleotide-binding P-loop forms a turn between a β-strand and an α-helix and directly contacts the ribose sugar and pyrophosphate. A Tyr-X-X-X-Lys motif, often in concert with a conserved Ser that orients substrate, catalyzes proton transfer to and from reduced and oxidized reaction intermediates. A flexible region in SDR enzymes, that often changes conformation upon substrate binding to shield the active site from bulk solvent, mediates enzyme specificity.
SDR oligomerization and intracellular localization is often mediated by extensions at the
N- and C-termini.
[0086] 1 Ib-HSDl is a NADPH-dependent enzyme that functions predominantly as a reductase in vivo. In cells, a single N-terminal transmembrane helix and associated linker anchors the C-terminal catalytic domain within the lumen of the endoplasmic reticulum
(ER).
[0087] 1 Ib-HSDl is important in regulating local concentrations of glucocorticoids in various tissue types, for example, adipose, vascular, brain, testis, ocular and placental.
Disregulation of 1 Ib-HSDl is implicated in such areas as the metabolic syndrome,
Cushing's disease, hypertension, cognitive function, and ocular function.
[0088] It is noted that the compounds of the present invention may also possess inhibitory activity for other short chain dehydrogenase family members and thus may be used to address disease states associated with these other family members.
Crystal Structure of llβ-Hydroxysteroid Dehydrogenase
[0089] Syrrx, Inc. (San Diego, California) solved the crystal structure of 1 lβ- hydroxysteroid dehydrogenase type 1 (1 Ib-HSDl) (U.S. Patent Application Serial Nos. 10/800,024, filed March 12, 2004, and 10/800,427, filed March 12, 2004, each of which is hereby incorporated herein by reference in its entirety). Knowledge of the crystal structure was used to guide the design of the inhibitors provided herein. [0090] The overall Rossman fold topology of 1 Ib-HSDl resembles other SDR enzymes in which a central 6-stranded, all-parallel β-sheet is sandwiched on both sides by 3 α-helices (Hosfield et al, J. Biol Chem., in press). A conformationally-variable β6-α6 insertion that forms one wall of the steroid binding pocket, an additional β-strand (β7) and two Cterminal α-helices (αE and αF) are appended to the core structure and complete the 1 Ib-HSDl fold. NADP+ binding to 1 Ib-HSDl is similar to other SDR enzymes, with the molecule binding in an extended conformation in which both ribose sugars adopt a C2- endo conformation. The adenine and nicotinamide rings are both well ordered and bind roughly perpendicular to the plane of the ribose sugars with the adenine adopting an anti configuration and the nicotinamide adopting a syn configuration. The adenosine moiety lies in a cleft formed by 4 loops (βl/αl, β2/α2, β3/α3, and β4/α4) and an α-helix (α4).
Hydroxysteroid Dehydrogenase Inhibitors
[0091] In one embodiment, hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
wherein:
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NR^;
Ri is selected from the group consisting of (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R2 is selected from the group consisting of
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-Io)alkyl, (C3_i2)cycloalkyl, hetero(C3-12)cycloalkyl, (Cg-i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(CM0)alkyl, halo(C1-10)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C]-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-i2)cycloalkyl, hetero(C3.12)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-io)alkyl, heteroaryl(C1-5)alkyl, (C3-12)cycloalkyl(C x .10)alkyl, halo(C i A 0)alkyl, carbonyl(C \ -3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, imino(C1.3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(Ci.10)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-1o)alkyl, (C3.12)cycloalkyl(Ci-i0)alkyl, halo(Ci.]o)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci.3)alkyl, amino (Ci-io)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-Io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3.12)bicycloalkyl, aryl(Ci.iO)alkyl, heteroaryl(Ci_5)alkyl, perhalo(Ci-io)alkyl, (C3.i2)cycloalkyl(Ci_io)alkyl, halo(Ci-io)alkyl, carbonyl(C1.3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(Ci_3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-Io)alkyl, (C3-)2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C1.5)alkyl, perhalo(C1-io)alkyl, (C3- 12)cycloalkyl(C i_10)alkyl, halo(C i . , 0)alkyl, carbonyl(C 1-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, amino (C1-i0)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9.]2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R9, Ri0, Rn and R12 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C].io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci.io)alkyl, (C3-i2)cycloalkyl(C1-io)alkyl, halo(Ci.i0)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (C]-Io)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9, Rio, Ri 1 and Ri2 are taken together to form a ring; Ri3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-1O)BIlCyI, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.iO)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci.i0)alkyl, (C3-12)cycloalkyl(Ci-i0)alkyl, halo(CM0)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C).3)alkyl, sulfinyl(Ci-3)alkyl, amino (C].iO)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or Ri3 and any one of R7, Rg and Rn are taken together to form a ring;
Ri5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl, halo(C1-K))alkyl, carbonyl(Ci_3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4_i2)bicycloaryl, each substituted or unsubstituted;
X is selected from the group consisting of unsubstituted and substituted Ci _6 alkylenes; and
Y is selected from the group consisting of (C3.i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted.
[0092] In one embodiment, hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
wherein: n is selected from the group consisting of 0, 1, 2,3, 4 and 5;
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NRi5; R2 is selected from the group consisting of
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci_5)alkyl, (C3-i2)cycloalkyl(Ci_io)alkyl, halo(Ci-io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3.i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-1o)alkyl, heteroaryl(C1-5)alkyl, (C3- 12)cycloalkyl(C i .10)alkyl, halo(C i . , 0)alkyl, carbonyl(C i -3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C]-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci_1o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-12)cycloalkyl, hetero(C3.i2)cycloalkyl, hetero(C3.12)bicycloalkyl, aryl(C1-ιo)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-io)alkyl, (C3-12)cycloalkyl(C1.1o)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, amino (C1-io)alkyl, imino(C! -3)alkyl, aryl, heteroaryl, (Cg-i^bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-Io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-5)alkyl, perhalo(C1-1o)alkyl, (C3-12)cycloalkyl(Ci-1o)alkyl, halo(C1-1o)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-Io)alkyl, (C3.i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci-io)alkyl, (C3.i2)cycloalkyl(Ci-io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci_3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci.io)alkyl, ImInO(Ci-S)OIlCyI, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R9, Rio, Rn and Ri2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-] 2)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-io)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(Ci_3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9, Rio, Rn and R]2 are taken together to form a ring;
Ri3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci_io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-]2)bicycloalkyl, aryl(Ci.iO)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci_io)alkyl, (C3-i2)cycloalkyl(Ci_io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or Rj3 and any one of R7, R9 and Rn are taken together to form a ring; each Ri4 is independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3_i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-io)alkyl, (C3-i2)cycloalkyl(Ci.i0)alkyl, halo(Ci_io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci_3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted; Ri5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-I2)CyCIo alky 1, hetero(C3-12)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-i0)alkyl, heteroaryl(C i -5)alkyl, (C3- 12)cycloalkyl(C i . i o)alkyl, halo(C \. io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
X is selected from the group consisting of unsubstituted and substituted C1-6 alkylenes; and
Y is selected from the group consisting of (C3.12)cycloalkyl, hetero(C3-12)cycloalkyl, (Cc1-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl, heteroaryl, (Cc)-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted.
[0093] In one embodiment, hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
wherein:
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond; M is selected from the group consisting of S, O and NRi5; R2 is selected from the group consisting of
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-io)alkyl, heteroaryl(C1-5)alkyl, (C3-12)cycloalkyl(C1-io)alkyl, halo(Ci.io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1.3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3.i2)cycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-10)alkyl, heteroaryl(Ci_5)alkyl, (C3-12)cycloalkyl(Ci-10)alkyl, halo(C,-1o)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4.12)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-Io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3_i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(CM0)alkyl, heteroaryl(C i -5)alkyl, perhalo(C i .10)alkyl, (C3-12)cycloalkyl(C i .10)alkyl, halo(C1-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-[2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-] 2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci_io)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci-i0)alkyl, (C3.12)cycloalkyl(C1.1o)alkyl, halo(Ci.io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C].3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-Io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-10)alkyl, (C3-i2)cycloalkyl, hetero(C3.12)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(C1-1o)alkyl, (C3-12)cycloalkyl(Ci.io)alkyl, halo(C1-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfmyl(C1-3)alkyl, amino (Ci.io)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R9, R10, Rn and Rj2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci.io)alkyl, (C3-12)cycloalkyl(Ci.io)alkyl, halo(Ci_io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4.i2)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9, Rio> Ri 1 and R12 are taken together to form a ring;
Ri3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci-Io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci_10)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-10)alkyl, (C3.12)cycloalkyl(C1-10)alkyl, halo(C,-10)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci_1o)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4_12)bicycloaryl, each substituted or unsubstituted, or R13 and any one of R7, R9 and R11 are taken together to form a ring;
Ri5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(C1-10)alkyl, heteroaryl(C1-5)alkyl, (C3-i2)cycloalkyl(C1-io)alkyl, halo(Ci.io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
X is selected from the group consisting of unsubstituted and substituted C1-6 alkylenes; and
Y is selected from the group consisting of (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted.
[0094] In one embodiment, hydroxysteroid dehydrogenase inhibitors of the present invention comprise: wherein:
R2 is selected from the group consisting of
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1O)HIlCyI, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-io)alkyl, heteroaryl(C1.5)alkyl, (C3-i2)cycloalkyl(Ci-10)alkyl, halo(C1-10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(Ci.3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C^i^bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-Io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3.i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg-i^bicycloalkyl, hetero(C3-]2)bicycloalkyl, aryl(C1-io)alkyl, heteroaryl(C i .5)alkyl, perhalo(C i .10)alkyl, (C3.12)cycloalkyl(C \ . \ o)alkyl, halo(Ci.1o)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-i0)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-ιo)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3.i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-10)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci_io)alkyl, (C3.i2)cycloalkyl(C1-10)alkyl, halo(Ci.io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-io)alkyl, imino(C]-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R9, Rio, Rn and R12 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci_1o)alkyl, heteroaryl(Ci_5)alkyl, perhalo(Ci.io)alkyl, (C3-i2)cycloalkyl(Ci.10)alkyl, halo(C1-10)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, and hetero(C4.i2)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9, Rio, Rn and R12 are taken together to form a ring;
R13 is selected from the group consisting of hydrogen, carbonyl, amino, (C1.1o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3.i2)cycloalkyl, hetero(C3_i2)cycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci.io)alkyl, (C3-i2)cycloalkyl(CM0)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or Ri3 and any one of R7, R9 and Rn are taken together to form a ring; X is selected from the group consisting of unsubstituted and substituted C)-6 alkylenes; and
Y is selected from the group consisting of (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3_i2)bicycloalkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted.
[0095] In one embodiment, hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
wherein:
R2 is selected from the group consisting of
R.5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3.12)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C1-5)alkyl, perhalo(Ci.i0)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(Ci.io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, amino (C1-i0)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3.12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-1o)alkyl, (C3-12)cycloalkyl(Ci.]0)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(C1_3)alkyl, sulfinyl(Ci-3)alkyl, amino (C]-10)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, and hetero(C4_12)bicycloaryl, each substituted or unsubstituted; and
Rc1, R1O, Rn and Ri2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3.i2)cycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(Ci-1o)alkyl, heteroaryl(Ci_5)alkyl, perhalo(Ci_io)alkyl, (C3_i2)cycloalkyl(C i _i o)alkyl, halo(C M o)alkyl, carbonyl(C i -3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9, Ri0, Ri 1 and Ri2 are taken together to form a ring.
[0096] In one embodiment, hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
wherein:
R2 is selected from the group consisting of
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-1o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-Io)alkyl, (C3-i2)cycloalkyl, hetero(C3_i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-5)alkyl, perhalo(Ci_io)alkyl, (C3-i2)cycloalkyl(Ci-i0)alkyl, halo(C1-1o)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C]-3)alkyl, sulfinyl(C1-3)alkyl, amino (C1-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C1-5)alkyl, perhalo(Ci-10)alkyl, (C3-] 2)cycloalkyl(C , _i 0)alkyl, halo(C i .10)alkyl, carbonyl(C i -3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Cμ3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted; and
R9, Rio, Rn and Ri2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-i0)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci.io)alkyl, (C3- 12)cycloalkyl(C 1-10)alkyl, halo(C i . , 0)alkyl, carbonyl(C i .3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C]-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9, R10, Rn and Ri2 are taken together to form a ring.
[0097] In one embodiment, hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
wherein:
Ri is selected from the group consisting of (C1-Io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R2 is selected from the group consisting of
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-10)alkyl, heteroaryl(Ci.5)alkyl, (C3.i2)cycloalkyl(Ci-io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4.12)bicycloaryl, each substituted or unsubstituted;
R.5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3.i2)cycloalkyl, hetero(C3.t2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C i _5)alkyl, perhaloCQ . io)alkyl, (C3_i 2)cycloalkyl(C i .10)alkyl, halo(C1-io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-Io)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9_12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3-12)cycloalkyl, hetero(C3.12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3.12)bicycloalkyl, aryl(Ci-10)alkyl, heteroaryl(Ci_5)alkyl, perhalo(C1-10)alkyl, (C3-i2)cycloalkyl(C1-1o)alkyl, halo(C1.1o)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1.3)alkyl, amino (Ci.io)alkyl, imino(Ci,3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R9, Rio, Rn and Rj2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3_i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C].5)alkyl, perhalo(Ci_io)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl, halo(Ci.io)alkyl, carbonyl(Ci_3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(Ci_3)alkyl, sulfinyl(Ci.3)alkyl, amino (Ci.io)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9, Rio, Rn and Ri2 are taken together to form a ring;
Ri3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-]0)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-10)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci_io)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (C1.10)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or Ri3 and any one of R7, R9 and Rn are taken together to form a ring;
X is selected from the group consisting of unsubstituted and substituted C1-6 alkylenes; and
Y is selected from the group consisting of (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted.
[0098] In one embodiment, hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
wherein:
Ri is selected from the group consisting of (C1.io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-i2)bicycloalkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, hetero(C4.]2)bicycloaryl, each substituted or unsubstituted;
R2 is selected from the group consisting of
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1.1o)alkyl, heteroaryl(C ] ^alkyl, perhalo(C ] . i o)alkyl, (C3-12)cycloalkyl(C] .] 0)alkyl, halo(Ci-1o)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci.io)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-5)alkyl, perhalo(C1-io)alkyl, (C3.12)cycloalkyl(C1-io)alkyl, halo(Ci-10)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-Io)alkyl, imino(C]-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted; and
R9, R1O, Rn and R12 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3.i2)cycloalkyl, hetero(C3.i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci_5)alkyl, perhalo(Ci.io)alkyl, (C3-i2)cycloalkyl(Ci-10)alkyl) halo(C1-10)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci_3)alkyl, sulfinyl(C1-3)alkyl, amino (C1-10)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4.i2)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9, Rio, Rn and Ri2 are taken together to form a ring.
[0099] In one embodiment, hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
wherein:
Ri is selected from the group consisting of (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R2 is selected from the group consisting of
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.iO)alkyl, (C3-i2)cycloalkyl, hetero(C3.i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(C 1.s)alkyl, perhalo(C 1. iO)alkyl, (C3- 12)cycloalkyl(C 1.1 o)alkyl, halo(Ci-io)alkyl, carbonyl(C1.3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, amino (C1.i0)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-i0)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3.12)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3_i2)bicycloalkyl, aryl(Ci-i0)alkyl, heteroaryl(Ci-5)alkyl, perhalo(C]-1o)alkyl, (C3-12)cycloalkyl(C1-1o)alkyl, halo(Ci.io)alkyl, carbonyl(Ci_3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl (C 1-3)alkyl, sulfinyl(Ci-3)alkyl, amino (C1-1o)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted; and
R9, R10, Rn and Ri2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3_i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(Ci.iO)alkyl, heteroaryl (C i-5)alkyl, perhalo(Ci-io)alkyl, (C3.12)cycloalkyl(C1-10)alkyl, halo(Ci.io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci_3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9, Rio, Rn and Rn are taken together to form a ring.
[0100] In one embodiment, hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
wherein: J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NR1S;
R1 is selected from the group consisting of (C]_io)alkyl, (C3-]2)cycloalkyl, hetero(C3-12)cycloalkyl, (Cg.^bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl, heteroaryl, (C9-12)bicycloaryl, hetero(C4-]2)bicycloaryl, each substituted or unsubstituted;
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3.12)cycloalkyl, (C9.]2)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1.5)alkyl, (C3-i2)cycloalkyl(Ci.i0)alkyl, halo(C1-1o)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C]-3)alkyl, sulfonyl(Ci_3)alkyl, sulfinyl(C1.3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3.i2)cycloalkyl, hetero(C3.12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-ι2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C]_5)alkyl, (C3-12)cycloalkyl(Ci-io)alkyl, halo(Ci.io)alkyl, carbonyl(C1.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-10)alkyl, heteroaryl(C i -5)alkyl, perhalo(C y . io)alkyl, (C3- 12)cycloalkyl(C i-io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ct.3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(C1.3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-Io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(C1-1o)alkyl, (C3-12)cycloalkyl(C1-io)alkyl, halo(C1-10)alkyl, carbonyl(Ci_3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, amino (C1-10)alkyl, imino(C1.3)alkyl, aryl, heteroaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Q.^alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(C1-5)alkyl, perhalo(Ci-1o)alkyl, (C3-i2)cycloalkyl(C1-10)alkyl, halo(Ci-10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-Io)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, or R7 and R8 are taken together to form a ring;
Ri3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3.i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C].io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-io)alkyl, (C3-12)cycloalkyl(Ci.io)alkyl, halo(C].io)alkyl, carbonyl(Ci_3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or Ri3 and R7 are taken together to form a ring; and R15 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-10)SIlCyI, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-10)alkyl, heteroaryl(C i -5)alkyl, (C3- 12)cycloalkyl(C i .10)alkyl, halo(C i .10)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted.
[0101] In one embodiment, hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
wherein:
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NR1S;
Ri is selected from the group consisting of (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, hetero(C4.i2)bicycloaryl, each substituted or unsubstituted;
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (d.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9.)2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.iO)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl, halo(Ci.io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (Cc)-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1_i0)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3.12)bicycloalkyl, aryl (C 1-1o)alkyl, heteroaryl(C i -5)alkyl, (C3-12)cycloalkyl(Ci-10)alkyl, halo(C1.io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (Cc,-12)bicycloaryl, and hetero(C4.12)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-Io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci_ιo)alkyl, heteroaryl(C]-5)alkyl, perhalo(Ci-1o)alkyl, (C3-12)cycloalkyl(C1-io)alkyl, halo(Ci_io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C]-3)alkyl, sulfinyl(Ci-3)alkyl, amino (C1.i0)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-1o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci.1o)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-io)alkyl, (C3-i2)cycloalkyl(C1.1o)alkyl, halo(Ci-i0)alkyl, carbonyl(Cj.3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (C1-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1.10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-10)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-io)alkyl, (C3-12)cycloalkyl(C1-10)alkyl, halo(Ci-10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or R7 and R8 are taken together to form a ring;
R13 is selected from the group consisting of hydrogen, carbonyl, amino, (C1-Io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-Io)alkyl, (C3.12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(C1-5)alkyl, perhalo(Ci-1o)alkyl, (C3-12)cycloalkyl(C1.10)alkyl, halo(C1.10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-iO)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, or R)3 and R7 are taken together to form a ring; and
R15 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-ι2)bicycloalkyl, aryl(Ci-1o)alkyl, heteroaryl(Ci-5)alkyl, (C3-12)cycloalkyl(C1-10)alkyl, halo(C1-10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4.i2)bicycloaryl, each substituted or unsubstituted.
[0102] In one embodiment, hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
wherein: J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NRi5;
Ri is selected from the group consisting of (Ci.io)alkyl, (C3-12)cycloalkyl, hetero(C3_i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl, heteroaryl, (C9_12)bicycloaryl, hetero(C4.i2)bicycloaryl, each substituted or unsubstituted;
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-)2)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(C].io)alkyl, heteroaryl(C1.5)alkyl, (C3-i2)cycloalkyl(C1-1o)alkyl, halo(C1.1o)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci,3)alkyl, sulfinyl(C]-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci_io)alkyl, heteroaryl(Ci-5)alkyl, (C3-12)cycloalkyl(C1-10)alkyl, halo(Ci-10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci_3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(d-10)alkyl, heteroaryl(C i -5)alkyl, perhalo(C i -10)alkyl, (C3.12)cycloalkyl(C i .10)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-Io)alkyl, (C3.i2)cycloalkyl, hetero(C3.i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci-1o)alkyl, heteroaryl(Ci-5)alkyl, perhalo(C1-10)alkyl, (C3-12)cycloalkyl(C1.1o)alkyl, halo(C]-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1.3)alkyl, amino (CMo)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci_5)alkyl, perhalo(C1-io)alkyl, (C3-12)cycloalkyl(C1-10)alkyl, halo(Ci.10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, amino (C1-io)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R9 and Rio are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3.i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci.io)alkyl, (C3- 12)cycloalkyl(C i . i o)alkyl, halo(C i . io)alkyl, carbonyl(C i .3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(C].3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9 and R10 are taken together to form a ring;
Ri3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9.12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.iO)alkyl, heteroaryl(C1-5)alkyl, perhalo(Ci-1o)alkyl, halo(Ci.io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (C1-io)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-]2)bicycloaryl, each substituted or unsubstituted, or R13 and any one of R7 and R9 are taken together to form a ring; and
R15 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci-10)alkyl, heteroaryl(C \ -5)alkyl, (C3.12)cycloalkyl(C { .1 o)alkyl, halo(C i.10)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted.
[0103] In one embodiment, hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
wherein:
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond; K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NRi5;
Ri is selected from the group consisting of (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3.i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl, heteroaryl, hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(Ci.i0)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (Cg.^bicycloaryl, and hetero(C4_i2)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(Ci.io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci_3)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4.i2)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3.i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci.io)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl, halo(Ci-10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, amino (C1.10)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-1o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1.1o)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryKQ.^alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-10)alkyl, (C3-i2)cycloalkyl(C1-10)alkyl, halo(C1.io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci.3)alkyl, amino (C1.10)alkyl, imino(C1.3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-ι2)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-10)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-5)alkyl, perhalo(Ct_io)alkyl, (C3- 12)cycloalkyl(C L 10)alkyl, halo(C i . x 0)alkyl, carbonyl(C i -3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R9 and R1O are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (Cg.^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Cι-io)alkyl, heteroaryl(C1-5)alkyl, perhalo(Ci-io)alkyl, (C3- 12)cycloalkyl(C 1.1 o)alkyl, 1IaIo(C1.^alkyl, carbonyl (C 1 -3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1.3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9 and Rio are taken together to form a ring; Ri3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-10)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(Ci-iO)alkyl, heteroaryl(C]-5)alkyl, perhalo(Ci.io)alkyl, (C3.i2)cycloalkyl(C1.io)alkyl, halo(CMo)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-10)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.)2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or Rt3 and any one of R7 and R9 are taken together to form a ring; and
Ri5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3.)2)cycloalkyl, hetero(C3.12)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-io)alkyl, heteroaryl(C1-5)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl, halo(Ci.10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, InUnO(C1 -3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted.
[0104] In one embodiment, hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
wherein:
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond; L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NRi5;
Ri is selected from the group consisting of (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C^i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-Io)alkyl, (C3.i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci-5)alkyl, (C3-12)cycloalkyl(Ci.io)alkyl, halo(C1.io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C]-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4.12)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3.i2)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci-5)alkyl, (C3- 12)cycloalkyl(C i -Io)alkyl, halo(C i . io)alkyl, carbonyl(C i -3)alkyl, thiocarbonyl(C1_3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, imino(C1_3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci_5)alkyl, perhalo(Ci.io)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl, halo(Ci.io)alkyl, carbonyl (C i.3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted; R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1.1o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3.i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C]-5)alkyl, perhalo(Ci-io)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(Ci.io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-1o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-iO)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9_12)bicycloalkyl, hetero(C3_12)bicycloalkyl, aryl(C1.1o)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci_io)alkyl, (C3-12)cycloalkyl(C1-10)alkyl, halo(C1-10)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1.3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4.12)bicycloaryl, each substituted or unsubstituted;
R9, R1O, Rn and Ri2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-io)alkyl, (C3-12)cycloalkyl(Ci-io)alkyl, halo(C1-io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9, Rio, Rn and Rj2 are taken together to form a ring;
Ri3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci-10)alkyl, heteroaryl(C1-5)alkyl, perhalo(C1-10)alkyl, (C3.i2)cycloalkyl(Ci-10)alkyl, halo(Ci-i0)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or R]3 and any one of R7, R9 and Rn are taken together to form a ring; and
Ri5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-]2)bicycloalkyl, aryl(C1-i0)alkyl, heteroaryl(C1-5)alkyl, (C3-i2)cycloalkyl(Ci-i0)alkyl, halo(Ci.i0)alkyl, carbonyl(Ci.3)ahcyl, thiocarbonyl(Ci-3)alkyl, sulfonyl (C i.3)alkyl, sulfinyl(C1.3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted.
[0105] In one embodiment, hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
wherein:
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NR )5; Ri is selected from the group consisting of (C1-Io)OIlCyI, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3.12)bicycloalkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(C1.io)alkyl, heteroaryl(Ci.5)alkyl, (C3-12)cycloalkyl(Ci.io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci_3)alkyl, sulfinyl(C1.3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4.12)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3.i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3_i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci_5)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl, halo(Ci.io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci.3)alkyl, imino(Ci_3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4_12)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-1o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3.12)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl (Ci -5)alkyl, perhalo(C1-10)alkyl, (C3-12)cycloalkyl(Ci-io)alkyl, halo(Ci_io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3_i2)cycloalkyl, (C9-12)bicycloalk:yl, hetero(C3-12)bicycloalkyl, OTyI(C1-10)BIlCyI, heteroaryl(Ci-5)alkyl, PCrIIaIo(Ci-Io)OIlCyI, (C3-i2)cycloalkyl(Ci-io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, amino (C1-10)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-Io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-1o)alkyl, heteroaryl(C].5)alkyl, perhalo(C1-10)alkyl, (C3-12)cycloalkyl(C1-1o)alkyl, halo(Ci-1o)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1.3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci.io)alkyl, imino(C1.3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R9, Rio, Rn and R12 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.1o)alkyl, heteroaryl(C1-5)alkyl, perhalo(Ci-io)alkyl, (C3-12)cycloalkyl(Ci.i0)alkyl, halo(Ci.i0)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-io)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4.i2)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9, Rio, Rn and Ri2 are taken together to form a ring;
Ri3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(C].iO)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-io)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(Ci.io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4.12)bicycloaryl, each substituted or unsubstituted, or Ri3 and any one of R7, R9 and Rn are taken together to form a ring; and
Ri5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3.i2)cycloalkyl, hetero(C3_i2)bicycloalkyl, aryl(Ci_io)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl, halo(Ci.io)alkyl, carbonyl(Ci_3)alkyl, thiocarbonyl(Ci_3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci_3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted.
[0106] In one embodiment, hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
R4 R3 \ v
\
wherein:
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NRi5;
Ri is selected from the group consisting of (C1-io)alkyl, (C3.]2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, hetero(C4-i2)bicycloaryl, each substituted or unsubstituted; R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3.i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(Ci.iO)alkyl, heteroaryl(Ci-5)alkyl, (C3.12)cycloalkyl(Ci.io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-io)alkyl, heteroaryl(C1-5)alkyl, (C3-12)cycloalkyl(C1.1o)alkyl, halo(C1-10)alkyl, carbonyl(C1.3)alkyl, thiocarbonyl(C!.3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-10)alkyl, heteroaryl(C1-5)alkyl, perhalo(Ci-1o)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl, halo(C1-1o)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci.3)alkyl, amino (C1-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-Io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci-iO)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci-io)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl, halo(Ci-io)alkyl, carbonyl(C1.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, amino (C1-10)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4.12)bicycloaryl, each substituted or unsubstituted;
Ri5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3_i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, (C3-12)cycloalkyl(Ci-io)alkyl, halo(Ci-10)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
X is selected from the group consisting of unsubstituted and substituted C1-6 alkylenes; and
Y is selected from the group consisting of (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3.12)bicycloalkyl, aryl, heteroaryl, (C9.12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted.
[0107] In one embodiment, hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
wherein: n is selected from the group consisting of 0, 1, 2,3, 4 and 5;
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that
K is CR6 and R6 is absent when K forms part of a double bond; L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NRi5;
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci_iO)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl, halo(CMo)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci.3)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3-ι2)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-i0)alkyl, heteroaryl(C1-5)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl, halo(C1-io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.12)bicycloaryl, and hetero(C4_i2)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Q.icOalkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-i2)cycloalkyl, hetero(C3.i2)cycloalkyl, (C9_12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C1-5)alkyl, perhalo(Ci-io)alkyl, (C3.12)cycloalkyl(Ci-io)alkyl, halo(Ci-1o)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci_3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-10)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-i0)alkyl, (C3-i2)cycloalkyl(Ci.10)alkyl, 1IaIo(C1. io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C|-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.jo)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3_12)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C1-5)alkyl, perhalo(Ci-io)alkyl, (C3-12)cycloalkyl(CMo)alkyl, halo(C1-1o)alkyl, carbonyl(d.3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, amino (C1-1o)alkyl, imino(C1.3)alkyl, aryl, heteroaryl, (C9_12)bicycloaryl, and hetero(C4_12)bicycloaryl, each substituted or unsubstituted, or R7 and R8 are taken together to form a ring;
R13 is selected from the group consisting of hydrogen, carbonyl, amino, (C1.1o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-Io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-10)alkyl, heteroaryl(C1-5)alkyl, perhalo(C1-ιo)alkyl, (C3-]2)cycloalkyl(C1.io)alkyl, halo(C1-10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, amino (C1-io)alkyl, imino(Cι-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, or R13 and R7 are taken together to form a ring; each Ru is independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-1o)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci_io)alkyl, (C3.12)cycloalkyl(C i . i o)alkyl, halo(C i . i o)alkyl, carbonyl(C i .3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(Ci_3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted; and
Ri5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-10)alkyl, heteroaryl(C i -5)alkyl, (C3- 12)cycloalkyl(C i . iO)alkyl, halo(C i . io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C]-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted.
[0108] In one embodiment, hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
wherein: n is selected from the group consisting of 0, 1, 2,3, 4 and 5;
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NRi5; R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-iO)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, (C3-12)cycloalkyl(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4.i2)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-Io)alkyl, (C3-]2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-] 2)bicycloalkyl, hetero(C3_i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl (C i.5)alkyl, (C3.12)cycloalkyl(C , .i 0)alkyl, halo(Q .i o)alkyl, carbonyl(C i .3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci.3)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (C9-] 2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-Io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C]-Io)alkyl, (C3-]2)cycloalkyl, hetero(C3-12)cycloalkyl, (Cg.^bicycloalkyl, hetero(C3.12)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-]o)alkyl, (C3-i2)cycloalkyl(C1-1o)alkyl, halo(Ci.io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-io)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C 1 -s)alkyl, perhalo(C 1.10)alkyl, (C3-) 2)cycloalkyl(C 1.1 o)alkyl, halo(Ci.io)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C]-3)alkyl, sulfinyl(C1-3)alkyl, amino (C1-Io)-UlCyI, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3_12)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-10)alkyl, heteroaryl(C1-5)alkyl, perhalo(Ci_io)alkyl, (C3- 12)cycloalkyl(C i . i o)alkyl, halo(C i . i o)alkyl, carbonyl(C i -3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R9 and R10 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-5)alkyl, perhalo(C1-io)alkyl, (C3-12)cycloalkyl(C1-1o)alkyl, halo(C1-10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C]-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-Io)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9 and R10 are taken together to form a ring;
R13 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci-Io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-io)alkyl, (C3-12)cycloalkyl(Ci.io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or R13 and any one of R7 and R9 are taken together to form a ring; each Ri4 is independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.iO)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci.io)alkyl, (C3- 12)cycloalkyl(C i . i o)alkyl, halo(C i . i o)alkyl, carbonyl (C i -3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, he'teroaryl, (Cg-i^bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted; and
R15 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cc>.i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C i -5)alkyl, (C3- 12)cycloalkyl(C i -io)alkyl, halo(C [ . io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci_3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(C1-3)alkyl, imino(C].3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4.i2)bicycloaryl, each substituted or unsubstituted.
[0109] In one embodiment, hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
wherein: n is selected from the group consisting of 0, 1, 2,3, 4 and 5;
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond; K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NRj5;
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-ι2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cc1-12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci-5)alkyl, (C3-12)cycloalkyl(Ci-io)alkyl, halo(Ci-1o)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C1.3)alkyl, sulfonyl(C1.3)alkyl, sulfinyl(C1-3)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-Io)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (Cg-i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, ^yI(C1.10)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(Ci-1o)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-Io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci_io)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci.i0)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci.3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted; R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C].1o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3.i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-)2)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-5)alkyl, perhalo(Ci-10)alkyl, (C3-12)cycloalkyl(Ci-10)alkyl, halo(Ci-1o)alkyl, carbonyl(C1.3)alkyl, thiocarbonyl(C]-3)alkyl, sulfonyl (C i_3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-Io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-12)cycloalkyl, hetero(C3.12)cycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-10)alkyl, heteroaryl(C1-5)alkyl, perhalo(C1-10)alkyl, (C3-i2)cycloalkyl(Ci-i0)alkyl, halo(Ci-1o)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4-ι2)bicycloaryl, each substituted or unsubstituted;
R9, R1O, Ri 1 and R12 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3-12)cycloalkyl, hetero(C3_i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3.12)bicycloalkyl, aryl(Ci.iO)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci_io)alkyl, (C3-i2)cycloalkyl(Ci-10)alkyl, halo(Ci.]0)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero^-i^bicycloaryl, each substituted or unsubstituted, or any two Of R7, R8, R9, Rio, Rn and Ri2 are taken together to form a ring;
R13 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.10)alkyl, (C3- 12)cycloalkyl, hetero(C3. ] 2)cycloalkyl, (Cg- 12)bicycloalkyl, hetero(C3-]2)bicycloalkyl, OTyI(C1-I0)BIlCyI, heteroaryl(Ci-5)alkyl, perhalo(Ci-10)alkyl, halo(C1-10)alkyl, carbonyl(C1.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or Ri3 and any one of R7, Rg and Rn are taken together to form a ring; each Ri4 is independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3_i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci.io)alkyl, (Cs.i^cycloalky^CM^alkyl, halo(Ci.io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted; and
Ri5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(Ci.1o)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted.
[0110] In one embodiment, hydroxysteroid dehydrogenase inhibitors of the present invention comprise:
wherein: n is selected from the group consisting of 0, 1, 2,3, 4 and 5;
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NRi5;
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamide, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-10)alkyl, heteroaryl(C1.5)alkyl, (C3-i2)cycloalkyl(Ci-10)alkyl, halo(Ci-10)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci_3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-iojalkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci-5)alkyl, (C3- 12)cycloalkyl(C i .10)alkyl, halo(C i .10)alkyl, carbonyl(C i -3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3.i2)cycloalkyl, (C9-)2)bicycloalkyl, hetero(C3_i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(C1_5)alkyl, perhalo(Ci-io)alkyl, (C3_i2)cycloalkyl(C1.10)alkyl, halo(Ci.io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci_3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci.io)alkyl, imino(C1.3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci^alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-12)cycloalkyl, hetero(C3.12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3.]2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(C1-5)alkyl, perhalo(C]-io)alkyl, (C3.12)cycloalkyl(C1-1o)alkyl, halo(Ci.io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted; each RH is independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci-10)alkyl, heteroaryl (C 1.5)alkyl, perhalo(CM0)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(Ci.!o)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-Io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
Ri5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.iO)alkyl, heteroaryl(C1-5)alkyl, (C3-i2)cycloalkyl(CM0)alkyl, halo(C1-io)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (C^i^bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
X is selected from the group consisting of unsubstituted and substituted Ci-6 alkylenes; and
Y is selected from the group consisting of (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted.
[0111] In one variation of each of the above embodiments, M is S. In another variation, M is O. In yet another variation, M is NR15 and R15 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3.i2)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci_iO)alkyl, heteroaryl(Ci-5)alkyl,
(C3-i2)cycloalkyl(C1.io)alkyl, halo(Ci_io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted. [0112] In one variation of each of the above embodiments and variations, J, K and L are CR6.
[0113] In another variation of each of the above embodiments and variations, Ri is selected from the group consisting of (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, hetero(C4-]2)bicycloaryl, each substituted or unsubstituted. In yet another variation, Ri is selected from the group consisting of (C3-6)alkyl, aryl, (C3-9)cycloalkyl, bicycloalkyl and adamantanyl, each unsubstituted or substituted. In still another variation, Ri is selected from the group consisting of alkylphenyl, halophenyl, alkylhalophenyl, alkoxyphenyl, alkylaminoalkoxyphenyl, heterocycloalkylalkoxyphenyl, alkylaminoalkylphenyl, heterocycloalkylalkylphenyl, cycloalkyl, bicycloalkyl and adamantanyl, each unsubstituted or substituted. In a further variation, Ri is substituted with a substituent selected from the group consisting of cyano, carboxamido, aminoalkyl, aminoalkoxy, heterocycloalkyl, heterocycloalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aryloxy, heteroaryloxy, bicycloaryl, heterobicycloaryl, bicycloaryloxy, and heterobicycloaryloxy, each unbsubstituted or substituted.
[0114] In another variation of each of the above embodiments and variations, R3 is H.
[0115] In yet another variation of each of the above embodiments and variations, R7 is
H.
[0116] In still another variation of each of the above embodiments and variations, R7 and R8 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heteroaryl, each unsubstituted or substituted. In a further variation, R7 and R8 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, alkylaminoalkyl, dialkylaminoalkyl, benzyl, halobenzyl, dihalobenzyl, phenylethyl, pyrimidinylalkyl, pyrazolylalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methylphenyl, dimethylphenyl, ethylphenyl, halophenyl, dihalophenyl, methoxyphenyl, cyanophenyl, haloalkylphenyl, pyridinyl, halopyridinyl, alkoxypyridinyl, tetrahydropyranyl, pyrazolyl and pyrimidinyl, each unsubstituted or substituted. In another variation, R7 and R8 are taken together to form a ring selected from the group consisting of a (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-12)bicycloalkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted.
[0117] In yet another variation of each of the above embodiments and variations, R13 is
H.
[0118] In still another variation of each of the above embodiments and variations, Ri4 is selected from the group consisting of cyano, carboxamido, aminoalkyl, aminoalkoxy, heterocycloalkyl, heterocycloalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aryloxy, heteroaryloxy, bicycloaryl, heterobicycloaryl, bicycloaryloxy, and heterobicycloaryloxy, each unsubstituted or substituted.
[0119] In a further variation of each of the above embodiments and variations, n is 0, 1 or 2.
[0120] In another variation of each of the above embodiments and variations, X is methylene. [0121] In yet another variation of each of the above embodiments and variations, Y is selected from the group consisting of aryl and heteroaryl, each unsubstituted or substituted. In still another variation, Y is selected from the group consisting of phenyl and pyridinyl, each unsubstituted or substituted. In a further variation, Y is selected from the group consisting of phenyl, halophenyl, dihalophenyl, methylphenyl, dimethylphenyl, cyanophenyl, aminocarboxyphenyl, haloalkylphenyl, alkoxyphenyl and oxopyridinyl. [0122] Particular examples of hydroxysteroid dehydrogenase inhibitors according to the present invention include, but are not limited to:
3-Chloro-N-(4-( 1 -hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-(l-hydroxypropyl)fhiazol-2-yl)-2- methylbenzenesulf onamide ; 3-Chloro-N-(4-(l-hydroxybutyl)thiazol-2-yl)-2- methylbenzenesulf onamide ; 3-Chloro-N-(4-(cyclopropyl(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide ; 3-Chloro-N-(4-(l-hydroxy-2-methylpropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-(cyclopentyl(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulf onamide ; 3-Chloro-N-(4-(cyclohexyl(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulf onamide ; 3-Chloro-N-(4-( 1 -hydroxy-2-phenylethyl)thiazol-2-yl)-2- methylbenzenesulf onamide ; 3-Chloro-N-(4-(l-hydroxy-3-phenylpropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(hydroxy(o-tolyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide;
3-chloro-N-(4-(hydroxy(o-ethylphenyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; -chloro-N-(4-((3-fluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; -chloro-N-(4-((3,4-difluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide ; -chloro-N-(4-((4-chloro-3-fluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; -chloro-N-(4-((3-chloro-5-fluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; -chloro-N-(4-((4-fluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulf onamide ; -chloro-N-(4-(hydroxy(phenyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; -chloro-N-(4-((4-chlorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide ; -chloro-N-(4-((3-chlorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; -chloro-N-(4-((3-chloro-4-fluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; -chloro-N-(4-((3,5-difluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; -chloro-N-(4-(hydroxy(m-tolyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide ; -chloro-N-(4-((2,3-dimethylphenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulf onamide ; -chloro-N-(4-(hydroxy(2-methoxyphenyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; -chloro-N-(4-((4-cyanophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfon amide ; -chloro-N-(4-(hydroxy(3-(trifluoromethyl)phenyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(hydroxy(pyridin-2-yl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-((2-chloropyridin-3-yl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(2-(diethylamino)-l-hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(l-hydroxy-2-(pyrimidin-4-yl)ethyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-((3-cyanophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-((2-cyanophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(hydroxy(3-methoxyphenyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; (R)-3-chloro-N-(4-( 1 -hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; (S)-3-chloro-N-(4-(l-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; (R)-3-chloro-N-(4-((2-ethylphenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; (S)-3-chloro-N-(4-((2-ethylphenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-{4-[hydroxy-(2-methoxy-pyridin-3-yl)-methyl]-thiazol-2-yl}-
2-methyl-benzenesulfonamide; 3-Chloro-N-{4-[(2-chloro-pyridin-3-yl)-hydroxy-methyl]-thiazol-2-yl}-2- methyl-benzenesulfonamide; 3-Chloro-N-[4-(l-hydroxy-2-pyrimidin-4-yl-ethyl)-thiazol-2-yl]-2-methyl- benzenesulf onamide ; l-[2-(3-Chloro-2-methyl-benzenesulfonylmethyl)-thiazol-4-yl]-2- pyridazin-3-yl-ethanol; 3-Chloro-N-{4-[l-hydroxy-2-(2H-ρyrazol-3-yl)-ethyl]-thiazol-2-yl}-2- methyl-benzenesulfonamide; and 3-Chloro-N- { 4-[ 1 -hydroxy-2-( 1 H-pyrazol-4-yl)-ethyl]-thiazol-2-yl } -2- methy 1-benzenesulfonamide .
[0123] Additional particular examples of hydroxysteroid dehydrogenase inhibitors according to the present invention include, but are not limited to:
3-chloro-N-(4-(2-hydroxypropan-2-yl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(4-hydroxyheptan-4-yl)thiazol-2-yl)-2- methylbenzenesulfonamide ; 3-chloro-N-(4-( 1 -hydroxycyclopropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-( 1 -hydroxycyclopentyl)thiazol-2-yl)-2- methylbenzenesulfonamide;
N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4-phenoxybenzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-6-phenoxypyridine-3- sulfonamide;
N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)naphthalene-2-sulfonamide; 2,3-dichloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzofuran-2-sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzo[d]thiazole-6-sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzo[b]thiophene-2- sulfonamide;
N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)naphthalene-l-sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-5-methylbenzo[b]thiophene-2- sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2,3-dihydrobenzofuran-5- sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)(p-tolyl)methanesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2-oxo-2H-chromene-6- sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2,4-dimethylthiazole-5- sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-5-(oxazol-5-yl)thiophene-2- sulfonamide; 5-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)naphthalene-2- sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzo[b]thiophene-3- sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2,3- dihydrobenzo [b] [ 1 ,4] dioxine-6-sulfonamide; 2-Chloro-4,5-difluoro-N-(4-(3-hydroxypentan-3-yl)thiazol-2- yl)benzenesulfonamide; N-(4-(3-Hydroxypentan-3-yl)thiazol-2-yl)-4-methyl-3,4-dihydro-2H- benzofb] [ 1 ,4]oxazine-6-sulfonamide; 5-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3- methylbenzo[b]thiophene-2-sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2,5- dimethylbenzenesulf onamide ; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3,4- dimethylbenzenesulf onamide ; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3,4- dimethoxybenzenesulfonamide; N-(4-(N-(4-(3-hydroxypentan-3-yl)thiazol-2- yl)sulfamoyl)phenyl)acetamide; 4-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3- nitrobenzenesulfonamide ; 2-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-5-(trifluoromethyl) benzenesulfonamide; 4,5-dichloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)thiophene-2- sulfonamide;
4-ethyl-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide; 4-propyl-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzo[c][l,2,5]thiadiazole-5- sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3,4-dihydro-2H-benzo[b][l,4] dioxepine-7-sulfonamide;
3-bromo-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2-(2,2,2-trifluoroacetyl)-l,2,3,4- tetrahydroisoquinoline-7-sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-l,2,3,4-tetrahydroisoquinoline-7- sulfonamide; 2-fluoro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-5- methylbenzenesulfonamide;
3-cyano-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide; 4-bromo-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2- methylbenzenesulfonamide; 4-bromo-2-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2- yl)benzenesulfonamide; 4-bromo-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2-(trifluoromethyl) benzenesulf onamide ; 4-bromo-5-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)thiophene-2- sulfonamide;
4-cyano-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3-nitrobenzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4-nitrobenzenesulfonamide; 2-chloro-4-cyano-N-(4-(3-hydroxypentan-3-yl)thiazol-2- yl)benzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4-(methylsulfonyl) benzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4-methoxybenzenesulfonamide;
N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4-isopropylbenzenesulfonamide;
4-(difluoromethoxy)-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl) benzenesulf onamide ; 3-(difluoromethoxy)-N-(4-(3-hydroxypentan-3-yl)thiazol-2- yl)benzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4- isopropoxybenzenesulfonamide; 2-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4-(trifluoromethyl) benzenesulf onamide ;
N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3-methoxybenzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzo[d][l,3]dioxole-5- sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3-oxo-3,4-dihydro-2H- benzo [b] [ 1 ,4] oxazine-6-sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4-methyl-3- nitrobenzenesulfonamide ;
4-acetyl-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2-methyl-5- nitrobenzenesulf onamide ;
3-acetyl-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3-(methylsulfonyl) benzenesulf onamide; and N-(2-chloro-4-(N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)sulfamoyl) phenyl)acetamide.
[0124] Further particular examples of hydroxysteroid dehydrogenase inhibitors according to the present invention include, but are not limited to: 3-Chloro-N-(4-(2-hydroxypentyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-(2-hydroxy-3-methylbutyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-(2-cyclopentyl-2-hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-(2-hydroxy-2-phenylethyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(2-hydroxy-3,3-diniethylbutyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(2-(3-fluorophenyl)-2-hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(3-(2,5-difluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(3-(4-fluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(3-(2-fluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide ; (S)-3-chloro-N-(4-(3-(2-fluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; (R)-3-chloro-N-(4-(3-(2-fluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(2-hydroxy-3-phenylpropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; (S)-3-Chloro-N-(4-(2-hydroxy-3-phenylpropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(3-(2,4-difluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulf onamide ; 3-chloro-N-(4-(3-(2,6-difluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulf onamide ; 3-chloro-N-(4-(3-(3-chlorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(2-cyclopropyl-2-hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulfonamide; (R)-3-Chloro-N-(4-(2-cyclopropyl-2-hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulfonamide; (S)-3-Chloro-N-(4-(2-cydopropyl-2-hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(2-hydroxy-3-(pyrimidin-4-yl)propyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 4-Fluoro-N- [4-(2-hydroxy-butyl)-thiazol-2-yl] -2-methyl- benzenesulf onamide ;
3-chloro-4-fluoro-N-(4-(2-hydroxybutyl)thiazol-2-yl)benzenesulfonamide; 3-fluoro-N-(4-(2-hydroxybutyl)thiazol-2-yl)benzenesulfonamide; (R)-3-Chloro-N-(4-(2-hydroxy-3-phenylpropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; N-[4-(2-Hydroxy-butyl)-thiazol-2-yl]-2-methyl-4-(2-morpholin-4-yl- ethoxy)-benzenesulfonamide; N-[4-(2-Hydroxy-butyl)-thiazol-2-yl]-2-methyl-4-(3-morpholin-4-yl- propoxy)-benzenesulfonamide; 3-Chloro-N-[4-(2-hydroxy-butyl)-thiazol-2-yl]-4-(2-morpholin-4-yl- ethoxy) -benzenesulf onamide ; 3-Chloro-N-[4-(2-hydroxy-butyl)-thiazol-2-yl]-4-(3-moφholin-4-yl- propoxy)-benzenesulfonamide; 3-Chloro-N-[4-(2-hydroxy-butyl)-thiazol-2-yl]-5-(2-morpholin-4-yl- ethoxy)-benzenesulfonamide; 3-Chloro-N-[4-(2-hydroxy-butyl)-thiazol-2-yl]-5-(3-moφholin-4-yl- propoxy)-benzenesulfonamide; 3-Chloro-N-[4-(2-hydroxy-3-pyridazin-3-yl-propyl)-thiazol-2-yl]-2- methyl-benzenesulf onamide; and 3-Chloro-N-{4-[2-hydroxy-3-(2H-pyrazol-3-yl)-propyl]-thiazol-2-yl}-2- methyl-benzenesulfonamide.
[0125] Other particular examples of hydroxysteroid dehydrogenase inhibitors according to the present invention include, but are not limited to: 3-chloro-N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-(2-hydroxy-2-propylρentyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(( 1 -hydroxycyclobutyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(( 1 -hydroxycyclopentyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; N-[4-(2-Ethyl-2-hydroxy-butyl)-thiazol-2-yl]-4-fluoro-2-methyl- benzenesulfonamide; 4-(2-Dimethylamino-ethoxy)-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-
2-methyl-benzenesulfonamide ; N-[4-(2-Ethyl-2-hydroxy-butyl)-thiazol-2-yl]-2-methyl-4-(2-moφholin-4- yl-ethoxy)-benzenesulfonamide; 4-(3-Dimethylamino-propoxy)-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2- yl]-2-methyl-benzenesulfonamide; 3-chloro-N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-4- fluorobenzenesulfonamide; 3-Chloro-4-(2-dimethylamino-ethoxy)-N-[4-(2-ethyl-2-hydroxy-butyl)- thiazol-2-yl]-benzenesulfonamide; 3-Chloro-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-5-(2-moφholin-4- yl-ethoxy)-benzenesulfonamide; 3-Chloro-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-4-(3-morpholin-4- yl-propoxy)-benzenesulfonamide; 3-Chloro-4-(3-dimethylamino-propoxy)-N-[4-(2-ethyl-2-hydroxy-butyl)- thiazol-2-yl]-benzenesulfonamide; N-[4-(2-Ethyl-2-hydroxy-butyl)-thiazol-2-yl]-2-methyl-4-(3-moφholin-4- yl-propoxy)-benzenesulfonamide;
N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-4-fluorobenzenesulfonamide; N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-3-fluorobenzenesulfonamide; N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-3-(3-moφholinopropoxy) benzenesulfonamide ; N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-4-(3-moφholinopropoxy) benzenesulfonamide; 4-(3-(dimethylamino)propoxy)-N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl) benzenesulfonamide; 3-(3-(dimethylamino)propoxy)-N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl) benzenesulfonamide; 3-chloro-N-(4-((4-hydroxy-tetrahydro-2H-pyran-4-yl)methyl)thiazol-2-yl)-
2-methylbenzenesulfonamide; 4-bromo-N-(4-(( 1 -hydroxycyclobutyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide ; N-[4-(l-Hydroxy-cyclopentylmethyl)-thiazol-2-yl]-2-methyl-4-(3- morpholin-4-yl-propoxy) -benzenesulfonamide ; N-[4-(l-Hydroxy-cyclohexylmethyl)-thiazol-2-yl]-2-methyl-4-(3- morpholin-4-yl-propoxy)-benzenesulfonamide; 3-Chloro-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-4-(2-morpholin-4- yl-ethoxy)-benzenesulfonamide; 3-Chloro-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-5-(3-morpholin-4- yl-propoxy)-benzenesulfonamide; 3-Chloro-4-(2-dimethylamino-ethoxy)-N- [4-( 1 -hydroxy- cyclopentylmethyl)-thiazol-2-yl]-benzenesulfonamide; 3-Chloro-4-(2-dimethylamino-ethoxy)-N-[4-(l-hydroxy- cyclohexylmethyl)-thiazol-2-yl]-benzenesulfonamide; 3-Chloro-5-(2-dimethylamino-ethoxy)-N-[4-(2-ethyl-2-hydroxy-butyl)- thiazol-2-yl]-benzenesulfonamide; 3-Chloro-5-(3-dimethylamino-propoxy)-N-[4-(2-ethyl-2-hydroxy-butyl)- thiazol-2-yl]-benzenesulfonamide; 3-Chloro-2-methyl-N-[4-(4-methyl-tetrahydro-pyran-4-ylmethyl)-thiazol-2- yl] -benzenesulfonamide ; N-[4-(2-Ethyl-2-hydroxy-butyl)-thiazol-2-yl]-2-methyl-4-(3-moφholin-4- yl-propyl)-benzenesulfonamide; N-[4-(2-Ethyl-2-hydroxy-butyl)-thiazol-2-yl]-2-methyl-4-(4-morpholin-4- yl-butyl)-benzenesulfonamide; 4-(3-Dimethylamino-propyl)-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-
2-methyl-benzenesulfonamide; 4-(4-Dimethylamino-butyl)-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-
2-methyl-benzenesulfonamide; 2-Chloro-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-4-(3-morpholin-4- yl-propyl)-benzenesulfonamide; 2-Chloro-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-4-(4-morpholin-4- yl-butyl)-benzenesulfonamide; 2-Chloro-4-(3-dimethylamino-propyl)-N-[4-(2-ethyl-2-hydroxy-butyl)- thiazol-2-yl] -benzenesulf onamide ; 2-Chloro-4-(4-dimethylamino-butyl)-N-[4-(2-ethyl-2-hydroxy-butyl)- thiazol-2-yl] -benzenesulf onamide ; N-[4-(2-Ethyl-2-hydroxy-butyl)-thiazol-2-yl]-4-(3-morpholin-4-yl-propyl)-
2-trifluoromethyl-benzenesulfonamide; N-[4-(2-Ethyl-2-hydroxy-butyl)-thiazol-2-yl]-4-(4-moφholin-4-yl-butyl)-
2-trifluoromethyl-benzenesulfonamide; 4-(3-Dimethylamino-propyl)-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-
2-trifluoromethyl-benzenesulfonamide; 4-(4-Dimethylamino-butyl)-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-
2-trifluoromethyl-benzenesulfonamide; Cyclopropanesulfonic acid [4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]- amide; Cyclopentanesulfonic acid [4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl] - amide; Cyclohexanesulfonic acid [4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl] - amide; Cycloheptanesulfonic acid [4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl] - amide; Cyclopropanesulfonic acid [4-( 1 -hydroxy-cyclopentylmethyl)-thiazol-2- yl]-amide; Cyclopropanesulfonic acid [4-(l-hydroxy-cyclohexylmethyl)-thiazol-2-yl]- amide; Adamantane- 1 -sulfonic acid [4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl] - amide; Adamantane- 1 -sulfonic acid [4-( 1 -hydroxy-cyclopentylmethyl)-thiazol-2- yl]-amide; Adamantane- 1 -sulfonic acid [4-( 1 -hydroxy-cyclohexylmethyl)-thiazol-2- yl]-amide; Bicyclo[2.2.2]octane-1 -sulfonic acid [4-(2-ethyl-2-hydroxy-butyl)-thiazol-
2-yl] -amide;
Ethanesulfonic acid [4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-amide; Ethanesulfonic acid [4-(l-hydroxy-cyclopentylmethyl)-thiazol-2-yl]-amide; Ethanesulfonic acid [4-(l-hydroxy-cyclohexylmethyl)-thiazol-2-yl]-amide; Propane- 1 -sulfonic acid [4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-amide; and 2-Methyl-propane-2-sulfonic acid [4-(2-ethyl-2-hydroxy-butyl)-thiazol-2- yl] -amide.
[0126] Still further particular examples of hydroxysteroid dehydrogenase inhibitors according to the present invention include, but are not limited to:
(S)-3-chloro-N-(4-(3-hydroxy-3-phenylpropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; (R)-3-chloro-N-(4-(3-hydroxy-3-phenylpropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 4-Fluoro-N-[4-(3-hydroxy-pentyl)-thiazol-2-yl]-2-methyl- benzenesulfonamide; N-[4-(3-Ethyl-3-hydroxy-pentyl)-thiazol-2-yl]-4-fluoro-2-methyl- benzenesulf onamide ; 4-(2-Dimethylamino-ethoxy)-N-[4-(3-ethyl-3-hydroxy-pentyl)-thiazol-2- yl]-2-methyl-benzenesulfonamide; N-[4-(3-Ethyl-3-hydroxy-pentyl)-thiazol-2-yl]-2-methyl-4-(2-morpholin-4- yl-ethoxy)-benzenesulfonamide; and N- { 4- [2-( 1 -Hydroxy-cyclohexyl)-ethyl]-thiazol-2-yl } -2-methyl-4-(3- morpholin-4-yl-propoxy)-benzenesulfonamide.
[0127] Still other particular examples of hydroxysteroid dehydrogenase inhibitors according to the present invention include, but are not limited to:
N-(4-(4-fluorobenzyl)thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide;
N-(4-benzylthiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide;
N-(4-(4-chlorobenzyl)thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide;
N-(4-(3-chlorobenzyl)thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide;
N-(4-(3-chloro-4-fluorobenzyl)thiazol-2-yl)-3-chloro-2- methylbenzenesulfonamide; N-(4-(3,5-difluorobenzyl)thiazol-2-yl)-3-chloro-2- methylbenzenesulfonamide;
3-chloro-N-(((m-tolyl)methyl)thiazol-2-yl)-2-methylbenzenesulfonamide; 3-chloro-N-(4-((2,5-dimethylphenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide;
3-chloro-N-(((o-tolyl)methyl)thiazol-2-yl)-2-methylbenzenesulfonamide; N-(4-(4-cyanobenzyl)thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide; 4-((2-(3-chloro-2-methylphenylsulfonamido)thiazol-4- yl)methyl)benzamide ;
N-(4-(3-cyanobenzyl)thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide; 3-((2-(3-chloro-2-methylphenylsulfonamido)thiazol-4- yl)methyl)benzamide; N-(4-(3-(trifluoromethyl)benzyl)thiazol-2-yl)-3-chloro-2- methylbenzenesulfonamide; 3-chloro-2-methyl-N-(4-((2-oxopyridin-l(2H)-yl)methyl)thiazol-2- yl)benzenesulfonamide; and N-(4-(3-methoxybenzyl)thiazol-2-yl)-3-chloro-2- methylbenzenesulfonamide.
[0128] It is noted that the compounds of the present invention may be in the form of a pharmaceutically acceptable salt, biohydrolyzable ester, biohydrolyzable amide, biohydrolyzable carbamate, solvate, hydrate or prodrug thereof. For example, the compound optionally comprises a substituent that is convertible in vivo to a different substituent such as a hydrogen.
[0129] It is further noted that the compound may be present in a mixture of stereoisomers, or the compound comprises a single stereoisomer. [0130] The present invention also provides a pharmaceutical composition comprising as an active ingredient a compound according to any one of the above embodiments and variations. In one particular variation, the composition is a solid formulation adapted for oral administration. In another particular variation, the composition is a liquid formulation adapted for oral administration. In yet another particular variation, the composition is a tablet. In still another particular variation, the composition is a liquid formulation adapted for parenteral administration.
[0131] In another of its aspects, there is provided a pharmaceutical composition comprising a compound according to any one of the above embodiments and variations, wherein the composition is adapted for administration by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, and intrathecally. [0132] In yet another of its aspects, there is provided a kit comprising a compound of any one of the above embodiments and variations; and instructions which comprise one or more forms of information selected from the group consisting of indicating a disease state for which the composition is to be administered, storage information for the composition, dosing information and instructions regarding how to administer the composition. In one particular variation, the kit comprises the compound in a multiple dose form. [0133] In still another of its aspects, there is provided an article of manufacture comprising a compound of any one of the above embodiments and variations; and packaging materials. In one variation, the packaging material comprises a container for housing the compound. In one particular variation, the container comprises a label indicating one or more members of the group consisting of a disease state for which the compound is to be administered, storage information, dosing information and/or instructions regarding how to administer the compound. In another variation, the article of manufacture comprises the compound in a multiple dose form.
[0134] In a further of its aspects, there is provided a therapeutic method comprising administering a compound of any one of the above embodiments and variations to a subject.
[0135] In another of its aspects, there is provided a method of inhibiting HSD comprising contacting HSD with a compound of any one of the above embodiments and variations.
[0136] In yet another of its aspects, there is provided a method of inhibiting HSD comprising causing a compound of any one of the above embodiments and variations to be present in a subject in order to inhibit HSD in vivo.
[0137] In a further of its aspects, there is provided a method of inhibiting HSD comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits HSD in vivo, the second compound being a compound according to any one of the abive embodiments and variations.
[0138] In another of its aspects, there is provided a method of treating a disease state for which HSD possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising causing a compound of any one of the above embodiments and variations to be present in a subject in a therapeutically effective amount for the disease state.
[0139] In yet another of its aspects, there is provided a method of treating a disease state for which HSD possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising administering a compound of any one of the above embodiments and variations to a subject, wherein the compound is present in the subject in a therapeutically effective amount for the disease state. [0140] In a further of its aspects, there is provided a method of treating a disease state for which HSD possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits
HSD in vivo, the second compound being a compound according to any one of the above embodiments and variations.
[0141] In one variation of each of the above methods the disease state is selected from the group consisting of the metabolic syndrome, Cushing's disease, hypertension, cognitive function, and ocular function.
[0142] In another variation of each of the above methods, the HSD is an 1 Ib-HSD 1.
Salts, Hydrates, and Prodrugs of Hydroxysteroid Dehydrogenase Inhibitors
[0143] It should be recognized that the compounds of the present invention may be present and optionally administered in the form of salts, hydrates and prodrugs that are converted in vivo into the compounds of the present invention. For example, it is within the scope of the present invention to convert the compounds of the present invention into and use them in the form of their pharmaceutically acceptable salts derived from various organic and inorganic acids and bases in accordance with procedures well known in the art.
[0144] When the compounds of the present invention possess a free base form, the compounds can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide; other mineral acids and their corresponding salts such as sulfate, nitrate, phosphate, etc.; and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate; and other organic acids and their corresponding salts such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate. Further acid addition salts of the present invention include, but are not limited to: adipate, alginate, arginate, aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptaoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate, lactobionate, malate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate and phthalate. It should be recognized that the free base forms will typically differ from their respective salt forms somewhat in physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base forms for the purposes of the present invention.
[0145] When the compounds of the present invention possess a free acid form, a pharmaceutically acceptable base addition salt can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Examples of such bases are alkali metal hydroxides including potassium, sodium and lithium hydroxides; alkaline earth metal hydroxides such as barium and calcium hydroxides; alkali metal alkoxides, e.g. potassium ethanolate and sodium propanolate; and various organic bases such as ammonium hydroxide, piperidine, diethanolamine and N- methylglutamine. Also included are the aluminum salts of the compounds of the present invention. Further base salts of the present invention include, but are not limited to: copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium and zinc salts. Organic base salts include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, e.g., arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N-methyl-D- glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris- (hydroxymethyl)-methylamine (tromethamine). It should be recognized that the free acid forms will typically differ from their respective salt forms somewhat in physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid forms for the purposes of the present invention. [0146] Compounds of the present invention that comprise basic nitrogen-containing groups may be quaternized with such agents as (Cj-4) alkyl halides, e.g., methyl, ethyl, iso- propyl and tert-butyl chlorides, bromides and iodides; di (C1-4) alkyl sulfates, e.g., dimethyl, diethyl and diamyl sulfates; (CiO-18) alkyl halides, e.g., decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl (Ci-4) alkyl halides, e.g., benzyl chloride and phenethyl bromide. Such salts permit the preparation of both water- soluble and oil-soluble compounds of the present invention.
[0147] N-oxides of compounds according to the present invention can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meto-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 0C. Alternatively, the N-oxides of the compounds can be prepared from the N-oxide of an appropriate starting material.
[0148] Prodrug derivatives of compounds according to the present invention can be prepared by modifying substituents of compounds of the present invention that are then converted in vivo to a different substituent. It is noted that in many instances, the prodrugs themselves also fall within the scope of the range of compounds according to the present invention. For example, prodrugs can be prepared by reacting a compound with a carbamylating agent (e.g., l.l-acyloxyalkylcarbonochloridate. pαra-nitrophenyl carbonate, or the like) or an acylating agent. Further examples of methods of making prodrugs are described in Saulnier et α/.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985.
[0149] Protected derivatives of compounds of the present invention can also be made. Examples of techniques applicable to the creation of protecting groups and their removal can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3r edition, John Wiley & Sons, Inc. 1999. [0150] Compounds of the present invention may also be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
[0151] A "pharmaceutically acceptable salt", as used herein, is intended to encompass any compound according to the present invention that is utilized in the form of a salt thereof, especially where the salt confers on the compound improved pharmacokinetic properties as compared to the free form of compound or a different salt form of the compound. The pharmaceutically acceptable salt form may also initially confer desirable pharmacokinetic properties on the compound that it did not previously possess, and may even positively affect the pharmacodynamics of the compound with respect to its therapeutic activity in the body. An example of a pharmacokinetic property that may be favorably affected is the manner in which the compound is transported across cell membranes, which in turn may directly and positively affect the absorption, distribution, biotransformation and excretion of the compound. While the route of administration of the pharmaceutical composition is important, and various anatomical, physiological and pathological factors can critically affect bioavailability, the solubility of the compound is usually dependent upon the character of the particular salt form thereof, which it utilized. One of skill in the art will appreciate that an aqueous solution of the compound will provide the most rapid absorption of the compound into the body of a subject being treated, while lipid solutions and suspensions, as well as solid dosage forms, will result in less rapid absorption of the compound.
Preparation Of Hydroxysteroid Dehydrogenase Inhibitors
[0152] Various methods may be developed for synthesizing compounds according to the present invention. Representative methods for synthesizing these compounds are provided in the Examples. It is noted, however, that the compounds of the present invention may also be synthesized by other synthetic routes that others may devise. [0153] It will be readily recognized that certain compounds according to the present invention have atoms with linkages to other atoms that confer a particular stereochemistry to the compound (e.g., chiral centers). It is recognized that synthesis of compounds according to the present invention may result in the creation of mixtures of different stereoisomers (enantiomers, diastereomers). Unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all of the different possible stereoisomers.
[0154] Various methods for separating mixtures of different stereoisomers are known in the art. For example, a racemic mixture of a compound may be reacted with an optically active resolving agent to form a pair of diastereoisomeric compounds. The diastereomers may then be separated in order to recover the optically pure enantiomers. Dissociable complexes may also be used to resolve enantiomers (e.g., crystalline diastereoisomeric salts). Diastereomers typically have sufficiently distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) that they can be readily separated by taking advantage of these dissimilarities. For example, diastereomers can typically be separated by chromatography or by separation/resolution techniques based upon differences in solubility. A more detailed description of techniques that can be used to resolve stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
Compositions Comprising Hydroxysteroid Dehydrogenase Inhibitors
[0155] A wide variety of compositions and administration methods may be used in conjunction with the hydroxysteroid dehydrogenase inhibitors of the present invention. Such compositions may include, in addition to the hydroxysteroid dehydrogenase inhibitors of the present invention, conventional pharmaceutical excipients, and other conventional, pharmaceutically inactive agents. Additionally, the compositions may include active agents in addition to the hydroxysteroid dehydrogenase inhibitors of the present invention. These additional active agents may include additional compounds according to the invention, and/or one or more other pharmaceutically active agents. [0156] The compositions may be in gaseous, liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration to be used. For oral administration, capsules and tablets are typically used. For parenteral administration, reconstitution of a lyophilized powder, prepared as described herein, is typically used. [0157] Compositions comprising hydroxysteroid dehydrogenase inhibitors of the present invention may be administered or coadministered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally. The compounds and/or compositions according to the invention may also be administered or coadministered in slow release dosage forms.
[0158] The hydroxysteroid dehydrogenase inhibitors and compositions comprising them may be administered or coadministered in any conventional dosage form. Coadministration in the context of this invention is intended to mean the administration of more than one therapeutic agent, one of which includes a hydroxysteroid dehydrogenase inhibitor, in the course of a coordinated treatment to achieve an improved clinical outcome. Such co-administration may also be coextensive, that is, occurring during overlapping periods of time.
[0159] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may optionally include one or more of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; agents for the adjustment of tonicity such as sodium chloride or dextrose, and agents for adjusting the acidity or alkalinity of the composition, such as alkaline or acidifying agents or buffers like carbonates, bicarbonates, phosphates, hydrochloric acid, and organic acids like acetic and citric acid. Parenteral preparations may optionally be enclosed in ampules, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material.
[0160] When hydroxysteroid dehydrogenase inhibitors according to the present invention exhibit insufficient solubility, methods for solubilizing the compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN, or dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions.
[0161] Upon mixing or adding hydroxysteroid dehydrogenase inhibitors according to the present invention to a composition, a solution, suspension, emulsion or the like may be formed. The form of the resulting composition will depend upon a number of factors, including the intended mode of administration, and the solubility of the compound in the selected carrier or vehicle. The effective concentration needed to ameliorate the disease being treated may be empirically determined.
[0162] Compositions according to the present invention are optionally provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, dry powders for inhalers, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds, particularly the pharmaceutically acceptable salts, preferably the sodium salts, thereof. The pharmaceutically therapeutically active compounds and derivatives thereof are typically formulated and administered in unit-dosage forms or multiple-dosage forms. Unit-dose forms, as used herein, refers to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit- dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit-dose forms include ampoules and syringes individually packaged tablet or capsule. Unit-dose forms may be administered in fractions or multiples thereof. A multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include vials, bottles of tablets or capsules or bottles of pint or gallons. Hence, multiple dose form is a multiple of unit-doses that are not segregated in packaging.
[0163] In addition to one or more hydroxysteroid dehydrogenase inhibitors according to the present invention, the composition may comprise: a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose; a lubricant, such as magnesium stearate, calcium stearate and talc; and a binder such as starch, natural gums, such as gum acaciagelatin, glucose, molasses, polvinylpyrrolidine, celluloses and derivatives thereof, povidone, crospovidones and other such binders known to those of skill in the art. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, or otherwise mixing an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents. Actual methods of preparing such dosage forms are known in the art, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975. The composition or formulation to be administered will, in any event, contain a sufficient quantity of a hydroxysteroid dehydrogenase inhibitor of the present invention to reduce hydroxysteroid dehydrogenase activity in vivo, thereby treating the disease state of the subject.
[0164] Dosage forms or compositions may optionally comprise one or more hydroxysteroid dehydrogenase inhibitors according to the present invention in the range of 0.005% to 100% (weight/weight) with the balance comprising additional substances such as those described herein. For oral administration, a pharmaceutically acceptable composition may optionally comprise any one or more commonly employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate, sodium saccharin, talcum. Such compositions include solutions, suspensions, tablets, capsules, powders, dry powders for inhalers and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparing these formulations are known to those skilled in the art. The compositions may optionally contain 0.01%- 100% (weight/weight) of one or more hydroxysteroid dehydrogenase inhibitors, optionally 0.1-95%, and optionally 1-95%. [0165] Salts, preferably sodium salts, of the hydroxysteroid dehydrogenase inhibitors may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings. The formulations may further include other active compounds to obtain desired combinations of properties.
Formulations For Oral Administration
[0166] Oral pharmaceutical dosage forms may be as a solid, gel or liquid. Examples of solid dosage forms include, but are not limited to tablets, capsules, granules, and bulk powders. More specific examples of oral tablets include compressed, chewable lozenges and tablets that may be enteric-coated, sugar-coated or film-coated. Examples of capsules include hard or soft gelatin capsules. Granules and powders may be provided in non- effervescent or effervescent forms. Each may be combined with other ingredients known to those skilled in the art.
[0167] In certain embodiments, hydroxysteroid dehydrogenase inhibitors according to the present invention are provided as solid dosage forms, preferably capsules or tablets. The tablets, pills, capsules, troches and the like may optionally contain one or more of the following ingredients, or compounds of a similar nature: a binder; a diluent; a disintegrating agent; a lubricant; a glidant; a sweetening agent; and a flavoring agent. [0168] Examples of binders that may be used include, but are not limited to, microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste.
[0169] Examples of lubricants that may be used include, but are not limited to, talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. [0170] Examples of diluents that may be used include, but are not limited to, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.
[0171] Examples of glidants that may be used include, but are not limited to, colloidal silicon dioxide. [0172] Examples of disintegrating agents that may be used include, but are not limited to, crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose.
[0173] Examples of coloring agents that may be used include, but are not limited to, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate.
[0174] Examples of sweetening agents that may be used include, but are not limited to, sucrose, lactose, mannitol and artificial sweetening agents such as sodium cyclamate and saccharin, and any number of spray-dried flavors.
[0175] Examples of flavoring agents that may be used include, but are not limited to, natural flavors extracted from plants such as fruits and synthetic blends of compounds that produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate.
[0176] Examples of wetting agents that may be used include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
[0177] Examples of anti-emetic coatings that may be used include, but are not limited to, fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates.
[0178] Examples of film coatings that may be used include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.
[0179] If oral administration is desired, the salt of the compound may optionally be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient.
[0180] When the dosage unit form is a capsule, it may optionally additionally comprise a liquid carrier such as a fatty oil. In addition, dosage unit forms may optionally additionally comprise various other materials that modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. [0181] Compounds according to the present invention may also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like. A syrup may optionally comprise, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. [0182] The hydroxysteroid dehydrogenase inhibitors of the present invention may also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. For example, if a compound is used for treating asthma or hypertension, it may be used with other bronchodilators and antihypertensive agents, respectively. [0183] Examples of pharmaceutically acceptable carriers that may be included in tablets comprising hydroxysteroid dehydrogenase inhibitors of the present invention include, but are not limited to binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents. Enteric-coated tablets, because of the enteric-coating, resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines. Sugar-coated tablets may be compressed tablets to which different layers of pharmaceutically acceptable substances are applied. Film-coated tablets may be compressed tablets that have been coated with polymers or other suitable coating. Multiple compressed tablets may be compressed tablets made by more than one compression cycle utilizing the pharmaceutically acceptable substances previously mentioned. Coloring agents may also be used in tablets. Flavoring and sweetening agents may be used in tablets, and are especially useful in the formation of chewable tablets and lozenges.
[0184] Examples of liquid oral dosage forms that may be used include, but are not limited to, aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
[0185] Examples of aqueous solutions that may be used include, but are not limited to, elixirs and syrups. As used herein, elixirs refer to clear, sweetened, hydroalcoholic preparations. Examples of pharmaceutically acceptable carriers that may be used in elixirs include, but are not limited to solvents. Particular examples of solvents that may be used include glycerin, sorbitol, ethyl alcohol and syrup. As used herein, syrups refer to concentrated aqueous solutions of a sugar, for example, sucrose. Syrups may optionally further comprise a preservative.
[0186] Emulsions refer to two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid. Emulsions may optionally be oil-in- water or water-in-oil emulsions. Examples of pharmaceutically acceptable carriers that may be used in emulsions include, but are not limited to non-aqueous liquids, emulsifying agents and preservatives.
[0187] Examples of pharmaceutically acceptable substances that may be used in non- effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents.
[0188] Examples of pharmaceutically acceptable substances that may be used in effervescent granules, to be reconstituted into a liquid oral dosage form, include organic acids and a source of carbon dioxide.
[0189] Coloring and flavoring agents may optionally be used in all of the above dosage forms.
[0190] Particular examples of preservatives that may be used include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. [0191] Particular examples of non-aqueous liquids that may be used in emulsions include mineral oil and cottonseed oil.
[0192] Particular examples of emulsifying agents that may be used include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate.
[0193] Particular examples of suspending agents that may be used include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluents include lactose and sucrose. Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as sodium cyclamate and saccharin.
[0194] Particular examples of wetting agents that may be used include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
[0195] Particular examples of organic acids that may be used include citric and tartaric acid. [0196] Sources of carbon dioxide that may be used in effervescent compositions include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof.
[0197] Particular examples of flavoring agents that may be used include natural flavors extracted from plants such fruits, and synthetic blends of compounds that produce a pleasant taste sensation.
[0198] For a solid dosage form, the solution or suspension, in for example propylene carbonate, vegetable oils or triglycerides, is preferably encapsulated in a gelatin capsule.
Such solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Pat.
Nos. 4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g., for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g. water, to be easily measured for administration.
[0199] Alternatively, liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g. propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
Other useful formulations include those set forth in U.S. Pat. Nos. Re 28,819 and
4,358,603.
Injectables, Solutions, and Emulsions
[0200] The present invention is also directed to compositions designed to administer the hydroxysteroid dehydrogenase inhibitors of the present invention by parenteral administration, generally characterized by injection, either subcutaneously, intramuscularly or intravenously. Injectables may be prepared in any conventional form, for example as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
[0201] Examples of excipients that may be used in conjunction with injectables according to the present invention include, but are not limited to water, saline, dextrose, glycerol or ethanol. The injectable compositions may also optionally comprise minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins. Implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained (see, e.g., U.S. Pat. No. 3,710,795) is also contemplated herein. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.
[0202] Parenteral administration of the formulations includes intravenous, subcutaneous and intramuscular administrations. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as the lyophilized powders described herein, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or nonaqueous.
[0203] When administered intravenously, examples of suitable carriers include, but are not limited to physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
[0204] Examples of pharmaceutically acceptable carriers that may optionally be used in parenteral preparations include, but are not limited to aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
[0205] Examples of aqueous vehicles that may optionally be used include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection.
[0206] Examples of nonaqueous parenteral vehicles that may optionally be used include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. [0207] Antimicrobial agents in bacteriostatic or fungistatic concentrations may be added to parenteral preparations, particularly when the preparations are packaged in multiple-dose containers and thus designed to be stored and multiple aliquots to be removed. Examples of antimicrobial agents that may be used include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride. [0208] Examples of isotonic agents that may be used include sodium chloride and dextrose. Examples of buffers that may be used include phosphate and citrate. Examples of antioxidants that may be used include sodium bisulfate. Examples of local anesthetics that may be used include procaine hydrochloride. Examples of suspending and dispersing agents that may be used include sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Examples of emulsifying agents that may be used include Polysorbate 80 (TWEEN 80). A sequestering or chelating agent of metal ions include EDTA.
[0209] Pharmaceutical carriers may also optionally include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.
[0210] The concentration of a hydroxysteroid dehydrogenase inhibitor in the parenteral formulation may be adjusted so that an injection administers a pharmaceutically effective amount sufficient to produce the desired pharmacological effect. The exact concentration of a hydroxysteroid dehydrogenase inhibitor and/or dosage to be used will ultimately depend on the age, weight and condition of the patient or animal as is known in the art. [0211] Unit-dose parenteral preparations may be packaged in an ampoule, a vial or a syringe with a needle. All preparations for parenteral administration should be sterile, as is know and practiced in the art.
[0212] Injectables may be designed for local and systemic administration. Typically a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1% w/w up to about 90% w/w or more, preferably more than 1% w/w of the hydroxysteroid dehydrogenase inhibitor to the treated tissue(s). The hydroxysteroid dehydrogenase inhibitor may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment will be a function of the location of where the composition is parenterally administered, the carrier and other variables that may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the age of the individual treated. It is to be further understood that for any particular subject, specific dosage regimens may need to be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations. Hence, the concentration ranges set forth herein are intended to be exemplary and are not intended to limit the scope or practice of the claimed formulations.
[0213] The hydroxysteroid dehydrogenase inhibitor may optionally be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease state and may be empirically determined.
Lyophilized Powders
[0214] The hydroxysteroid dehydrogenase inhibitors of the present invention may also be prepared as lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures. The lyophilized powders may also be formulated as solids or gels.
[0215] Sterile, lyophilized powder may be prepared by dissolving the compound in a sodium phosphate buffer solution containing dextrose or other suitable excipient. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. Briefly, the lyophilized powder may optionally be prepared by dissolving dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agent, about 1-20%, preferably about 5 to 15%, in a suitable buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, typically, about neutral pH. Then, a hydroxysteroid dehydrogenase inhibitor is added to the resulting mixture, preferably above room temperature, more preferably at about 30-35 0C, and stirred until it dissolves. The resulting mixture is diluted by adding more buffer to a desired concentration. The resulting mixture is sterile filtered or treated to remove particulates and to insure sterility, and apportioned into vials for lyophilization. Each vial may contain a single dosage or multiple dosages of the hydroxysteroid dehydrogenase inhibitor.
Topical Administration
[0216] The hydroxysteroid dehydrogenase inhibitors of the present invention may also be administered as topical mixtures. Topical mixtures may be used for local and systemic administration. The resulting mixture may be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration. [0217] The hydroxysteroid dehydrogenase inhibitors may be formulated as aerosols for topical application, such as by inhalation (see, U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation will typically have diameters of less than 50 microns, preferably less than 10 microns.
[0218] The hydroxysteroid dehydrogenase inhibitors may also be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the hydroxysteroid dehydrogenase inhibitor alone or in combination with other pharmaceutically acceptable excipients can also be administered.
Formulations For Other Routes of Administrations
[0219] Depending upon the disease state being treated, other routes of administration, such as topical application, transdermal patches, and rectal administration, may also be used. For example, pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories are used herein mean solid bodies for insertion into the rectum that melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases may be used. Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. The typical weight of a rectal suppository is about 2 to 3 gm. Tablets and capsules for rectal administration may be manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration.
Examples of Formulations
[0220] The following are particular examples of oral, intravenous and tablet formulations that may optionally be used with compounds of the present invention. It is noted that these formulations may be varied depending on the particular compound being used and the indication for which the formulation is going to be used.
ORAL FORMULATION
Compound of the Present Invention 10- 100 mg
Citric Acid Monohydrate 105 mg
Sodium Hydroxide 18 mg
Flavoring
Water q.s. to 100 mL
INTRAVENOUS FORMULATION
Compound of the Present Inventior i 0.1-10 mg
Dextrose Monohydrate q.s. to make isotonic
Citric Acid Monohydrate 1.05 mg
Sodium Hydroxide 0.18 mg
Water for Injection q.s. to 1.0 mL TABLET FORMULATION
Compound of the Present Invention 1 %
Microcrystalline Cellulose 73%
Stearic Acid 25%
Colloidal Silica 1%.
Kits Comprising Hydroxysteroid dehydrogenase Inhibitors
[0221] The invention is also directed to kits and other articles of manufacture for treating diseases associated with hydroxysteroid dehydrogenases. It is noted that diseases are intended to cover all conditions for which the hydroxysteroid dehydrogenases possess activity that contributes to the pathology and/or symptomology of the condition. [0222] In one embodiment, a kit is provided that comprises a composition comprising at least one hydroxysteroid dehydrogenase inhibitor of the present invention in combination with instructions. The instructions may indicate the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition. The kit may also comprise packaging materials. The packaging material may comprise a container for housing the composition. The kit may also optionally comprise additional components, such as syringes for administration of the composition. The kit may comprise the composition in single or multiple dose forms.
[0223] In another embodiment, an article of manufacture is provided that comprises a composition comprising at least one hydroxysteroid dehydrogenase inhibitor of the present invention in combination with packaging materials. The packaging material may comprise a container for housing the composition. The container may optionally comprise a label indicating the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition. The kit may also optionally comprise additional components, such as syringes for administration of the composition. The kit may comprise the composition in single or multiple dose forms.
[0224] It is noted that the packaging material used in kits and articles of manufacture according to the present invention may form a plurality of divided containers such as a divided bottle or a divided foil packet. The container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. The container that is employed will depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle that is in turn contained within a box. Typically the kit includes directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral, topical, transdermal and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
[0225] One particular example of a kit according to the present invention is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening. [0226] Another specific embodiment of a kit is a dispenser designed to dispense the daily doses one at a time in the order of their intended use. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter that indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery- powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
EXAMPLES Preparation of Hydroxysteroid dehydrogenase Inhibitors
[0227] Various methods may be developed for synthesizing compounds according to the present invention. Representative methods for synthesizing these compounds are provided in the Examples. It is noted, however, that the compounds of the present invention may also be synthesized by other synthetic routes that others may devise. [0228] It will be readily recognized that certain compounds according to the present invention have atoms with linkages to other atoms that confer a particular stereochemistry to the compound (e.g., chiral centers). It is recognized that synthesis of compounds according to the present invention may result in the creation of mixtures of different stereoisomers (enantiomers, diastereomers). Unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all of the different possible stereoisomers.
[0229] Various methods for separating mixtures of different stereoisomers are known in the art. For example, a racemic mixture of a compound may be reacted with an optically active resolving agent to form a pair of diastereoisomeric compounds. The diastereomers may then be separated in order to recover the optically pure enantiomers. Dissociable complexes may also be used to resolve enantiomers (e.g., crystalline diastereoisomeric salts). Diastereomers typically have sufficiently distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) that they can be readily separated by taking advantage of these dissimilarities. For example, diastereomers can typically be separated by chromatography or by separation/resolution techniques based upon differences in solubility. A more detailed description of techniques that can be used to resolve stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
[0230] Compounds according to the present invention can also be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds are set forth in the definitions section of this Application. Alternatively, the salt forms of the compounds can be prepared using salts of the starting materials or intermediates.
[0231] The free acid or free base forms of the compounds can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc).
[0232] The iV-oxides of compounds according to the present invention can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, metα-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 0C. Alternatively, the Λf-oxides of the compounds can be prepared from the Λf-oxide of an appropriate starting material.
[0233] Compounds in an unoxidized form can be prepared from Λf-oxides of compounds by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 800C.
[0234] Prodrug derivatives of the compounds can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et «/.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate, pαra-nitrophenyl carbonate, or the like).
[0235] Protected derivatives of the compounds can be made by methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999. [0236] Compounds according to the present invention may be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
[0237] Compounds according to the present invention can also be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of compounds, dissociable complexes are preferred (e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
[0238] As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or thee-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams);
L (liters); mL (milliliters); μL (microliters); psi (pounds per square inch);
M (molar); mM (millimolar); i.v. (intravenous); Hz (Hertz);
MHz (megahertz); mol (moles); mmol (millimoles); RT (ambient temperature); min (minutes); h (hours); mp (melting point); TLC (thin layer chromatography);
Tr (retention time); RP (reverse phase);
MeOH (methanol); i-PrOH (isopropanol);
TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran);
DMSO (dimethylsulfoxide); EtOAc (ethyl acetate);
DME (1,2-dimethoxyethane); DCM (dichloromethane);
DCE (dichloroethane); DMF (N,N-dimethylformamide);
DMPU (N,N'-dimethylpropyleneurea); CDI (1,1-carbonyldiimidazole);
IBCF (isobutyl chloroformate); HOAc (acetic acid);
HOSu (N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole);
Et2O (diethyl ether); EDCI (ethylcarbodiimide hydrochloride); BOC (tert-butyloxycarbonyl);FMOC (9-fluorenylmethoxycarbonyl);
DCC (dicyclohexylcarbodiimide); CBZ (benzyl oxycarbonyl);
Ac (acetyl); atm (atmosphere);
TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl);
TIPS (triisopropylsilyl); TBS (t-butyldimethylsilyl);
DMAP (4-dimethylaminopyridine); Me (methyl);
OMe (methoxy); Et (ethyl);
Et (ethyl); tBu (tert-butyl);
HPLC (high pressure liquid chromatography);
BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride);
TBAF (tetra-n-butylammonium fluoride); mCPBA (meta-chloroperbenzoic acid.
[0239] AU references to ether or Et2O are to diethyl ether; brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in 0C (degrees Centigrade). All reactions conducted under an inert atmosphere at RT unless otherwise noted.
[0240] 1H NMR spectra were recorded on a Bruker Avance 400. Chemical shifts are expressed in parts per million (ppm). Coupling constants are in units of Hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).
[0241] Low-resolution mass spectra (MS) and compound purity data were acquired on a Waters ZQ LC/MS single quadrupole system equipped with electrospray ionization (ESI) source, UV detector (220 and 254 nm), and evaporative light scattering detector (ELSD). Thin-layer chromatography was performed on 0.25 mm E. Merck silica gel plates (60F-254), visualized with UV light, 5% ethanolic phosphomolybdic acid, Ninhydrin or p-anisaldehyde solution. Flash column chromatography was performed on silica gel (230-400 mesh, Merck).
[0242] The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as the Aldrich Chemical Company (Milwaukee, WI), Bachem (Torrance, CA), Sigma (St. Louis, MO), or may be prepared by methods well known to a person of ordinary skill in the art, following procedures described in such standard references as Fieser and Fieser's Reagents for Organic Synthesis, vols. 1-17, John Wiley and Sons, New York, NY, 1991; Rodd's Chemistry of Carbon Compounds, vols. 1-5 and supps., Elsevier Science Publishers, 1989; Organic Reactions, vols. 1-40, John Wiley and Sons, New York, NY, 1991; March J.: Advanced Organic Chemistry, 4th ed., John Wiley and Sons, New York, NY; and Larock: Comprehensive Organic Transformations, VCH Publishers, New York, 1989. [0243] The entire disclosure of all documents cited throughout this application are incorporated herein by reference.
Synthetic Schemes For Hydroxysteroid Dehydrogenase Inhibitors Of The Present Invention
[0244] Hydroxysteroid dehydrogenase inhibitors according to the present invention may be synthesized according to the reaction schemes shown below. Other reaction schemes could be readily devised by those skilled in the art. It should also be appreciated that a variety of different solvents, temperatures and other reaction conditions can be varied to optimize the yields of the reactions.
[0245] In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.
Scheme 1
DMAP LiAIH4
MgCl [0246] To obtain the secondary α- alcohols such as those in Scheme 1, the key ester can be prepared by coupling a carboxy-substituted aminothiazole and various sulfonyl chlorides in pyridine with DMAP. The key ester can then be reduced to the alcohol with LAH and oxidized to the corresponding aldehyde using MnO2. The resulting aldehyde can then be treated with a variety of nucleophiles, such as Grignard reagents, to give the desired product.
Scheme 2
[0247] The tertiary α-alcohols of Scheme 2 can be prepared by reacting the key ester (see Scheme 1) with a variety of Grignard reagents.
Scheme 3
[0248] Cyclic alcohols, such as those in Scheme 3, can be synthesized by the addition of bis-organomagnesium species, or by Kulinkovich cyclopropanation.
Scheme 4
. J/> W "^ M9CI
[0249] To obtain the tertiary β-alcohols such as those in Scheme 4, the key ester can be prepared by coupling a carboxymethyl-substituted aminothiazole and various sulfonyl chlorides in pyridine with DMAP. The key ester can then be reacted with a variety of Grignard reagents to give the desired product.
Scheme 5
[0250] Alternatively, tertiary β-alcohols such as those in Scheme 5 can be prepared from a samarium(II) mediated Barbier reaction of cyclic ketones and chloromethyl- substituted N-sulfonylaminothiazoles, which can be obtained from sulfonylation of the known chloromethyl-substituted aminothiazole HCl salt by various sulfonyl chlorides.
Scheme 6
DIBAL-H
[0251] To obtain secondary β-alcohols such as those in Scheme 6, the key ester can be reduced to the corresponding aldehyde with DEBAL-H at low temperature. The desired product can then be obtained by addition of various nucleophiles, such as Grignard reagents. Scheme 7
MgCI
[0252] Alternatively, to obtain secondary β-alcohols such as those in Scheme 7, the key ester can be reacted with various nucleophiles such as Grignard reagents, followed by reduction of the resulting ketone with LAH or NaBH4.
Scheme 8
separation of diastereomers
[0253] For the separation of racemic mixtures of β-alcohols such as those in Scheme 8, the alcohols can be derivatized with the R or S enantiomer of O-methoxyphenylacetic acid. Separation of the resulting diastereomeric products can be accomplished chromatographically or by other means. Separated diastereomers can then be reduced to the corresponding alcohols.
Scheme 9
[0254] Secondary γ-alcohols such as those in Scheme 9 can be obtained via aldol condensation of the key aldehyde with a methyl ketone, followed by the hydrogenation of the resulting double bond using PtO2 as a catalyst and asymmetric reduction of the ketone functionality with either (+) or (-)-DIPCl. Alternatively, other methods for asymmetric reduction known to those skilled in the art can be used.
Scheme 10
[0255] To obtain benzylic compounds such as those in Scheme 10, an aryl secondary α-alcohol can be reacted by ionic hydrogenation according to the procedure described in Carey, F.A., Tremper, H.S; J. Am. Chem. Soc. 1968, 90, 2578-2583. Scheme 11 o H O O H
X"y™u (CHojoSI NaH ^O
HN(FUb1 AW. \'VN PH
[0256] To obtain secondary α-alcohols such as those in Scheme 11, the intermediate epoxide can be prepared from trimethylsulfonium iodide and a key aldehyde according to the procedure described in Corey, E.J., Chaykovsky, M.; J. Am. Chem. Soc. 1965, 87, 1353-1364. Exposure of the epoxide to commercially available amines in the presence of activated alumina can provide the desired products in a regioselective manner, as described in Posner, G.H., Rogers, D.Z.; J. Am. Chem. Soc, 1977, 99, 8214-8218.
Scheme 12
[0257] To obtain tertiary β-alcohols such as those in Scheme 12, the key ester can be prepared by coupling a carboxymethyl-substituted aminothiazole and various fluorine substituted arylsulfonyl chlorides in pyridine with DMAP. The key ester can then be reacted with Grignard reagents to give the desired intermediate alcohol. Aromatic nucleophilic substitution with a variety of nucleophiles provides the desired product.
Scheme 13 i) sat NaHCO3
Rb and Rc may bθ taken together to form a πng
[0258] Tertiary β-alcohols such as those in Scheme 13 can also be obtained from Boc- protected 4-(chloromethyl)thiazol-2-amine via samarium(H) mediated Barbier reaction with various cyclic or acyclic ketones. Acidolysis of the Boc protecting group of the resulting intermediate, followed by sulfonylation by various sulfonyl chlorides, gives the desired tertiary β-alcohols.
Scheme 14
[0259] Tertiary α-alcohols such as those in Scheme 14 can also be prepared from ethyl 2-aminothiazole-4-carboxylate. For example, ethyl 2-aminothiazole-4-carboxylate can be reacted with ethylmagnesium chloride to provide the corresponding diethylhydroxy derivative. The amine functionality was then coupled with a variety of sulfonyl chlorides to afford the desired sulfonamides.
[0260] Chiral components can be separated and purified using any of a variety of techniques known to those skilled in the art. For example, chiral components can be purified using supercritical fluid chromatography (SFC). In one particular variation, chiral analytical SFC/MS analyses are conducted using a Berger analytical SFC system (AutoChem, Newark, DE) which consists of a Berger SFC dual pump fluid control module with a Berger FCM 1100/1200 supercritical fluid pump and FCM 1200 modifier fluid pump, a Berger TCM 2000 oven, and an Alcott 718 autosampler. The integrated system can be controlled by BI-SFC Chemstation software version 3.4. Detection can be accomplished with a Watrers ZQ 2000 detector operated in positive mode with an ESI interface and a scan range from 200-800 Da with 0.5 second per scan. Chromatographic separations can be performed on a ChiralPak AD-H, ChiralPak AS-H, ChiralCel OD-H, or ChiralCel OJ-H column (5μ, 4.6 x 250 mm; Chiral Technologies, Inc. West Chester, PA) with 10 to 40% methanol as the modifier and with or without ammonium acetate (10 mM). Any of a variety of flow rates can be utilized including, for example, 1.5 or 3.5 rnL/min with an inlet pressure set at 100 bar. Additonally, a variety of sample injection conditions can be used including, for example, sample injections of either 5 or lOμL in methanol at 0.1 mg/mL in concentration.
[0261] In another variation, preparative chiral separations are performed using a Berger MultiGram II SFC purification system. For example, samples can be loaded onto a ChiralPak AD column (21 x 250 mm, 10 μ). In particular variations, the flow rate for separation can be 70 mL/min, the injection volume up to 2 mL, and the inlet pressure set at 130 bar. Stacked injections can be applied to increase the efficiency. [0262] For example, the above reaction schemes, and variations thereof, can be used to prepare the following:
[0263] In each of the above reaction procedures or schemes, the various substituents may be selected from among the various substituents otherwise taught herein. [0264] Descriptions of the syntheses of particular compounds according to the present invention based on the above reaction scheme are set forth herein.
Examples of Hydroxysteroid dehydrogenase Inhibitors
[0265] The present invention is further exemplified, but not limited by, the following examples that describe the synthesis of particular compounds according to the invention. Example 1-1: 3-Chloro-N-(4-(l-hydroxyethyl)thiazol-2-yl)-2-methylbenzenesulfonamide
Step A: Ethyl 2-(3-chloro-2-methylphenylsulfonamido)thiazole-4-carboxylate
[0266] Referring to Scheme 1, DMAP (150 mg, 1.23 mmol) was added to a stirred solution of 3-chloro-2-methylbenzene-l-sulfonyl chloride (4.54 g, 20.2 mmol) and ethyl 2- aminothiazole-4-carboxylate (2.89 g, 16.8 mmol) in pyridine (30 mL). The reaction mixture was stirred at 20°C for 19h and another portion of the sulfonyl chloride was added (1.58 g, 7.02 mmol). After a total of 3d, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (150 mL), washed with phosphoric acid (IN, 2x50 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The crude product was suspended in ether (150 mL), stirred vigorously until a fine suspension resulted, cooled to 10°C, filtered and dried in vacuo to afford the title compound as a beige solid (3.70 g, 61%). 1U NMR (400 MHz, CDCl3) δ, ppm: 1.37 (t, /=7.20 Hz, 3 H), 2.73 (s, 3 H), 4.37 (q, 7=7.24 Hz, 2 H), 7.24 (t, J = 7.9 Hz, 1 H), 7.27 (s, 1 H), 7.54 (d, 7=8.08 Hz, 1 H), 8.00 (d, 7=8.08 Hz, 1 H), 9.37 (br s, 1 H); ESI-MS: m/z 361.1 (M+H)+.
Step B: 3-Chloro-N-(4-(hydroxymethyl)thiazol-2-yl)-2-methylbenzenesulfonamide
[0267] Ethyl 2-(3-chloro-2-methylphenylsulfonamido)thiazole-4-carboxylate (1.50 g, 4.16 mmol) was dissolved in THF (30 mL) and cooled to 0°C under nitrogen. A solution of lithium aluminum hydride (IM in THF, 15 mL, 15 mmol) was added dropwise over 5 min. The reaction mixture was stirred at 0°C for 30 min and was carefully quenched with tartaric acid (aq. 10%, 10 mL) and the reaction mixture was allowed to warm to room temperature. It was extracted with ethyl acetate (3x50 mL), the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was suspended in ether (150 mL), stirred vigorously until a fine suspension resulted, filtered and dried in vacuo to afford the title compound as an off-white solid (1.32 g, quant). 1H NMR (400 MHz, CDCl3) δ, ppm: 2.62 (s, 3 H), 4.25 (d, 7=5.31 Hz, 2 H), 5.39 (t, 7=5.68 Hz, 1 H), 6.58 (s, 1 H), 7.37 (t, 7=7.96 Hz, 1 H), 7.65 (d, 7=7.07 Hz, 1 H), 7.88 (d, 7=7.83 Hz, 1 H), 12.86 (br s, 1 H); ESI-MS: m/z 363.1 (M+H)+.
Step C: 3-Chloro-N-(4-formylthiazol-2-yl)-2-methylbenzenesulfonamide
[0268] 3-Chloro-N-(4-(hydroxymethyl)thiazol-2-yl)-2-methylbenzenesulfonamide (1.10 g, 3.45 mmol) was suspended in methanol (25 mL) and treated with MnO2 (85%, activated powder, 6.00 g). The reaction mixture was stirred vigorously for 3 h and was filtered through a plug consisting of silica (bottom part, 6 mL) and celite (top part, 15 mL). The plug was washed well with methanol (100 mL, agitation of celite was required to achieve filtration) and the filtrate was concentrated in vacuo to afford the title compound as a yellow solid (1.07 g, 98%). This material was sufficiently clean to be used in the next step without further purification. 1H NMR (400 MHz, CDCl3) 6, ppm: 2.63 (s, 3 H), 7.23 (t, 7=7.83 Hz, 1 H), 7.48 (d, 7=7.83 Hz, 1 H), 7.65 (s, 1 H), 7.84 (d, 7=7.33 Hz, 1 H), 9.47 (s, 1 H); ESI-MS: m/z 317.1 (M+H)+.
Step D: 3-Chloro-N-(4-(l-hydroxyethyl)thiazol-2-yl)-2-methylbenzenesulfonamide [0269] 3-Chloro-N-(4-formylthiazol-2-yl)-2-methylbenzenesulfonamide (64 mg, 0.202 mmol) was suspended in THF and treated with a solution of methylmagnesium chloride (3.0M in THF, 0.33 mL, 1.0 mmol) at room temperature. The reaction mixture was stirred for 15 min, quenched with NH4Cl (sat. aq) - ice mixture (1: 1, 5 mL), stirred vigorously for 5 min and extracted with ethyl acetate (5 mL). The extract was dried (MgSO4), filtered and concentrated. The residue was purified by HPLC (45-60% acetonitrile in water, TFA buffered) to afford the title compound as a white solid (52.5 mg, 72%). 1H NMR (400 MHz, DMSO-D6) 5, ppm: 1.54 (d, 7=6.57 Hz, 3 H), 2.63 (s, 3 H), 4.86 (q, 7=6.32 Hz, 1 H), 6.30 (s, 1 H), 7.23 (t, 7 = 8.08 Hz, 1 H), 7.57 (d, 7=8.08 Hz, 1 H), 8.00 (d, 7=7.83 Hz, 1 H), 11.85 (br s, 1 H); ESI-MS: m/z 333.1 (M+H)+.
Example 1-2: 3-Chloro-N-(4-(l-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0270] The title compound was prepared as described for Example 1-1, with the exception that ethylmagnesium bromide was used (l.OM in THF, 1.00 mL, 1.00 mmol). HPLC (35-55% acetonitrile in water, TFA buffered) afforded the title compound as a white solid (39.5 mg, 56%). 1H NMR (400 MHz, CDCl3) δ, ppm: 1.04 (t, 7=7.33 Hz, 3 H), 1.85 (quint, 7=7.26 Hz, 2 H), 2.62 (s, 3 H), 4.55 (t, 7=6.82 Hz, 1 H), 6.30 (s, 1 H), 7.24 (t, 7 = 8.08 Hz, 1 H), 7.57 (d, 7=8.08 Hz, 1 H), 8.00 (d, 7=8.08 Hz, 1 H), 11.84 (br s, 1 H); ESI-MS: m/z 347.1 (M+H)+.
Example 1-3: 3-Chloro-N-(4-(l-hydroxybutyl)thiazol-2-yl)-2-methylbenzenesulfonamide
[0271] The title compound was prepared as described for Example 1-1, with the exception that n-propylmagnesium chloride was used (2.0M in THF, 0.50 mL, 1.00 mmol). HPLC (45-60% acetonitrile in water, TFA buffered) afforded the title compound as a white solid (46.5 mg, 64%). 1H NMR (400 MHz, CDCl3) δ, ppm: 0.96 (t, 7=7.45 Hz, 3 H), 1.38 - 1.49 (m, 1 H), 1.50 - 1.62 (m, 1 H), 1.72 - 1.84 (m, 2 H), 2.63 (s, 3 H), 4.64 (dd, 7=8.46, 5.18 Hz, 1 H), 6.28 (s, 1 H), 7.24 (t, 7=8.08 Hz, 1 H), 7.57 (d, 7=7.83 Hz, 1 H), 8.00 (d, 7=8.08 Hz, 1 H), 11.60 (br s, IH); ESI-MS: m/z 361.2 (M+H)+.
Example 1-4: 3-Chloro-N-(4-(cyclopropyl(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0272] The title compound was prepared as described for Example 1-1, with the exception that cyclopropylmagnesium bromide was used (0.5M in THF, 2.00 mL, 1.00 mmol). HPLC (45-60% acetonitrile in water, TFA buffered) afforded the title compound as a white solid (52.5 mg, 72%). 1H NMR (400 MHz, CDCl3) δ, ppm: 0.36 - 0.43 (m, 1 H), 0.50 - 0.57 (m, 1 H), 0.62 - 0.73 (m, 2 H), 1.19 - 1.29 (m, 1 H), 2.64 (s, 3 H), 4.04 (d, 7=7.83 Hz, 1 H), 6.46 (s, 1 H), 7.23 - 7.25 (t, 7 = 8.08 Hz, 1 H), 7.56 (d, 7=8.08 Hz, 1 H), 8.00 (d, 7=8.08 Hz, 1 H), 11.51 (br s, IH); ESI-MS: m/z 359.1 (M+H)+. ESI-MS: m/z 359.1 (M+H)+.
Example 1-5: 3-Chloro-N-(4-( 1 -hydroxy-2-methylpropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0273] The title compound was prepared as described for Example 1-1, with the exception that i-propylmagnesium chloride was used (2.0M in ethyl ether, 0.50 mL, 1.00 mmol). HPLC (45-60% acetonitrile in water, TFA buffered) afforded the title compound as a white solid (13.2 mg, 18%). 1H NMR (400 MHz, CDCl3) δ, ppm: 0.93 (d, 7=6.57 Hz, 3 H), 1.05 (d, 7=6.57 Hz, 3 H), 2.01 - 2.10 (sept, 7=6.76 Hz, 1 H), 2.61 (s, 3 H), 3.84 (br s, 1 H), 4.33 (d, 7=6.57 Hz, 1 H), 6.26 (s, 1 H), 7.23 (t, 7=7.96 Hz, 1 H), 7.56 (d, 7=8.08 Hz, 1 H), 8.00 (d, 7=8.08 Hz, 1 H), 11.43 (br s, 1 H). ESI-MS: m/z 361.2 (M+H)+. Example 1-6: 3-Chloro-N-(4-(cyclopentyl(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0274] The title compound was prepared as described for Example 1-1, with the exception that cyclopentylmagnesium bromide was used (2.0M in ethyl ether, 0.50 niL, 1.00 mmol). HPLC (45-60% acetonitrile in water, TFA buffered) afforded the title compound as a white solid (7.8 mg, 10%). 1H NMR (400 MHz, CDCl3) δ, ppm: 1.18 - 1.29 (m, 1 H), 1.55 - 1.67 (m, 6 H), 1.83 - 1.94 (m, 1 H), 2.27 - 2.34 (m, 1 H), 2.64 (s, 3 H), 4.37 (d, 7=8.59 Hz, 1 H), 6.27 (s, 1 H), 7.24 (t, 7=7.96 Hz, 1 H), 7.56 (d, 7=7.83 Hz, 1 H), 8.00 (d, 7=7.83 Hz, 1 H), 11.42 (br s, IH). ESI-MS: m/z 387.1 (M+H)+.
Example 1-7: 3-Chloro-N-(4-(cyclohexyl(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0275] The title compound was prepared as described for Example 1-1, with the exception that cyclohexylmagnesium bromide was used (2.0M in ethyl ether, 0.50 mL, 1.00 mmol). HPLC (45-60% acetonitrile in water, TFA buffered) afforded the title compound as a white solid (33.1 mg, 41%). 1H NMR (400 MHz, CDCl3) δ, ppm: 0.93 - 1.33 (m, 3 H), 1.38 - 1.47 (m, 1 H), 1.64 - 1.74 (m, 3 H), 1.76 - 1.82 (m, 1 H), 1.95 - 2.03 (m, 1 H), 2.63 (s, 3 H), 4.31 (d, 7=7.58 Hz, 1 H), 6.25 (s, 1 H), 7.23 (t, 7=7.96 Hz, 1 H), 7.56 (d, 7=8.08 Hz, 1 H), 8.00 (d, 7=7.83 Hz, 1 H), 11.43 (br s, 1 H); ESI-MS: m/z 401.2 (M+H)+. Example 1-8: 3-Chloro-N-(4-(l-hydroxy-2-phenylethyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0276] The title compound was prepared as described for Example 1-1, with the exception that benzylmagnesium chloride was used (l.OM in THF, 1.00 mL, 1.00 mmol). HPLC (45-60% acetonitrile in water, TFA buffered) afforded the title compound as a white solid (23.2 mg, 28%). 1H NMR (400 MHz, CDCl3) δ, ppm: 2.64 (s, 3 H), 3.05 - 3.15 (m, 2 H), 4.91 (dd, 7=7.83, 6.06 Hz, 1 H), 6.25 (s, 1 H), 7.20 - 7.35 (m, 6 H), 7.56 (d, 7=7.83 Hz, 1 H), 8.00 (d, 7=8.08 Hz, 1 H), 11.44 (br s, IH). ESI-MS: m/z 409.2 (M+H)+.
Example 1-9: 3-Chloro-N-(4-(l-hydroxy-3-phenylpropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0277] The title compound was prepared as described for Example 1-1, with the exception that the following amounts were used: aldehyde (3-chloro-N-(4-formylthiazol- 2-yl)-2-methylbenzenesulfonamide) (250 mg, 0.789 mmol), THF (2 mL), phenethylmagnesium chloride (IM in THF, 3.00 mL, 3.00 mmol). HPLC (45-60% acetonitrile in water, TFA buffered) afforded the title compound as a white solid (15 mg, 4.5%). 1H NMR (400 MHz, CHLOROFORM-D) δ, ppm: 1.99 - 2.09 (m, 1 H), 2.11 - 2.22 (m, 1 H), 2.61 (s, 3 H), 2.69 - 2.80 (m, 1 H), 2.83 - 2.92 (m, 1 H), 4.60 (m, 1 H), 6.26 (s, 1 H), 7.17 - 7.29 (m, 10 H), 7.55 (d, 7=8.08 Hz, 1 H), 7.97 (d, 7=7.83 Hz, 1 H), 11.40 (br s, 1 H); ESI-MS: m/z 423.2 (M+H)+. Example 1-10: 3-chloro-N-(4-(hydroxy(o-tolyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0278] The title compound was prepared as described for Example 1-1. H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.26 (s, 3 H), 2.72 (s, 3 H), 4.40 (br s, 1 H), 5.73 (d, 7=0.76 Hz, 1 H), 5.96 (s, 1 H), 7.16 - 7.25 (m, 2 H), 7.27 - 7.30 (m, 2 H), 7.53 - 7.57 (m, 1 H), 7.58 (d, 7=8.08 Hz, 1 H), 8.00 (d, 7=7.83 Hz, 1 H), 11.86 (br s, 1 H). ESI-MS: m/z 409.1 (M+H)+.
Example 1-11: 3-chloro-N-(4-(hydroxy(o-ethylphenyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0279] The title compound was prepared as described for Example 1-1. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.07 (t, 7=7.71 Hz, 3 H), 2.53 - 2.65 (m, 5 H), 5.69 (s, 1 H), 6.07 (s, 1 H), 6.28 (s, 1 H), 7.16 - 7.26 (m, 3 H), 7.32 - 7.39 (m, 2 H), 7.66 (d, 7=8.08 Hz, 1 H), 7.88 (d, 7=8.08 Hz, 1 H), 12.89 (s, 1 H). ESI-MS: m/z 423.1 (M+H)+.
Example 1-12: 3-chloro-N-(4-((3-fluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0280] The title compound was prepared as described for Example 1-1. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.65 (br s, 1 H), 2.69 (s, 3 H), 5.83 (s, 1 H), 5.85 (s, 1 H), 7.05 (td, 7=8.21, 2.02 Hz, 1 H), 7.15 - 7.21 (m, 2 H), 7.23 - 7.28 (m, 1 H), 7.36 (td, 7=7.96, 5.81 Hz, 1 H), 7.59 (d, 7=8.08 Hz, 1 H), 7.99 (d, 7=7.83 Hz, 1 H), 12.08 (br s, 1 H). ESI-MS: m/z 413.1 (M+H)+.
Example 1-13: 3-chloro-N-(4-((3,4-difluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0281] The title compound was prepared as described for Example 1-1. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.68 (s, 3 H), 4.87 (br d, 7=6.08 Hz, 1 H), 5.81 (s, 1 H), 5.83 (s, 1 H), 7.12 - 7.32 (m, 4 H), 7.60 (d, 7=8.08 Hz, 1 H), 7.99 (d, 7=7.83 Hz, 1 H), 12.27 (br s, 1 H). ESI-MS: m/z 431.1 (M+H)+.
Example 1-14: 3-chloro-N-(4-((4-chloro-3-fluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0282] The title compound was prepared as described for Example 1-1. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.60 (s, 3 H), 5.48 (s, 1 H), 6.05 (s, 1 H), 6.35 (s, 1 H), 7.19 (d, 7=8.34 Hz, 1 H), 7.27 (t, 7=7.45 Hz, 1 H), 7.36 (d, 7=10.11 Hz, 1 H), 7.46 - 7.57 (m, 2 H), 7.84 (d, 7=7.33 Hz, 1 H), 12.9 (br s, 1 H). ESI-MS: m/z 447.0 (M+H)+. Example 1-15: 3-chloro-N-(4-((3-chloro-5-fluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0283] The title compound was prepared as described for Example 1-1. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.68 (s, 3 H), 4.96 (s, 1 H), 5.83 (s, 1 H), 5.87 (s, 1 H), 7.09 (m, 2 H), 7.21 - 7.28 (m, 2 H), 7.60 (d, 7=8.08 Hz, 1 H), 7.98 (d, 7=7.83 Hz, 1 H), 12.29 (s, 1 H). ESI-MS: m/z 447.0 (M+H)+.
Example 1-16: 3-chloro-N-(4-((4-fluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0284] Commercially available 4-fluorophenylmagnesium bromide (0.950 mL, 1.0M in THF 0.950 mmol) was added dropwise to a stirring solution of 3-chloro-N-(4- formylthiazol-2-yl)-2-methylbenzenesulfonamide Example 1-1-C (0.100 g, 0.32 mmol) in tetrahydrofuran (3 mL) and allowed to stir for Ih. The reaction mixture was quenched by addition to a cold solution of saturated ammonium chloride (3 mL). The resulting solution was extracted with ethyl acetate (2 x 3 mL). The combined organic fractions were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography on SiO2 eluted with hexanes/ethyl acetate (1:1) to yield 0.096 g (74 %) of the title compound as a white foam. 1H NMR (400 MHz, DMSO- d6) 5, ppm: 2.62 (s, 3 H), 5.54 (d, 7=4.29 Hz, 1 H,) 6.19 (d, 7=4.55 Hz, 1 H), 6.44 (s, 1 H), 7.16 (t, 7=8.84 Hz, 2 H), 7.36 (t, 7=7.96 Hz, 1 H), 7.42 (dd, 7=8.72, 5.68 Hz, 2 H), 7.64 (d, 7=7.83 Hz, 1 H), 7.87 (d, 7=6.57 Hz, 1 H), 12.86 (s, 1 H); ESI-MS: m/z 413.1 (M+H)+. Example 1-17: 3-chloro-N-(4-(hydroxy(phenyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0285] The title compound was prepared from commercially available phenylmagnesium bromide (3.0 M in diethyl ether) and 3-chloro-N-(4-formylthiazol-2- yl)-2-methylbenzenesulfonamide Example 1-1-C according to the procedure described in Example 1-16. 1H NMR (400 MHz, DMSO-d6) 5, ppm: 2.61 (s, 3 H), 5.52 (d, 7=4.29 Hz, 1 H), 6.19 (d, 7=4.80 Hz, 1 H), 6.43 (s, 1 H), 7.28 (t, 7=7.20 Hz, 1 H), 7.32 - 7.39 (m, 5 H), 7.65 (d, 7=9.35 Hz, 1 H), 7.87 (d, 7=7.83 Hz, 1 H), 12.91 (s, 1 H); ESI-MS: m/z 395.1 (M+H)+.
Example 1-18: 3-chloro-N-(4-((4-chlorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0286] The title compound was prepared from commercially available 4- chlorophenylmagnesium bromide (1.0 M in Et2O) and 3-chloro-N-(4-formylthiazol-2-yl)- 2-methylbenzenesulfonamide Example 1-1-C according to the procedure described in Example 1-16. 1H NMR (400 MHz, DMSO-d6) δ, ppm: 2.61 (s, 3 H), 5.54 (d, 7=4.55 Hz, 1 H), 6.28 (d, 7=4.55 Hz, 1 H), 6.45 (s, 1 H), 7.34 - 7.43 (m, 5 H), 7.65 (d, 7=7.83 Hz, 1 H), 7.87 (d, 7=7.83 Hz, 1 H), 12.93 (s, 1 H); ESI-MS: m/z 429.1 (M+H)+.
Example 1-19: 3-chloro-N-(4-((3-chlorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0287] The title compound was prepared from commercially available 3- chlorophenylmagnesium bromide (0.5 M in THF) and 3-chloro-N-(4-formylthiazol-2-yl)- 2-methylbenzenesulfonamide Example 1-1-C according to the procedure described in Example 1-16. 1H NMR (400 MHz, DMSO-d6) 5, ppm: 2.62 (s, 9 H), 2.66 (s, 1 H), 5.56 (d, 7=4.55 Hz, 3 H), 6.33 (s, 3 H), 6.50 (s, 4 H), 7.31 - 7.40 (m, 13 H), 7.49 (s, 4 H), 7.65 (d, 7=8.08 Hz, 4 H), 7.87 (d, 7=7.83 Hz, 3 H), 12.93 (s, 3 H); ESI-MS: m/z 429.1 (M+H)+.
Example 1-20: 3-chloro-N-(4-((3-chloro-4-fluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0288] The title compound was prepared from commercially available 3-chloro-4- fluorophenylmagnesium bromide (0.5 M in THF) and 3-chloro-N-(4-formylthiazol-2-yl)- 2-methylbenzenesulfonamide Example 1-1-C according to the procedure described in Example 1-16. 1H NMR (400 MHz, DMSO-d6) δ, ppm: 2.61 (s, 3 H), 5.57 (d, 7=4.55 Hz, 1 H), 6.37 (d, 7=4.55 Hz, 1 H), 6.51 (s, 1 H), 7.34 - 7.44 (m, 3 H), 7.60 - 7.68 (m, 2 H), 7.87 (d, 7=7.83 Hz, 1 H), 12.93 (s, .1 H); ESI-MS: m/z 447.1 (M+H)+.
Example 1-21: 3-chloro-N-(4-((3,5-difluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0289] The title compound was prepared from commercially available 3,5- difluorophenylmagnesium bromide (0.5 M in THF) and 3-chloro-N-(4-formylthiazol-2- yl)-2-methylbenzenesulfonamide Example 1-1-C according to the procedure described in Example 1-16. 1H NMR (400 MHz, DMSO-d6) 5, ppm: 2.62 (s, 3 H), 5.59 (d, 7=4.55 Hz, 1 H), 6.44 (d, 7=4.55 Hz, 1 H), 6.52 (s, 1 H), 7.10 - 7.20 (m, 3 H), 7.34 - 7.40 (m, 1 H), 7.65 (d, 7=8.34 Hz, 1 H), 7.87 (d, 7=7.83 Hz, 1 H), 12.95 (s, 1 H); ESI-MS: m/z 431.1
(M+H)+.
Example 1-22: 3-chloro-N-(4-(hydroxy(m-tolyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0290] The title compound was prepared from commercially available m- tolylmagnesium bromide (1.0 M in THF) and 3-chloro-N-(4-formylthiazol-2-yl)-2- methylbenzenesulfonamide Example 1-1-C according to the procedure described in Example 1-16. 1H NMR (400 MHz, DMSO-d6) 6, ppm: 2.28 (s, 2 H), 2.61 (s, 2 H), 5.47 (d, 7=4.80 Hz, 1 H), 6.14 (d, 7=3.54 Hz, 1 H), 6.43 (s, 1 H), 7.09 (d, 7=7.58 Hz, 1 H), 7.14 - 7.26 (m, 3 H), 7.36 (t, 7=7.96 Hz, 1 H), 7.65 (d, 7=8.08 Hz, 1 H), 7.87 (d, 7=7.58 Hz, 1 H), 12.88 (s, 1 H); ESI-MS: m/z 409.2 (M+H)+.
Example 1-23: 3-chloro-N-(4-((2,3-dimethylphenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0291] The title compound was prepared from commercially available 2,3- dimethylphenylmagnesium bromide (0.5 M in THF) and 3-chloro-N-(4-formylthiazol-2- yl)-2-methylbenzenesulfonamide Example 1-1-C according to the procedure described in Example 1-16. 1H NMR (400 MHz, DMSO-d6) δ, ppm: 2.17 (s, 3 H), 2.24 (s, 3 H), 2.62 (s, 3 H), 5.61 (d, 7=4.80 Hz, 1 H), 6.03 (d, 7=4.80 Hz, 1 H), 6.31 (s, 1 H), 6.98 - 7.07 (m, 2 H), 7.18 (s, 1 H), 7.37 (t, 7=7.96 Hz, 1 H), 7.66 (d, 7=8.08 Hz, 1 H), 7.88 (d, 7=7.33 Hz, 1 H), 12.86 (s, 1 H); ESI-MS: m/z 423.2 (M+H)+. Example 1-24: 3-chloro-N-(4-(hydroxy(2-methoxyphenyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0292] The title compound was prepared from commercially available 2- methoxyphenylmagnesium bromide (1.0 M in THF) and 3-chloro-N-(4-formylthiazol-2- yl)-2-methylbenzenesulfonamide Example 1-1-C according to the procedure described in Example 1-16. 1H NMR (400 MHz, DMSO-d6) δ, ppm: 2.63 (s, 2 H), 3.73 (s, 2 H), 5.76 (d, 7=5.31 Hz, 1 H), 5.97 - 6.03 (m, 1 H), 6.17 (s, 1 H), 6.93 - 7.01 (m, 2 H), 7.28 (t, 7=8.34 Hz, 1 H), 7.36 (t, 7=8.08 Hz, 1 H), 7.43 (d, 7=7.58 Hz, 1 H), 7.65 (d, 7=8.08 Hz, 1 H), 7.84 - 7.92 (m, 1 H), 12.91 (s, 1 H); ESI-MS: m/z 425.1 (M+H)+.
Example 1-25: 3-chloro-N-(4-((4-cyanophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0293] Commercially available isopropylmagnesium chloride (1.42 mL, 2.0 M in diethyl ether, 2.84 mmol) was added to a stirring solution of 4-iodobenzonitrile (0.651 g. 2.84 mmol) in THF at -10 0C. The reaction was allowed to warm to room temperature and stirred Ih, whereupon it was added to a stirring solution of 3-chloro-N-(4-formylthiazol-2- yl)-2-methylbenzenesulfonamide Example 1-1-C (0.150 g, 0.474 mmol) in 3 mL of THF at room temperature. The reaction was stirred at ambient temperature for Ih and quenched with saturated ammonium chloride solution (5 mL). The resulting solution was extracted with ethyl acetate (2 x 3 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography on SiO2 eluted with hexanes/ethyl acetate (2: 1) to yield 0.115 g (58 %) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ, ppm: 2.60 (s, 3 H), 5.64 (t, 7=4.55 Hz, 1 H), 6.38 - 6.45 (m, 1 H), 6.50 (s, 1 H), 7.35 (t, 7=8.08 Hz, 1 H), 7.58 (d, 7=8.08 Hz, 2 H), 7.64 (d, 7=7.58 Hz, 1 H), 7.81 (d, 7=8.59 Hz, 2 H), 7.86 (d, 7=7.83 Hz, 1 H), 12.97 (s, 1 H); ESI-MS: m/z 420.1 (M+H)+.
Example 1-26: 3-chloro-N-(4-(hydroxy(3-(trifluoromethyl)phenyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0294] The title compound was prepared from commercially available l-iodo-3- (trifluoromethyl)benzene and 3-chloro-N-(4-formylthiazol-2-yl)-2- methylbenzenesulfonamide Example 1-1-C according to the procedure described in Example 1-25. 1H NMR (400 MHz, DMSO-d6) δ, ppm: 2.61 (s, 3 H), 5.67 (d, 7=4.55 Hz, 1 H), 6.42 (d, 7=4.80 Hz, 1 H), 6.53 (s, 1 H), 7.36 (t, 7=7.71 Hz, 1 H), 7.58 (t, 7=7.58 Hz, 1 H), 7.63 - 7.69 (m, 3 H), 7.79 (s, 1 H), 7.87 (d, 7=6.57 Hz, 1 H), 12.97 (s, 1 H); ESI- MS: m/z 463.1 (M+H)+.
Example 1-27: 3-chloro-N-(4-(hydroxy(pyridin-2-yl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0295] The title compound was prepared from commercially available 2- pyridylmagnesium bromide (7.6 mL, 0.25 M in diethyl ether) and 3-chloro-N-(4- forrnylthiazol-2-yl)-2-methylbenzenesulfonarnide Example 1-1-C according to the procedure described in Example 1-16. 1H NMR (400 MHz, DMSO-d6) δ, ppm: 2.61 (s, 3 H), 5.52 (d, J=5.05 Hz, 1 H), 6.30 (s, 1 H), 6.44 (s, 1 H), 7.30 (dd, J=I 1.12, 5.81 Hz, 1 H), 7.33 - 7.38 (m, 1 H), 7.57 (d, J=8.08 Hz, 1 H), 7.62 (d, J=9.09 Hz, 1 H), 7.79 - 7.85 (m, 1 H), 7.86 (d, J=8.34 Hz, 1 H), 12.94 (s, 1 H); ESI-MS: m/z 396.1 (M+H)+. Example 1-28: 3-chloro-N-(4-((2-chloropyridin-3-yl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0296] The title compound was prepared from commercially available 2-chloro-3- iodopyridine and 3-chloro-N-(4-formylthiazol-2-yl)-2-methylbenzenesulfonamide Example 1-1-C according to the procedure described in Example 1-25. 1H NMR (400 MHz, DMSO-d6) δ, ppm: 2.62 (s, 3 H), 5.71 (d, 7=5.05 Hz, 1 H), 6.38 (s, 1 H), 6.45 (s, 1 H), 7.35 (t, 7=8.08 Hz, 1 H), 7.45 - 7.53 (m, 1 H), 7.63 (d, 7=7.83 Hz, 1 H), 7.87 (d, 7=7.83 Hz, 1 H), 8.01 (d, 7=7.33 Hz, 1 H), 8.32 - 8.40 (m, 1 H), 13.07 (s, 1 H); ESI-MS: m/z 430.1 (M+H)+.
Example 1-29: 3-chloro-N-(4-(2-(diethylamino)- 1 -hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0297] Sodium hydride (0.080 g 95 % dry, 3.2 mmol) was added to a stirring solution of trimethylsulfonium iodide (0.644 g, 3.2 mmol) in dimethylsulfoxide (1 mL). The resulting reaction was stirred at ambient temperature for 0.5 h until gas evolution ceased. A solution of 3-chloro-N-(4-formylthiazol-2-yl)-2-methylbenzenesulfonamide Example 1-1-C (0.100 g, 0.32 mmol) in dimethylsulfoxide (1 mL) was added via syringe and the resulting reaction was stirred for Ih at ambient temperature, then quenched with pH 7 phosphate buffer (2 mL). The resulting solution was extracted with ethyl acetate (2 x 2 mL). The combined organic fractions were dried over anhydrous sodium sulfate and concentrated in vacuo. The yellow oily residue was dissolved in THF (1 mL) and added to a stirring solution of N,N-diethylamine (0.136 mL, 1.31 mmol) and Brockmann neutral alumina (2.4 g, 23.5 mmol) in THF (1 mL). After 1 h, the reaction was filtered, rinsed with methanol (4 mL) and concentrated. The resulting yellow residue was purified by preparative HPLC-MS (5 - 95 % CH3CN in H2O) to give 0.003 g of the title compound as a white foam. 1H NMR (400 MHz, Methanol-d4) δ, ppm: 1.24 (t, 7=7.20 Hz, 6 H), 2.70 (s, 3 H), 2.93 - 3.04 (m, 2 H), 3.17 - 3.28 (m, 2 H), 3.84 (dd, 7=12.51, 4.67 Hz, 1 H), 3.99 (dd, 7=12.38, 7.58 Hz, 1 H), 4.31 (dd, 7=7.71, 4.67 Hz, 1 H), 6.74 (s, 1 H), 7.22 (t, 7=8.21 Hz, 1 H), 7.49 (d, 7=8.84 Hz, 1 H), 7.97 (d, 7=7.83 Hz, 1 H); ESI-MS: m/z 404.2 (M+H)+.
Example 1-30: 3-chloro-N-(4-( 1 -hydroxy-2-(pyrimidin-4-yl)ethyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0298] The title compound was prepared from 4-methypyrimidine and 3-chloro-N-(4- formylthiazol-2-yl)-2-methylbenzenesulfonamide Example 1-1-C according to the procedure described in Example 2-20. 1H NMR (400 MHz, Methanol-d4) δ, ppm: 2.71 (s, 3 H), 3.13 - 3.20 (m, 2 H), 4.97 - 5.04 (m, 1 H), 6.48 (s, 1 H), 7.29 (t, J=7.96 Hz, 1 H), 7.40 (d, J=6.57 Hz, 1 H), 7.58 (d, J=7.83 Hz, 1 H), 7.96 (d, J=7.83 Hz, 1 H), 8.63 (d, J=5.3O Hz, 1 H), 9.03 (s, 1 H); m/z 411.1 (M+H)+.
Example 1-31: 3-chloro-N-(4-((3-cyanophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0299] 3-Iodobenzonitrile (0.33 g, 1.4 mmol) was dissolved in THF (10 ml) and was cooled to -10 0C. Isopropylmagnesium chloride (0.71 ml, 1.4 mmol) was added dropwise and was stirred at -10 0C for 1.5 h. This mixture was then added to a solution of 3- chloro-N-(4-formylthiazol-2-yl)-2-methylbenzenesulfonamide (0.15 g, 0.47 mmol) in THF (4 ml) at -20 0C. After stirring at -10 0C for 3 h, the reaction mixture was quenched with saturated NH4Cl at 0 0C. The mixture was further diluted with brine, and extracted three times with EtOAc. Combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography on SiO2 eluted with EtOAc/hexanes (3: 1) to yield 0.11 g (55 %) of the title compound. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.62 (s, 3H), 5.09 (bs, 1 H), 5.83 (s, 1 H), 5.89 (s, 1 H), 7.23 (t, 7=8.0 Hz, 1 H), 7.23 (t, 7=8.1 Hz, 1 H), 7.48 (t, 7=7.7 Hz, 1 H), 7.56 (d, 7=7.8 Hz, 1 H), 7.61 (d, 7=7.6 Hz, 1 H), 7.66 (d, 7=7.8 Hz, 1 H), 7.73 (s, 1 H), 7.94 (d, 7=7.8 Hz, 1 H); 13C NMR (100 MHz, CHLOROFORM-D) 6 ppm 14.2, 17.3, 21.1, 60.5, 67.4, 106.3, 112.7, 118.4, 126.4, 127.6, 129.5, 130.3, 131.2, 132.2, 133.84, 135.03, 137.2, 140.11, 140.4, 141.2, 171.1; ESI-MS: m/z 420.1 (M+H)+.
Example 1-32: 3-chloro-N-(4-((2-cyanophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0300] The title compound was prepared from commercially available 2- iodobenzonitrile and 3-chloro-N-(4-formylthiazol-2-yl)-2-methylbenzenesulfonamide according to the procedure described in Example 1-31. The crude product was purified by column chromatography on SiO2 eluted with EtOAc/hexanes (3:1) to yield 0.10 g (50 %) of the title compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.61 (s, 3 H), 5.74 - 5.77 (m, 1 H), 6.42 (s, 1 H), 6.63 (m, 1 H), 7.37 (t, 7=8.0 Hz, 1 H), 7.52 (t, 7=7.6 Hz, 1 H), 7.63 (d, 7=7.8 Hz, 1 H), 7.66 (d, 7=7.8 Hz, 1 H), 7.73 (t, 7=7.6 Hz, 1 H), 7.83 (d, 7=7.6 Hz, 1 H), 7.87 (d, 7=8.0 Hz, 1 H), 13.03 (s, 1 H); ESI-MS: m/z 420.1 (M+H)+.
Example 1-33: 3-chloro-N-(4-(hydroxy(3-methoxyphenyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0301] The title compound was prepared from commercially available 3- methoxyphenylmagnesium bromide (1.0 M in THF) and 3-chloro-N-(4-formylthiazol-2- yl)-2-methylbenzenesulfonamide according to the procedure described in Example 1-25.
The crude product was purified by column chromatography on SiO2 eluted with EtOAc/hexanes (3:2) to yield 0.12 g (60 %) of the title compound as a white foam. ESI- MS: m/z 425.1 (M+H)+.
Example 1-34: (R)-3-chloro-N-(4-( 1 -hydroxyproρyl)thiazol-2-yl)-2- methylbenzenesulf on amide
[0302] The title compound was prepared as described for Example 1-2 except that (+)DIPC1 was used for the asymmetric reduction (82% ee). Stereo-configuration was assigned based on precedents of DIPCl reduction. 1H NMR (400 MHz, CDCl3) 5, ppm: 1.04 (t, 7=7.33 Hz, 3 H), 1.85 (quint, 7=7.26 Hz, 2 H), 2.62 (s, 3 H), 4.55 (t, 7=6.82 Hz, 1 H), 6.30 (s, 1 H), 7.24 (t, 7 = 8.08 Hz, 1 H), 7.57 (d, 7=8.08 Hz, 1 H), 8.00 (d, 7=8.08 Hz, 1 H), 11.84 (br s, 1 H); ESI-MS: m/z 347.1 (M+H)+; chiral analytical SFC retention time: 5.2 min.
Example 1-35: (S)-3-chloro-N-(4-(l-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0303] The title compound was prepared from 3-chloro-2-methyl-N-(4- propionylthiazol-2-yl)benzenesulfonamide as described for Example 1-2 by asymmetric reduction using (-)DIPCl in 81% ee. Stereo-configuration was assigned based on precedents of DIPCl reduction. 1H NMR (400 MHz, CDCl3) δ, ppm: 1.04 (t, 7=7.33 Hz, 3 H), 1.85 (quint, 7=7.26 Hz, 2 H), 2.62 (s, 3 H), 4.55 (t, 7=6.82 Hz, 1 H), 6.30 (s, 1 H), 7.24 (t, 7= 8.08 Hz, 1 H), 7.57 (d, 7=8.08 Hz, 1 H), 8.00 (d, 7=8.08 Hz, 1 H), 11.84 (br s,
1 H); ESI-MS: m/z 347.1 (M+H)+; chiral analytical SFC retention time: 5.9 min. Example 1-36: (R)-3-chloro-N-(4-((2-ethylphenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0304] The title compound was prepared by means of preparative SFC separation of Example 1-11 as described above (>98% ee). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.07 (t, 7=7.71 Hz, 3 H), 2.53 - 2.65 (m, 5 H), 5.69 (s, 1 H), 6.07 (s, 1 H), 6.28 (s, 1 H), 7.16 - 7.26 (m, 3 H), 7.32 - 7.39 (m, 2 H), 7.66 (d, 7=8.08 Hz, 1 H), 7.88 (d, 7=8.08 Hz, 1 H), 12.89 (s, 1 H). ESI-MS: m/z 423.1 (M+H)+; chiral analytical SFC retention time: 2.1 min.
Example 1-37: (S)-3-chloro-N-(4-((2-ethylphenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0305] The title compound was prepared by means of preparative SFC separation of Example 1-11 as described above (>98% ee). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.07 (t, 7=7.71 Hz, 3 H), 2.53 - 2.65 (m, 5 H), 5.69 (s, 1 H), 6.07 (s, 1 H), 6.28 (s, 1 H), 7.16 - 7.26 (m, 3 H), 7.32 - 7.39 (m, 2 H), 7.66 (d, 7=8.08 Hz, 1 H), 7.88 (d, 7=8.08 Hz, 1 H), 12.89 (s, 1 H). ESI-MS: m/z 423.1 (M+H)+; chiral analytical SFC retention time: 3.7 min. Example 2-1: 3-Chloro-N-(4-(2-hydroxypentyl)thiazol-2-yl)-2- methylbenzenesulfonamide
Step A: Ethyl 2-(2-(3-chloro-2-methylphenylsulfonamido)thiazol-4-yl)acetate
[0306] DMAP (50 mg, 0.41 mmol) was added to a stirred solution of 3-chloro-2- methylbenzene-1-sulfonyl chloride (3.92 g, 17.4 mmol) and ethyl 2-(2-aminothiazol-4- yl)acetate (3.21 g, 17.2 mmol) in pyridine (20 mL). The reaction mixture was stirred at 2O0C for 16h and was concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL), washed with HCl (6N, 3 x 50 mL), water (5OmL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The crude product was suspended in ether (150 mL), stirred vigorously until a fine suspension resulted, cooled to 100C, filtered and dried in vacuo to afford the title compound as a pink solid (5.39 g, 83%). 1H NMR (400 MHz, CDCl3) δ, ppm: 1.25 (t, 7=7.20 Hz, 3 H), 2.63 (s, 3 H), 3.75 (s, 2 H), 4.18 (q, 7=7.07 Hz, 2 H), 6.33 (s, 1 H), 7.21 (t, 7=8.34 Hz, 1 H), 7.53 (d, 7=8.08 Hz, 1 H), 8.00 (d, 7=8.08 Hz, 1 H), 11.85 (br s, 1 H). ; ESI-MS: m/z 375.2 (M+H)+.
Step B: 3-Chloro-2-methyl-N-(4-(2-oxoethyl)thiazol-2-yl)benzenesulfonamide
[0307] To a cold (-780C) solution of ethyl 2-(2-(3-chloro-2- methylphenylsulfonamido)thiazol-4-yl)acetate (0.188 g, 0.502 mmol) in dichloromethane (2 mL) and toluene (3 mL), was added DIBAL-H (IM in hexanes, 1.10 mL, 1.10 mmol) over the period of 5 min. The reaction mixture was stirred at -78°C for 40 min. Acetone (0.4 mL) was added and stirring continued for 10 min. The reaction was then treated with tartaric acid (10% aq., 10 mL) and the mixture was allowed to warm to room temperature, stirred overnight and was extracted with ethyl acetate (4x3mL). The combined organic layers were washed with brine (5 mL), dried (MgSO4), filtered and concentrated in vacuo. Flash column chromatography on silica gel (40 mL SiO2, hexanes - ethyl acetate 1:4, 300 mL) afforded the title compound as a brownish solid (0.107 g, 64%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.57 (s, 3 H) 3.93 (s, 2 H) 6.34 (s, 1 H) 7.21 (t, 7=7.83 Hz, 1 H) 7.53 (d, 7=8.08 Hz, 1 H) 7.96 (d, 7=7.83 Hz, 1 H) 9.69 (s, 1 H) 12.02 (s, 1 H). ESI-MS: m/z 317.1 (M+H)+.
Step C: 3-Chloro-N-(4-(2-hydroxypentyl)thiazol-2-yl)-2-methylbenzenesulfonamide [0308] 3-Chloro-2-methyl-N-(4-(2-oxoethyl)thiazol-2-yl)benzenesulfonamide (0.190 g, 0.534 mmol) was dissolved in THF and cooled to -100C in nitrogen atmosphere, n- Propylmagnesium chloride (2M solution in ethyl ether, 0.600 mL, 1.20 mmol) was added dropwise and the reaction mixture was stirred for 40 min. It was quenched with a cooled NH4Cl (sat. aq, 5mL) - water (5 mL) mixture and stirred vigorously for 5 min. The resulting mixture was extracted with ethyl acetate (3x7 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by TLC (ethyl acetate) to afford the title compound as a white solid (37.2 mg, 19%). 1H NMR (400 MHz, CHLOROFORM-D) δ, ppm: 0.93 (t, 7=7.07 Hz, 3 H), 1.29 - 1.54 (m, 4 H), 2.44 (br s, 1 H), 2.62 (dd, 7=15.3, 7.96 Hz, 1 H), 2.70 (s, 3 H), 2.78 (dd, 7=15.2, 3.30 Hz, 1 H), 3.83-3.90 (m, 1 H), 6.09 (s, 1 H), 7.21 (t, 7=7.96 Hz, 1 H), 7.52 (d, 7=7.58 Hz, 1 H), 8.02 (d, 7=7.33 Hz, 1 H), 10.81 (br s, 1 H). ESI-MS: m/z 375.1 (M+H)+.
Example 2-2: 3-Chloro-N-(4-(2-hydroxy-3-methylbutyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0309] The title compound was prepared as described for Example 2-1. 1H NMR (400 MHz, CHLOROFORM-D) 6 ppm 0.94 (d, 7=6.82 Hz, 3 H), 0.97 (d, 7=6.82 Hz, 3 H), 1.66 - 1.72 (m, 1 H), 2.02 - 2.09 (br s, 1 H), 2.55-2.72 (m, 2 H), 2.74 (s, 3 H), 3.56 - 3.66 (m, 1 H), 6.05 (s, 1 H), 7.21 (t, 7=7.45 Hz, 1 H), 7.51 (d, 7=7.58 Hz, 1 H), 8.02 (d, 7=7.33 Hz, 1 H), 10.17 (br s, IH). ESI-MS: m/z 375.1 (M+H)+.
Example 2-3: 3-Chloro-N-(4-(2-cyclopentyl-2-hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0310] The title compound was prepared as described for Example 2-1. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.09 - 0.92 (m, 9 H), 2.59 (dd, 7=15.4, 8.08 Hz, 1 H), 2.73 (s, 3 H), 2.77 (dd, 7=15.4, 2.56 Hz, 1 H), 3.61 - 3.67 (m, 1 H), 6.05 (s, 1 H), 7.21 (t, 7=7.45 Hz, 1 H), 7.51 (d, 7=7.58 Hz, 1 H), 8.02 (d, 7=7.33 Hz, 1 H), 10.18 (br s, IH). ESI- MS: m/z 401.1 (M+H)+.
Example 2-4: 3-Chloro-N-(4-(2-hydroxy-2-phenylethyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0311] The title compound was prepared as described for Example 2-1. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.60 (br s, 1 H), 2.73 (s, 3 H), 2.94 (d, 7=5.81 Hz, 2 H), 4.97 (t, 7=5.68 Hz, 1 H), 6.01 (s, 1 H), 7.22 (t, 7=7.96 Hz, 1 H), 7.33 (m, 5 H), 7.53 (d, 7=7.33 Hz, 1 H), 8.03 (d, 7=7.83 Hz, 1 H), 10.47 (s, 1 H). ESI-MS: m/z 409.1 (M+H)+.
Example 2-5: 3-chloro-N-(4-(2-hydroxy-3,3-dimethylbutyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0312] The title compound was prepared as described for Example 2-1. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.95 (s, 9 H), 1.70 (br s, IH), 2.52 (ddd, 7=15.22, 10.55, 1.26 Hz, 1 H), 2.69 - 2.75 (m, 4 H), 3.46 (dd, 7=10.74, 1.64 Hz, 1 H), 6.08 (s, 1 H), 7.21 (t, 7=7.96 Hz, 1 H), 7.52 (d, 7=7.83 Hz, 1 H), 8.02 (d, 7=8.08 Hz, 1 H), 10.90 (br s, 1 H). ESI-MS: m/z 389.1 (M+H)+.
Example 2-6: 3-chloro-N-(4-(2-(3-fluorophenyl)-2-hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0313] The title compound was prepared as described for Example 2-1. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.62 (br s, 1 H), 2.69 (s, 3 H) 2.93 - 3.04 (m, 2 H), 4.97 (dd, 7=7.96, 3.66 Hz, 1 H), 6.05 (s, 1 H), 6.94 - 7.01 (m, 1 H), 7.04 - 7.13 (m, 2 H), 7.23 (t, 7=7.96 Hz, 1 H), 7.31 (m, 1 H), 7.54 (d, 7=8.08 Hz, 1 H), 8.02 (d, 7=8.08 Hz, 1 H), 10.99 (br s, 1 H). ESI-MS: m/z 409.1 (M+H)+. Example 2-7: 3-chloro-N-(4-(3-(2,5-difluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
Step A: 3-chloro-N-(4-(3-(2,5-difluorophenyl)-2-oxopropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0314] Mg turnings (0.729 g, 30.0 mmol) were placed in a flame-dried flask and ethyl ether (2 mL) was added under nitrogen. 1 ,2-Dibromoethane (0.1 mL) was added and once the gas evolution almost subsided a solution of 2-(bromomethyl)-l,4-difluorobenzene (2.07 g, 10.0 mmol) in ethyl ether (8 mL) was added at a rate to sustain gentle reflux (20 min). The reaction mixture was then heated to reflux for 10 min and cooled to room temperature. Half of the resulting solution was added to a solution of ethyl 2-(2-(3-chloro- 2-methylphenylsulfonamido)thiazol-4-yl)acetate (0.325 g, 0.865 mmol) in THF (2 mL) at room temperature over 1 min and the resulting mixture was stirred for 30 min. It was then quenched with a cooled (0°C) NH4Cl (sat. aq., 5 mL)- water (5 mL) mixture and stirred vigorously for 5 min. The resulting mixture was extracted with ethyl acetate (3x3 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was dissolved in THF (2 mL) and treated with the remaining half of the Grignard solution in the same fashion as described above. The resulting crude product was purified by HPLC (45-60% acetonitrile in water, TFA buffered) to afford the title compound as a white solid (0.160 g, 41%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.55 (s, 3 H) 3.87 (s, 2 H) 3.99 (s, 2 H) 6.27 (s, 1 H) 6.88 - 7.00 (m, 3 H) 7.22 (t, 7=7.96 Hz, 1 H) 7.56 (d, 7=8.08 Hz, 1 H) 8.00 (d, 7=8.08 Hz, 1 H) 12.12 (s, 1 H). ESI- MS: m/z 457.1 (M+H)+. Step B: 3-chloro-N-(4-(3-(2,5-difluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0315] 3-chloro-N-(4-(3-(2,5-difluorophenyl)-2-oxopropyl)thiazol-2-yl)-2- methylbenzenesulfon-amide (60 mg, 0.131 mmol) was dissolved in THF (1.5 mL) and cooled to -10°C in nitrogen. LiAlH4 (1.0 M in THF, 1.00 mL, 1.00 mmol) was added over 1 min and the reaction mixture was warmed to room temperature and stirred for 1.5 h. It was then quenched with tartaric acid (10% aq., 3 mL) and extracted with ethyl acetate (3x3 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. HPLC (45-60% acetonitrile in water, TFA buffered) afforded the title compound as a white solid (34.3 mg, 57%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.68 (s, 3 H), 2.69 - 2.93 (m, 4 H) 4.11 (m, 1 H) 6.15 (s, 1 H) 6.88 - 7.00 (m, 3 H) 7.22 (t, 7=7.83 Hz, 1 H) 7.54 (d, 7=8.59 Hz, 1 H) 8.01 (d, 7=7.83 Hz, 1 H) 11.11 (br s, 1 H). ESI-MS: m/z 459.1 (M+H)+.
Example 2-8: 3-chloro-N-(4-(3-(4-fluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0316] The title compound was prepared as described for Example 2-7. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.58 (br s, 1 H) 2.63- 2.89 (m, 7 H) 4.03 (m, 1 H) 6.12 (s, 1 H) 7.00 (t, 7=8.46 Hz, 2 H) 7.16 (t, 7=6.32 Hz, 2 H) 7.22 (t, 7=7.83 Hz, 1 H) 7.54 (d, 7=8.08 Hz, 1 H) 8.01 (d, 7=7.83 Hz, 1 H) 11.03 (br s, 1 H). ESI-MS: m/z 441.1 (M+H)+.
Example 2-9: 3-chloro-N-(4-(3-(2-fluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0317] The title compound was prepared as described for Example 2-7. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.65 - 2.73 (m, 4 H) 2.76 - 2.87 (m, 2 H) 2.88 - 2.98 (m, 1 H) 4.13 (m, 1 H) 6.12 (s, 1 H) 7.01 - 7.12 (m, 2 H) 7.17 - 7.26 (m, 3 H) 7.52 (d, 7=8.08 Hz, 1 H) 8.01 (d, 7=7.83 Hz, 1 H), 10.80 (br s, 1 H). ESI-MS: m/z 441.1 (M+H)+.
Example 2-10: (S)-3-chloro-N-(4-(3-(2-fluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
Step A: (R)-((S)-l-(2-(3-chloro-2-methylphenylsulfonamido)thiazol-4-yl)-3-(2- fluorophenyl)propan-2-yl) 2-methoxy-2-phenylacetate
[0318] 3-chloro-N-(4-(3-(2-fluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide Example 2-9 (0.140 g, .330 mmol) and R-(-)-α- methoxyphenylacetic acid (65.0 mg, 0.391 mmol) were dissolved in dichloromethane (5 mL) and EDCI (77.0 mg, 0.402 mmol) was added followed by DMAP (10 mg, 0.082 mmol). The reaction mixture was stirred for 15 h and was diluted with ethyl acetate (10 mL) and washed with water (5 mL), sodium bicarbonate (sat. aq., 10 mL), dried (MgSO4) and concentrated in vacuo. HPLC (60-99% acetonitrile in water, TFA buffered) afforded a 1: 1 diastereomeric mixture of esters as a white solid (0.151 mg, 78%). The diastereomers were separated using preparative silica gel TLC (dichloromethane - ethyl acetate 40:1, four 20x20 cm plates, 1 mm thickness). The bottom band contained the title compound (78.8 mg, 41%, 95% ee). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.70 - 2.79 (m, 4 H) 2.85 - 2.95 (m, 3 H) 3.33 (s, 3 H) 4.76 (s, 1 H) 5.28 - 5.36 (m, 1 H) 5.94 (s, 1 H) 6.90 - 6.98 (m, 3 H) 7.12 - 7.19 (m, 1 H) 7.23 (t, 7=7.96 Hz, 1 H) 7.30 - 7.36 (m, 5 H) 7.54 (d, 7=8.08 Hz, 1 H) 8.02 (d, 7=7.33 Hz, 1 H) 10.70 (br s, IH). ESI-MS: m/z 589.2 (M+H)+. [0319] The top band contained the other diastereomer (63.1 mg, 32%, >99: 1 dr). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.65 - 2.74 (m, 4 H) 2.82 - 2.89 (m, 2 H) 2.92 - 2.99 (m, 1 H) 3.34 (s, 3 H) 4.70 (s, 1 H) 5.29 - 5.37 (m, 1 H) 5.62 (s, 1 H) 6.89 - 6.99 (m, 3 H) 7.12 - 7.19 (m, 1 H) 7.21 - 7.26 (m, 1 H) 7.31 - 7.38 (m, 5 H) 7.54 (d, 7=7.83 Hz, 1 H) 8.02 (d, 7=7.83 Hz, 1 H) 10.80 (br s, 1 H). ESI-MS: m/z 589.2 (M+H)+.
Step B: (S)-3-chloro-N-(4-(3-(2-fluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0320] (R)-C(S)- 1 -(2-(3-chloro-2-methylphenylsulfonarnido)thiazol-4-yl)-3-(2- fluorophenyl)propan-2-yl) 2-methoxy-2-phenylacetate (78.0 mg, 0.132 mmol) was dissolved in dichloromethane, cooled to -78°C in nitrogen and was treated with DIBAL-H (l.OM in hexanes, 1.20 mL, 1.20 mmol). The reaction mixture was allowed to warm to room temperature over 30 min and stirred for 5 min. It was then cooled to -780C and methanol (1 mL) was added and stirred for 5 min. The mixture was then treated with Rochelle salt solution (20% aq., 8 mL), diluted with ethyl ether (8 mL) and stirred vigorously overnight. The bottom aqueous layer was discarded and the the organic layer was dried (MgSO4), filtered and concentrated in vacuo. HPLC (60-99% acetonitrile in water, TFA buffered) afforded the title compound as a white solid (45.7 mg, 79%). Stereo-configuration was assigned based on NMR analysis of the methoxyphenylacetic acid derivatized diastereomers of Example 2-9 and Example 2-13 with known configurations. Example 2-11: (R)-3-chloro-N-(4-(3-(2-fluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0321] The title compound was obtained as described for Example 2-10-B, starting from the other diastereomer isolated by preparative TLC in Example 2-10-A, except that the following quantities were used: (R)-((R)-l-(2-(3-chloro-2- methylphenylsulfonamido)thiazol-4-yl)-3-(2-fluorophenyl)propan-2-yl) 2-methoxy-2- phenylacetate (63.0 mg, 0.107 mmol), DIBAL-H (1.00 mL, 1.00 mmol), dichloromethane (5 mL). The title compound was obtained as a white solid (38.4 mg, 81%). Stereo- configuration was assigned based on NMR analysis of the methoxyphenylacetic acid derivatized diastereomers of Example 2-9 and Example 2-13 with known configurations.
Example 2-12: 3-chloro-N-(4-(2-hydroxy-3-phenylpropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0322] The title compound was prepared as described for Example 2-7, with the exception that commercially available benzylmagnesium chloride (IM in ethyl ether) was used. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.55 (br s, 1 H) 2.64 - 2.71 (m, 4 H) 2.74 - 2.80 (m, 1 H) 2.82 - 2.89 (m, 2 H) 4.03 - 4.12 (m, 1 H) 6.10 (s, 1 H) 7.17 - 7.27 (m, 4 H) 7.29 - 7.35 (m, 2 H) 7.53 (d, 7=7.83 Hz, 1 H) 8.02 (d, 7=8.08 Hz, 1 H) 10.90 (s, 1 H) ESI-MS: m/z 423.1 (M+H)+. Example 2-13: (S)-3-Chloro-N-(4-(2-hydroxy-3-ρhenylpropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0323] The title compound was prepared by means of preparative SFC separation of Example 2-12 as described above (> 98% ee). Stereo-configuration was assigned based on the X-ray co-crystal structure. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.55 (br s, 1 H) 2.64 - 2.71 (m, 4 H) 2.74 - 2.80 (m, 1 H) 2.82 - 2.89 (m, 2 H) 4.03 - 4.12 (m, 1 H) 6.10 (s, 1 H) 7.17 - 7.27 (m, 4 H) 7.29 - 7.35 (m, 2 H) 7.53 (d, 7=7.83 Hz, 1 H) 8.02 (d, 7=8.08 Hz, 1 H) 10.90 (s, 1 H) ESI-MS: m/z 423.1 (M+H)+.
Example 2-14: 3-chloro-N-(4-(3-(2,4-difluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0324] The title compound was prepared as described for Example 2-7. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.67 - 2.91 (m, 7 H) 4.04 - 4.11 (m, 1 H) 6.14 (s, 1 H) 6.76 - 6.86 (m, 2 H) 7.15 - 7.25 (m, 2 H) 7.54 (d, 7=8.08 Hz, 1 H) 8.01 (d, 7=7.83 Hz, 1 H) 11.01 (s, 1 H); ESI-MS: m/z 459.1 (M+H)+.
Example 2-15: 3-chloro-N-(4-(3-(2,6-difluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0325] The title compound was prepared as described for Example 2-7. 1H NMR (400
MHz, CHLOROFORM-D) δ ppm 2.57 - 2.94 (m, 7 H) 4.15 (m, 1 H) 6.11 (s, 1 H) 6.85 - 6.92 (m, 2 H) 7.17 - 7.25 (m, 2 H) 7.52 (d, 7=7.83 Hz, 1 H) 8.01 (d, 7=7.83 Hz, 1 H) 10.60 (s, 1 H) ESI-MS: m/z 459.1 (M+H)+.
Example 2-16: 3-chloro-N-(4-(3-(3-chlorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0326] The title compound was prepared as described for Example 2-7. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.55 (d, 7=4.29 Hz, 1 H) 2.64 - 2.78 (m, 5 H) 2.79 - 2.89 (m, 2 H) 4.07 (m, 1 H) 6.12 (s, 1 H) 7.03 - 7.14 (m, 1 H) 7.19 - 7.28 (m, 4 H) 7.54 (d, 7=7.83 Hz, 1 H) 8.02 (d, 7=8.08 Hz, 1 H) 10.88 (s, 1 H). ESI-MS: m/z 457.1 (M+H)+.
Example 2-17: 3-chloro-N-(4-(2-cyclopropyl-2-hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0327] The title compound was prepared as described for Example 2-7. U NMR (400 MHz, CHLOROFORM-D) δ ppm 0.18 - 0.29 (m, 1 H) 0.31 - 0.40 (m, 1 H) 0.51 - 0.60 (m, 2 H) 0.88 - 0.98 (m, 1 H) 2.63 (br s, 1 H) 2.69 (s, 3 H) 2.76 - 2.83 (dd, 7=15.2, 7.82 Hz, 1 H) 2.89 - 2.95 (dd, 7=15.2, 3.04 Hz, 1 H) 3.10 (t, 7=7.45 Hz, 1 H) 6.13 (s, 1 H) 7.21 (t, 7=7.96 Hz, 1 H) 7.52 (d, 7=8.08 Hz, 1 H) 8.02 (d, 7=7.83 Hz, 1 H) 10.87 (s, 1 H). ESI- MS: m/z 373.1 (M+H)+. Example 2-18: (R)-3-Chloro-N-(4-(2-cyclopropyl-2-hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0328] The title compound was prepared as described for Example 2-10 with the exception that dichloromethane - ethyl ether (7:1) was used for the preparative TLC separations. Stereo-configuration was assigned based on NMR analysis of the methoxyphenylacetic acid derivatized diastereomers of Example 2-17 and Example 2-13 with known configurations. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.18 - 0.29 (m, 1 H) 0.31 - 0.40 (m, 1 H) 0.51 - 0.60 (m, 2 H) 0.88 - 0.98 (m, 1 H) 2.63 (br s, 1 H) 2.69 (s, 3 H) 2.76 - 2.83 (dd, 7=15.2, 7.82 Hz, 1 H) 2.89 - 2.95 (dd, 7=15.2, 3.04 Hz, 1 H) 3.10 (t, 7=7.45 Hz, 1 H) 6.13 (s, 1 H) 7.21 (t, 7=7.96 Hz, 1 H) 7.52 (d, 7=8.08 Hz, 1 H) 8.02 (d, 7=7.83 Hz, 1 H) 10.87 (s, 1 H). ESI-MS: m/z 373.1 (M+H)+; chiral analytical SFC retention time: 7.0 min.
Example 2-19: (S)-3-Chloro-N-(4-(2-cyclopropyl-2-hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulfonamide
s
[0329] The title compound was prepare s escri Hb0ed for Example 2-11 with the exception that dichloromethane - ethyl ether (7:1) was used for preparative TLC separations. Stereo-configuration was assigned based on NMR analysis of the methoxyphenylacetic acid derivatized diastereomers of Example 2-17 and Example 2-13 with known configurations. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.18 - 0.29 (m, 1 H) 0.31 - 0.40 (m, 1 H) 0.51 - 0.60 (m, 2 H) 0.88 - 0.98 (m, 1 H) 2.63 (br s, 1 H) 2.69 (s, 3 H) 2.76 - 2.83 (dd, 7=15.2, 7.82 Hz, 1 H) 2.89 - 2.95 (dd, 7=15.2, 3.04 Hz, 1 H) 3.10 (t, 7=7.45 Hz, 1 H) 6.13 (s, 1 H) 7.21 (t, 7=7.96 Hz, 1 H) 7.52 (d, 7=8.08 Hz, 1 H) 8.02 (d, 7=7.83 Hz, 1 H) 10.87 (s, 1 H). ESI-MS: m/z 373.1 (M+H)+; chiral analytical SFC retention time: 6.3 min.
Example 2-20: 3-chloro-N-(4-(2-hydroxy-3-(pyrimidin-4-yl)propyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0330] Lithium diisopropylamide (9 mL, 0.44 M solution in THF) was added to a stirring solution of 4-methylpyrimidine in THF (7 mL) at - 78 0C. After stirring for 0.5 h, the resulting solution was added via cannula to a stirring solution of 3-chloro-2-methyl-N- (4-(2-oxoethyl)thiazol-2-yl)benzenesulfonamide Example 2-1-B in THF (2 mL) at - 78 0C. The resulting reaction was stirred 0.5h at - 78 0C and then allowed to warm to ambient temperature. After 2h the reaction was quenched with saturated ammonium chloride solution (10 mL). The resulting solution was extracted with ethyl acetate (2 x 20 mL). The combined organic fractions were dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting brown oil was purified by preparative HPLC-MS (30 - 45 % CH3CN in H2O) to yield 0.003 g of the title compound as a yellow oil. 1H NMR (400 MHz, Methanol-d4) δ, ppm: 2.63 - 2.70 (m, 1 H), 2.71 (s, 3 H), 2.73 - 2.79 (m, 1 H), 2.83 - 2.90 (m, 1 H), 2.93 - 2.98 (m, 1 H), 4.21 - 4.31 (m, J=8.34, 8.34, 4.42, 4.17 Hz, 1 H), 6.40 (s, 1 H), 7.28 (t, J=7.96 Hz, 1 H), 7.42 (dd, J=5.18, 1.39 Hz, 1 H), 7.57 (dd, J=7.96, 1.14 Hz, 1 H), 7.97 (d, J=LOl Hz, 1 H), 8.63 (d, J=5.O5 Hz, 1 H), 9.04 (s, 1 H); m/z 425.1 (M+H)+.
Example 2-21 : 4-fluoro-N-(4-(2-hydroxybutyl)thiazol-2-yl)-2-methylbenzenesulfonamide
Step A: Ethyl 2-(2-(4-fluoro-2-methylphenylsulfonamido)thiazol-4-yl)acetate
[0331] The title compound was prepared as described in Example 2-1-A. 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.15 - 1.21 (t, J=7.24 Hz, 3 H), 2.58 (s, 3 H), 3.64 (s, 2 H), 4.09 (q, J=7.24 Hz, 2 H), 6.61 (s, 1 H), 7.18 (t, J=8.34 Hz, 1 H), 7.26 (d, J=9.85 Hz, 1 H), 7.93 (t, J=6.95 Hz, 1 H), 12.73 (s, 1 H); ESI-MS: m/z 359.2 (M+H)+.
Step B: 4-fluoro-N-(4-(2-hydroxybutyl)thiazol-2-yl)-2-methylbenzenesulfonamide [0332] The title compound was prepared as described in Example 2-1. 1H NMR (400 MHz, Chloroform -d) δ ppm: 0.95 (t, J=7.33 Hz, 3 H), 1.16 - 1.28 (q, J=7.33 Hz, 2 H), 2.53 (d, J=14.40 Hz, 1 H), 2.64 (s, 3 H), 2.76 (d, J=14.40 Hz, 1 H), 3.78 (m, 1 H), 6.06 (s, 1 H), 6.95 (d, J=9.85 Hz, 2 H), 8.06 (s, 1 H); ESI-MS: m/z 345.2 (M+H)+.
Example 2-22: 3-chloro-4-fluoro-ΛT-(4-(2-hydroxybutyl)thiazol-2-yl)benzenesulfonamide
[0333] The title compound was prepared as described in Example 2-1. 1H NMR (400 MHz, Chloroform-d) δ ppm: 0.94 (t, J=7.33 Hz, 3 H), 1.51 (dq, J=7.33, 7.07 Hz, 2 H), 2.60 - 2.71 (m, 1 H), 2.76 - 2.86 (m, 1 H), 3.72 - 3.81 (m, 1 H), 6.17 (s, 1 H), 7.18 (t, J=8.46 Hz, 1 H), 7.77 (ddd, J=8.59, 4.55, 2.27 Hz, 1 H), 7.94 (dd, J=6.57, 2.27 Hz, 1 H); ESI-MS: m/z 365.2 (M+H)+.
Example 2-23: 3-fluoro-N-(4-(2-hydroxybutyl)thiazol-2-yl)benzenesulfonamide
[0334] The title compound was prepared as described in Example 2-1. 1H NMR (400 MHz, Chloroform-d) δ ppm: 0.95 (t, J=7.45 Hz, 3 H) 1.46 - 1.56 (m, J=7.58, 7.33, 7.20, 7.20 Hz, 2 H) 2.56 - 2.63 (m, 1 H) 2.72 - 2.79 (m, 1 H) 3.75 - 3.83 (m, 1 H) 6.10 (s, 1 H) 7.11 (t, J=8.46 Hz, 2 H) 7.94 (dd, J=8.46, 5.18 Hz, 2 H); ESI-MS: m/z 331.2 (M+H)+. Example 2-24: 3-fluoro-N-(4-(2-hydroxybutyl)thiazol-2-yl)benzenesulfonarnide
[0335] The title compound was prepared as described in Example 2-1. 1H NMR (400 MHz, Chloroform-d) δ ppm: 0.95 (t, J=7.45 Hz, 3 H) 1.52 (dq, J=7.45, 7.20 Hz, 2 H) 2.59 (dd, J=15.41, 7.83 Hz, 1 H) 2.71 - 2.79 (m, 1 H) 3.75 - 3.85 (m, 1 H) 6.11 (s, 1 H) 7.21 (td, J=8.34, 2.53 Hz, 1 H) 7.43 (td, J=8.08, 5.56 Hz, 1 H) 7.63 (dt, J=8.27, 1.80 Hz, 1 H) 7.72 (dd, J=8.08, 1.26 Hz, 1 H); ESI-MS: m/z 331.2 (M+H)+.
Example 2-25: (R)-3-Chloro-N-(4-(2-hydroxy-3-phenylpropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0336] The title compound was prepared by means of preparative SFC separation of Example 2-12 as described above (> 98% ee). Stereo-configuration was assigned based on the X-ray co-crystal structure. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.55 (br s, 1 H) 2.64 - 2.71 (m, 4 H) 2.74 - 2.80 (m, 1 H) 2.82 - 2.89 (m, 2 H) 4.03 - 4.12 (m, 1 H) 6.10 (s, 1 H) 7.17 - 7.27 (m, 4 H) 7.29 - 7.35 (m, 2 H) 7.53 (d, 7=7.83 Hz, 1 H) 8.02 (d, 7=8.08 Hz, 1 H) 10.90 (s, 1 H) ESI-MS: m/z 423.1 (M+H)+.
Example 3-1: (S)-3-chloro-N-(4-(3-hydroxy-3-phenylpropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
Step A: 3-Chloro-2-methyl-N-(4-(3-oxo-3-phenylpropyl)thiazol-2-yl)benzenesulfonamide
[0337] 3-Chloro-N-(4-formylthiazol-2-yl)-2-methylbenzenesulfonamide Example 1-1- C (0.859 g, 2.71 mmol) was suspended in EtOH (20 mL) and acetophenone (0.350 mL, 3.00 mmol) was added. The mixture was treated with NaOH (5M in water, 5 mL) and the resulting clear red mixture was stirred for 5 min. The reaction mixture was diluted with NH4Cl until pH 7 (approx. 50 mL) and extracted with ethyl acetate (50 mL). The organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude product (1.25 g) was suspended in ethyl acetate (150 mL) and PtO2 was added (100 mg, 0.440 mmol). The reaction mixture was hydrogenated at room temperature at 40 psi H2 for 20 h. It was diluted with MeOH (100 mL), filtered through a plug, consisting of celite (top, 10 mL) and silica gel (bottom, 3 mL). The plug was washed well with MeOH and the filtrate was concentrated in vacuo. The resulting crude product was recrystallized from ethyl acetate - ethyl ether (1:2, 50 mL) to afford the title compound as an off-white solid (0.313 g, 27%). 1H NMR (400 MHz, DMSO-D6) δ ppm 2.64 (s, 3 H) 2.77 (t, 7=7.33 Hz, 2 H) 3.38 (t, 7=7.20 Hz, 2 H) 6.50 (s, 1 H) 7.37 (t, 7=7.96 Hz, 1 H) 7.51 (t, 7=7.58 Hz, 2 H) 7.60 - 7.69 (m, 2 H) 7.89 (d, 7=7.83 Hz, 1 H) 7.97 (d, 7=7.33 Hz, 2 H) 12.82 (s, 1 H). ESI-MS: m/z 421.1 (M+H)+.
Step B: (S)-3-chloro-N-(4-(3-hydroxy-3-phenylpropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0338] 3-chloro-2-methyl-N-(4-(3-oxo-3-phenylpropyl)thiazol-2- yl)benzenesulfonamide (90.0 mg, 0.214 mmol) was dissolved in THF and cooled to -100C under nitrogen. (-)DIPCl (150 mg, 0.468 mmol) was added quickly in one portion and the reaction mixture was allowed to warm to room temperature over 3 h period and stirred overnight. It was then treated with EtOH (0.8 mL), NaOH (3M in water, 0.15 mL), and H2O2 (35% in water, 0.15 mL) and stirred at 60°C for 1.5 h. The mixture was cooled, diluted with water (3 mL) and extracted with ethyl acetate (3 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude product was subjected to HPLC (45-60% acetonitrile in water, TFA buffered) and the resulting material was recrystallized from chloroform-ethyl ether-hexane (1:1:1, 3 rnL) to afford the title compound as a white solid (46 mg, 51%, 98% ee). Stereo-configuration was assigned based on the X-ray co-crystal structure. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.78 - 1.89 (m, 2 H) 2.38 - 2.54 (m, 2 H) 2.62 (s, 3 H) 4.45 - 4.53 (m, 1 H) 5.28 - 5.33 (m, 1 H) 6.42 (s, 1 H) 7.16 - 7.23 (m, 1 H) 7.26 - 7.32 (m, 4 H) 7.36 (t, /=8.08 Hz, 1 H) 7.65 (d, 7=8.84 Hz, 1 H) 7.88 (d, 7=8.08 Hz, 1 H) 12.72 (s, 1 H). ESI-MS: m/z 423.1 (M+H)+.
Example 3-2: (R)-3-chloro-N-(4-(3-hydroxy-3-phenylρropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0339] The title compound was prepared from 3-chloro-2-methyl-N-(4-(3-oxo-3- phenylpropyl)thiazol-2-yl)benzenesulfonamide as described for Example 3-1 -B except that (+)DIPC1 was used for the asymmetric reduction (98% ee). Stereo-configuration was assigned based on the X-ray co-crystal structure. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.78 - 1.89 (m, 2 H) 2.38 - 2.54 (m, 2 H) 2.62 (s, 3 H) 4.45 - 4.53 (m, 1 H) 5.28 - 5.33 (m, 1 H) 6.42 (s, 1 H) 7.16 - 7.23 (m, 1 H) 7.26 - 7.32 (m, 4 H) 7.36 (t, 7=8.08 Hz, 1 H) 7.65 (d, 7=8.84 Hz, 1 H) 7.88 (d, 7=8.08 Hz, 1 H) 12.72 (s, 1 H). ESI-MS: m/z 423.1 (M+H)+.
Example 4-1: 3-chloro-N-(4-(2-hydroxypropan-2-yl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0340] Ethyl 2-(3-chloro-2-methylphenylsulfonamido)thiazole-4-carboxylate (0.109 g,
0.302 mmol) was dissolved in THF (2 mL) and treated with methylmagnesuim chloride I (3.0M in ethyl ether, 0.5 mL, 1.5 mmol) over 1 min. The reaction mixture was stirred for
0.5 h, quenched with a cold (0°C) NH4Cl (sat. aq., 2.5 mL) - water (2.5 mL) mixture and extracted with ethyl acetate (5 mL). The organic extract was dried (MgSO4), filtered and concentrated in vacuo. The resulting crude product was purified by HPLC (20-60% acetonitrile in water, TFA buffered) to afford the title compound as a white solid (53.4 mg, 51%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.36 (s, 6 H) 2.64 (s, 3 H) 5.37 (s, 1 H) 6.48 (s, 1 H) 7.38 (t, 7=7.96 Hz, 1 H) 7.66 (d, 7=8.08 Hz, 1 H) 7.89 (d, 7=7.83 Hz, 1 H) 12.74 (s, 1 H) ESI-MS: m/z 347.1 (M+H)+
Example 4-2: 3-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0341] The title compound was obtained as described for Example 4-1. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.66 (t, 7=7.33 Hz, 6 H) 1.58 - 1.68 (m, 4 H) 2.62 (s, 3 H) 4.99 (s, 1 H) 6.44 (d, 7=1.52 Hz, 1 H) 7.38 (t, 7=7.96 Hz, 1 H) 7.66 (d, 7=8.08 Hz, 1 H) 7.89 (d, 7=7.83 Hz, 1 H) 12.58 (s, 1 H). ESI-MS: m/z 375.1 (M+H)+
Example 4-3: 3-chloro-N-(4-(4-hydroxyheptan-4-yl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0342] The title compound was obtained as described for Example 4-1. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.90 (t, 7=7.33 Hz, 6 H) 1.23 - 1.35 (m, 4 H) 1.64 - 1.76 (m, 4 H) 2.61 (s, 3 H) 2.99 (s, 1 H) 6.04 (s, 1 H) 7.21 (t, 7=8.08 Hz, 1 H) 7.53 (d, 7=8.08 Hz, 1 H) 8.01 (d, 7=8.08 Hz, 1 H) 10.24 (s, 1 H). ESI-MS: m/z 403.2 (M+H)+ Example 4-4: 3-chloro-N-(4-( 1 -hydroxycyclopropyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0343] Ethyl 2-(3-chloro-2-methylphenylsulfonamido)thiazole-4-carboxylate (180.4 mg, 0.500 mmol) was dissolved in THF (3 niL) and cooled to O0C in nitrogen. Ti(OiPr)4 (0.15 mL, 0.49 mmol) was then added dropwise over the period of 30 min. The resulting dark mixture was quenched with a cold (0°C) NH4Cl (sat. aq. 2.5 mL)-water (2.5 mL) mixture and stirred vigorously for 5 min. The resulting mixture was diluted with ethyl acetate (10 mL) and the bottom aqueous layer was discarded. The top layer was passed through a plug of celite (2 mL). The plug was washed well with ethyl acetate and the filtrate was concentrated in vacuo. The resulting crude product was purified by HPLC (40- 50% acetonitrile in water, TFA buffered) to afford the title compound as a white solid (34.6 mg, 20%). 1H NMR (400 MHz, DMS0-D6) δ ppm 0.96 (app d, 7=9.09 Hz, 4 H) 2.63 (s, 3 H) 6.25 (s, 1 H) 6.50 (s, 1 H) 7.37 (t, 7=8.46 Hz, 1 H) 7.66 (d, 7=7.83 Hz, 1 H) 7.89 (d, 7=8.08 Hz, 1 H) 12.58 (s, 1 H). ESI-MS: m/z 345.1 (M+H)+
Example 4-5: 3-chloro-N-(4-(l-hydroxycyclopentyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0344] Magnesium turnings (3.90 g, 0.160 mol) in THF (5 mL) under nitrogen were treated with 1,2-dibromoethane (0.1 mL). When gas evolution subsided, a solution of 1,4- dibromoethane (3.1 mL, 26.2 mmol) in THF (10 mL) was added at a rate to sustain reflux (approx. 20 min). After the addition was complete the reaction mixture was heated at reflux for 10 min and cooled to room temperature. 4 mL of the resulting solution (approx. 5 mmol of Grignard reagent) was added to a solution of ethyl 2-(3-chloro-2- methylphenylsulfonamido)thiazole-4-carboxylate (0.361 g, 1.00 mmol) in THF (2 mL). The reaction mixture was stirred for 30 min and was quenched very carefully with a cold (0°C) NH4Cl (sat. aq. 2.5 mL)-water (2.5 mL) mixture, stirred vigorously for 5 min and extracted with ethyl acetate (10 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. HPLC (45-60% acetonitrile in water, TFA buffered) afforded the title compound as a white solid (0.181 g, 49%). 1H NMR (400 MHz, DMSO- D6) δ ppm 1.63 (m, 2 H) 1.76 (m, 6 H) 2.64 (s, 3 H) 5.17 (s, 1 H) 6.53 (s, 1 H) 7.38 (t, 7=7.96 Hz, 1 H) 7.66 (d, 7=8.59 Hz, 1 H) 7.89 (d, 7=8.08 Hz, 1 H) 12.74 (s, 1 H). ESI- MS: m/z 373.1 (M+H)+
Example 4-6: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4-phenoxybenzenesulfonamide
[0345] The title compound was obtained from ethyl 2-(4- phenoxyphenylsulfonamido)thiazole-4-carboxylate and ethyl magnesium bromide as described for Example 4-1. IH NMR (400 MHz, DMSO-D6) 5 ppm 0.66 (t, 7=7.33 Hz, 6 H) 1.57 - 1.67 (m, 4 H) 4.97 (br s, 1 H) 6.42 (s, 1 H) 7.06 (d, 7=8.84 Hz, 2 H) 7.11 (d, 7=8.59 Hz, 2 H) 7.23 (t, 7=7.45 Hz, 1 H) 7.44 (t, 7=7.45 Hz, 2 H) 7.78 (d, 7=8.84 Hz, 2 H) 12.48 (br s, 1 H); ESI-MS: m/z 419.3 (M+H)+.
Example 4-7: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-6-phenoxypyridine-3- sulfonamide
[0346] The title compound was obtained from ethyl 2-(2-phenoxypyridine-5- sulfonamido)thiazole-4-carboxylate and ethyl magnesium bromide as described for Example 4-1. IH NMR (400 MHz, DMSO-D6) δ ppm 0.66 (t, 7=7.33 Hz, 5 H) 1.58 - 1.69 (m, 4 H) 4.99 (br s, 1 H) 6.48 (s, 1 H) 7.14 (d, 7=9.09 Hz, 1 H) 7.18 (d, 7=8.34 Hz, 2 H) 7.26 (t, 7=7.45 Hz, 1 H) 7.43 (t, 7=7.58 Hz, 2 H) 8.15 (ddd, 7=8.59, 2.53, 1.26 Hz, 1 H) 8.50 (d, 7=3.03 Hz, 1 H) 12.64 (br s, 1 H); ESI-MS: m/z 420.3 (M+H)+.
Example 4-8: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)naphthalene-2-sulfonamide
[0347] The title compound was obtained from ethyl 2-(naphthalene-3- sulfonamido)thiazole-4-carboxylate and ethyl magnesium bromide as described for Example 4-1. IH NMR (400 MHz, DMSO-D6) δ ppm 0.63 (t, 7=7.20 Hz, 6 H) 1.56 - 1.67 (m, 4 H) 4.95 (br s, 1 H) 6.43 (s, 1 H) 7.61 - 7.69 (m, 2 H) 7.79 (d, 7=8.59 Hz, 1 H) 8.00 (d, 7=7.07 Hz, 1 H) 8.06 (d, 7=8.59 Hz, 1 H) 8.15 (d, 7=7.58 Hz, 1 H) 8.44 (s, 1 H) 12.55 (br s, 1 H); ESI-MS: m/z 377.3 (M+H)+.
Example 4-9: 2,3-dichloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide
[0348] The title compound was obtained from ethyl 2-(2,3- dichlorophenylsulfonamido)thiazole-4-carboxylate and ethyl magnesium bromide as described for Example 4-1. IH NMR (400 MHz, DMSO-D6) δ ppm 0.67 (t, 7=7.33 Hz, 5 H) 1.59 - 1.70 (m, 4 H) 5.00 (br s, 1 H) 6.50 (s, 1 H) 7.54 (td, 7=7.96, 1.01 Hz, 1 H) 7.87 (dt, 7=8.02, 1.29 Hz, 1 H) 8.04 (dt, 7=7.83, 1.26 Hz, 1 H) 12.70 (br s, 1 H); ESI-MS: m/z 395.2 (M+H)+.
Example 4-10: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzofuran-2-sulfonamide
[0349] The title compound was obtained from ethyl 2-(benzofuran-2- sulfonamido)thiazole-4-carboxylate and ethyl magnesium bromide as described for Example 4-1. IH NMR (400 MHz, DMSO-D6) δ ppm 0.65 (t, 7=7.45 Hz, 5 H) 1.59 - 1.70 (m, 4 H) 5.02 (br s, 1 H) 6.56 (s, 1 H) 7.34 (t, 7=7.45 Hz, 1 H) 7.42 - 7.51 (m, 2 H)
7.66 (d, 7=8.59 Hz, 1 H) 7.76 (d, 7=7.83 Hz, 1 H) 12.90 (s, 1 H); ESI-MS: m/z 367.3 (M+H)+.
Example 4-11: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzo[d]thiazole-6-sulfonamide
[0350] The title compound was obtained from ethyl 2-(benzo[d]thiazole-6- sulfonamido)thiazole-4-carboxylate and ethyl magnesium bromide as described for Example 4-1. IH NMR (400 MHz, DMSO-D6) δ ppm 0.64 (t, 7=7.33 Hz, 6 H) 1.56 -
1.67 (m, 4 H) 4.96 (br s, 1 H) 6.44 (s, 1 H) 7.90 (dt, 7=8.59, 1.52 Hz, 1 H) 8.20 (d, 7=8.08 Hz, 1 H) 8.71 (s, 1 H) 9.57 (s, 1 H) 12.56 (br s, 1 H); ESI-MS: m/z 384.2 (M+H)+.
Example 4-12: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzo[b]thiophene-2- sulfonamide
[0351] The title compound was obtained from ethyl 2-(benzo[b]thiophene-2- sulfonamido)thiazole-4-carboxylate and ethyl magnesium bromide as described for Example 4-1. IH NMR (400 MHz, DMSO-D6) δ ppm 0.65 (t, 7=7.20 Hz, 6 H) 1.58 - 1.70 (m, 4 H) 5.01 (br s, 1 H) 6.53 (s, 1 H) 7.43 - 7.52 (m, 2 H) 7.94 (s, 1 H) 7.99 (d, 7=7.33 Hz, 1 H) 8.02 (d, 7=7.07 Hz, 1 H) 12.81 (br s, 1 H); ESI-MS: m/z 383.2 (M+H)+. Example 4-13: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)naphthalene-l-sulfonamide
[0352] The title compound was obtained from ethyl 2-(naphthalene-l- sulfonamido)thiazole-4-carboxylate and ethyl magnesium bromide as described for Example 4-1. IH NMR (400 MHz, DMSO-D6) δ ppm 0.61 (t, 7=7.20 Hz, 6 H) 1.50 - 1.67 (m, 4 H) 4.92 (br s, 1 H) 6.41 (s, 1 H) 7.59 - 7.68 (m, 3 H) 8.04 (d, 7=8.08 Hz, 1 H) 8.14 - 8.19 (m, 2 H) 8.70 (d, 7=8.08 Hz, 1 H) 12.49 (br s, 1 H); ESI-MS: m/z 377.3 (M+H)+.
Example 4-14: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-5-methylbenzo[b]thiophene-2- sulfonamide
[0353] The title compound was obtained from ethyl 2-(5-methylbenzo[b]thiophene-2- sulfonamido)thiazole-4-carboxylate and ethyl magnesium bromide as described for Example 4-1. IH NMR (400 MHz, CHLOROFORM-D) δ ppm 0.88 (t, 7=7.33 Hz, 6 H) 1.78 (q, 7=7.58 Hz, 4 H) 2.45 (s, 3 H) 6.12 (s, 1 H) 7.22 (d, 7=8.34 Hz, 1 H) 7.53 (d, 7=8.34 Hz, 1 H) 7.59 (s, 1 H) 7.81 (s, 1 H), NH proton not observed; ESI-MS: m/z 397.2 (M+H)+.
Example 4-15: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2,3-dihydrobenzofuran-5- sulfonamide
Step A: 3-(2-aminothiazol-4-yl)pentan-3-ol
[0354] Ethyl-2-aminothiazole-4-carboxylate (0.861 g, 5.00 mmol) was suspended in THF (10 mL) and treated with ethylmagnesium chloride (2M in ethyl ether, 10 mL, 20.0 mmol) over 3 min. After the exothermic reaction subsided, the mixture was stirred for 30 min and quenched with NaHCO3 (sat. aq., 10 mL). The resulting mixture was extraceted with EtOAc (6x3 mL). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. This crude material was purified by HPLC (5-15% acetonitrile in water, 0.05%TFA) to afford the title compound as an off-white solid (0.267 g, 29%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.65 (t, 7=7.33 Hz, 6 H) 1.48 - 1.58 (m, 2 H) 1.64 - 1.73 (m, 2 H) 4.27 (s, 1 H) 6.18 (s, 1 H) 6.75 (s, 2 H). ESI-MS: m/z 187.3 (M+H)+.
Step B: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2,3-dihydrobenzofuran-5-sulfonamide [0355] 3-(2-aminothiazol-4-yl)pentan-3-ol (18.7 mg, 0.100 mmol), 2,3- dihydrobenzofuran-5-sulfonyl chloride (37.2 mg, 0.170 mmol) and DMAP (1.0 mg, 0.0082 mol) were dissolved in pyridine and stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the crude material was purified using HPLC (35-50% acetonitrile in water, 0.05% TFA) to afford the title compound as a white solid (24.4 mg, 66%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.65 (t, 7=7.33 Hz, 6 H) 1.55 - 1.66 (m, 4 H) 3.21 (t, 7=8.72 Hz, 2 H) 4.59 (t, 7=8.84 Hz, 2 H) 4.94 (br s, 1 H) 6.39 (s, 1 H) 6.84 (d, 7=8.34 Hz, 1 H) 7.55 (dd, 7=8.46, 1.89 Hz, 1 H) 7.61 (s, 1 H) 12.36 (s, 1 H). ESI-MS: m/z 369.3 (M+H)+.
Example 4-16: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)(p-tolyl)methanesulfonamide
[0356] The title compound was prepared from ethyl-2-aminothiazole-4-carboxylate and p-tolylmethanesulfonyl chloride as described for Example 4-15. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.67 (t, 7=7.33 Hz, 6 H) 1.52 - 1.62 (m, 2 H) 1.63-1.70 (m, 2 H) 2.23 (s, 3 H) 4.20 (s, 2 H) 4.90 (br s, 1 H) 6.26 (s, 1 H) 7.05 (d, 7=7.58 Hz, 2 H) 7.18 (d, 7=7.83 Hz, 2 H) 12.27 (br s, 1 H). ESI-MS: m/z 355.3 (M+H)+.
Example 4-17: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2-oxo-2H-chromene-6- sulfonamide
[0357] The title compound was prepared from ethyl-2-aminothiazole-4-carboxylate and 2-oxo-2H-chromene-6-sulfonyl chloride as described for Example 4-15. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.64 (t, 7=7.33 Hz, 6 H) 1.55 - 1.66 (m, 4 H) 4.97 (br s, 1 H) 6.46 (s, 1 H) 6.59 (d, 7=9.35 Hz, 1 H) 7.52 (d, 7=8.84 Hz, 1 H) 7.94 (dd, 7=8.59, 2.53 Hz, 1 H) 8.19 - 8.24 (m, 2 H) 12.58 (br s, 1 H). ESI-MS: m/z 395.2 (M+H)+.
Example 4-18: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2,4-dimethylthiazole-5- sulfonamide
[0358] The title compound was prepared from ethyl-2-aminothiazole-4-carboxylate and 2,4-dimethylthiazole-5-sulfonyl chloride as described for Example 4-15. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.66 (t, 7=7.33 Hz, 6 H) 1.59 - 1.70 (m, 4 H) 2.47 (s, 3 H) 2.59 (s, 3 H) 5.01 (br s, 1 H) 6.50 (d, 7=1.77 Hz, 1 H) 12.75 (br s, 1 H). ESI-MS: m/z 362.2 (M+H)+. Example 4-19: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-5-(oxazol-5-yl)thiophene-2- sulfonamide
[0359] The title compound was prepared from ethyl-2-aminothiazole-4-carboxylate and 5-(oxazol-5-yl)thiophene-2-sulfonyl chloride as described for Example 4-15. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.65 (t, 7=7.33 Hz, 6 H) 1.58 - 1.68 (m, 4 H) 5.01 (br s, 1 H) 6.53 (s, 1 H) 7.43 (d, 7=3.79 Hz, 1 H) 7.56 (d, 7=3.79 Hz, 1 H) 7.69 (s, 1 H) 8.47 (s, 1 H) 12.79 (br s, 1 H). ESI-MS: m/z 400.2 (M+H)+.
Example 4-20: 5-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)naphthalene-2- sulfonamide
[0360] The title compound was prepared from ethyl-2-aminothiazole-4-carboxylate and 5-chloronaphthalene-2-sulfonyl chloride as described for Example 4-15. 1H NMR (400 MHz, DMSO-D6) 5 ppm 0.63 (t, 7=7.33 Hz, 6 H) 1.54 - 1.65 (m, 4 H) 4.96 (br s, 1 H) 6.45 (s, 1 H) 7.63 (t, 7=7.83 Hz, 1 H) 7.85 (dd, 7=7.45, 1.14 Hz, 1 H) 7.96 (dd, 7=9.09, 1.77 Hz, 1 H) 8.19 (d, 7=8.34 Hz, 1 H) 8.31 (d, 7=8.84 Hz, 1 H) 8.54 (s, 1 H) 12.61 (br s, 1 H). ESI-MS: m/z 411.2 (M+H)+. Example 4-21: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzo[b]thiophene-3- sulfonamide
[0361] The title compound was prepared from ethyl-2-aminothiazole-4-carboxylate and benzo[b]thiophene-3-sulfonyl chloride as described for Example 4-15. 1H NMR (400 MHz, DMSO-D6) 6 ppm 0.62 (t, 7=7.45 Hz, 6 H) 1.55 - 1.66 (m, 4 H) 4.95 (br s, 1 H) 6.46 (d, 7=1.52 Hz, 1 H) 7.43 - 7.51 (m, 2 H) 8.07 (dd, 7=7.33, 1.26 Hz, 1 H) 8.11 (dd, 7=7.70, 1.39 Hz, 1 H) 8.43 (s, 1 H) 12.56 (br s, 1 H). ESI-MS: m/z 383.2 (M+H)+.
Example 4-22: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2,3- dihydrobenzo [b] [ 1 ,4] dioxine-6-sulf onamide
[0362] The title compound was prepared from ethyl-2-aminothiazole-4-carboxylate and 2,3-dihydrobenzo[b][l,4]dioxine-6-sulfonyl chloride as described for Example 4-15. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.65 (t, 7=7.33 Hz, 6 H) 1.55 - 1.66 (m, 4 H) 4.24 - 4.31 (m, 4 H) 4.96 (br s, 1 H) 6.41 (s, 1 H) 6.97 (d, 7=8.34 Hz, 1 H) 7.19 (d, 7=2.27 Hz, 1 H) 7.25 (dd, 7=8.46, 2.15 Hz, 1 H) 12.44 (br s, 1 H). ESI-MS: m/z 385.3 (M+H)+.
Example 4-23: 2-Chloro-4,5-difluoro-N-(4-(3-hydroxypentan-3-yl)thiazol-2- yl)benzenesulfonamide
[0363] The title compound was prepared from ethyl-2-aminothiazole-4-carboxylate and 2-chloro-4,5-difluorobenzene-l-sulfonyl chloride as described for Example 4-15. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.67 (t, 7=7.33 Hz, 6 H) 1.57 - 1.72 (m, 4 H) 5.01 (br s, 1 H) 6.51 (s, 1 H) 7.94 (dd, 7=10.23, 6.95 Hz, 1 H) 8.03 (dd, 7=10.11, 8.34 Hz, 1 H) 12.76 (br s, 1 H). ESI-MS: m/z 397.2 (M+H)+.
Example 4-24: N-(4-(3-Hydroxypentan-3-yl)thiazol-2-yl)-4-methyl-3,4-dihydro-2H- benzo[b] [ 1 ,4]oxazine-6-sulfonamide
[0364] The title compound was prepared from ethyl-2-aminothiazole-4-carboxylate and 4-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-6-sulfonyl chloride as described for Example 4-15. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.66 (t, 7=7.33 Hz, 6 H) 1.55 - 1.67 (m, 4 H) 2.83 (s, 3 H) 3.24 - 3.30 (m, 2 H) 4.23 - 4.28 (m, 2 H) 4.94 (br s, 1 H) 6.38 (s, 1 H) 6.75 (d, 7=8.08 Hz, 1 H) 6.97 - 7.04 (m, 2 H) 12.36 (br s, 1 H). ESI-MS: m/z 398.3 (M+H)+.
Example 4-25: 5-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3- methylbenzo[b]thiophene-2-sulfonamide
[0365] The title compound was prepared from ethyl-2-aminothiazole-4-carboxylate and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride as described for Example 4-15. 1H NMR (400 MHz, DMSO-D6) 6 ppm 0.65 (t, 7=7.45 Hz, 6 H) 1.58 - 1.69 (m, 4 H) 2.58 (s, 3 H) 5.00 (br s, 1 H) 6.50 (d, 7=1.77 Hz, 1 H) 7.53 (dd, 7=8.59, 2.02 Hz, 1 H) 7.98 (d, 7=1.52 Hz, 1 H) 8.05 (d, 7=8.84 Hz, 1 H) 12.80 (br s, 1 H). ESI-MS: m/z 431.2 (M+H)+.
Example 4-26: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2,5- dimethylbenzenesulfonamide
[0366] The title compound was prepared as described for Example 4-15. IH NMR (400 MHz, DMSO-D6) δ ppm 0.66 (t, 7=7.33 Hz, 6 H) 1.54 - 1.72 (m, 4 H) 2.31 (s, 3 H) 4.96 (s, 1 H) 6.39 (s, 1 H) 7.20 - 7.24 (m, 1 H) 7.24 - 7.29 (m, 1 H) 7.69 (s, 1 H) 12.41 (s, 1 H); ESI-MS: m/z 355.2 (M+H)+.
Example 4-27: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3,4- dimethylbenzenesulfonamide
[0367] The title compound was prepared as described for Example 4-15. ESI-MS: m/z
355.2 (M+H)+. Example 4-28: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3,4- dimethoxybenzenesulfonamide
[0368] The title compound was prepared as described for Example 4-15. ESI-MS: m/z
387.3 (M+H)+.
Example 4-29: N-(4-(N-(4-(3-hydroxypentan-3-yl)thiazol- yl)sulfamoyl)phenyl)acetamide
[0369] The title compound was prepared as described for Example 4-15. ESI-MS: m/z
387.3 (M+H)+.
Example 4-30: 4-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3- nitrobenzenesulfonamide
[0370] The title compound was prepared as described for Example 4-15. ESI-MS: m/z 406.2 (M+H)+.
Example 4-31: 2-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-5-(trifluoromethyl) benzenesulfonamide
[0371] The title compound was prepared as described for Example 4-15. IH NMR (400 MHz, DMSO-D6) δ ppm 0.66 (t, /=7.45 Hz, 6 H) 1.55 - 1.75 (m, 4 H) 5.01 (s, 1 H) 6.53 (d, /=1.26 Hz, 1 H) 7.89 (d, /=8.34 Hz, 1 H) 7.99 (dd, /=8.34, 2.27 Hz, 1 H) 8.24 (d, /=2.02 Hz, 1 H) 12.83 (s, 1 H); ESI-MS: m/z 429.2 (M+H)+.
Example 4-32: 4,5-dichloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)thiophene-2- sulfonamide
[0372] The title compound was prepared as described for Example 4-15. IH NMR (400 MHz, DMSO-D6) δ ppm 0.67 (t, /=7.33 Hz, 6 H) 1.56 - 1.73 (m, /=29.43, 14.59, 14.34, 7.33 Hz, 4 H) 5.05 (s, 1 H) 6.59 (s, 1 H) 7.63 (s, 1 H) 12.95 (s, 1 H); ESI-MS: m/z 401.1
(M+H)+.
Example 4-33: 4-ethyl-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide
[0373] The title compound was prepared as described for Example 4-15. ESI-MS: m/z
355.3 (M+H)+. Example 4-34: 4-propyl-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide
[0374] The title compound was prepared as described for Example 4-15. ESI-MS: m/z 369.3 (M+H)+.
Example 4-35: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzo[c][l,2,5]thiadiazole-5- sulfonamide
[0375] The title compound was prepared as described for Example 4-15. IH NMR (400 MHz, DMSO-D6) δ ppm 0.64 (t, 7=7.33 Hz, 6 H) 1.53 - 1.70 (m, 4 H) 4.99 (s, 1 H) 6.49 (s, 1 H) 7.96 (dd, 7=9.09, 1.77 Hz, 1 H) 8.25 (d, 7=9.35 Hz, 1 H) 8.46 (d, 7=1.77 Hz, 1 H) 12.76 (s, 1 H); ESI-MS: m/z 385.2 (M+H)+.
Example 4-36: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3,4-dihydro-2H-benzo[b][l,4] dioxepine-7-sulfonamide
[0376] The title compound was prepared as described for Example 4-15. ESI-MS: m/z 399.3 (M+H)+.
Example 4-37: 3-bromo-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide
[0377] The title compound was prepared as described for Example 4-15. IH NMR (400 MHz, DMSO-D6) δ ppm 0.65 (t, 7=7.33 Hz, 6 H) 1.53 - 1.72 (m, 4 H) 5.00 (s, 1 H) 6.48 (s, 1 H) 7.51 (t, 7=7.96 Hz, 1 H) 7.77 - 7.83 (m, 7=7.83, 7.83, 1.64, 0.88 Hz, 2 H) 7.87 (t, 7=1.77 Hz, 1 H) 12.65 (s, 1 H); ESI-MS: m/z 405.0 (M+H)+.
Example 4-38: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2-(2,2,2-trifluoroacetyl)-l ,2,3,4- tetrahydroisoquinoline-7-sulfonamide
[0378] The title compound was prepared as described for Example 4-15. IH NMR (400 MHz, DMSO-D6) 6 ppm 0.65 (t, 7=7.33 Hz, 6 H) 1.53 - 1.70 (m, 4 H) 2.92 - 2.99 (m, 2 H) 3.78 - 3.84 (m, 2 H) 4.79 - 4.85 (m, 2 H) 4.96 (s, 1 H) 6.43 (s, 1 H) 7.36 (d, 7=8.08 Hz, 1 H) 7.63 (td, 7=7.89, 1.89 Hz, 1 H) 7.68 - 7.76 (m, 1 H) 12.49 (s, 1 H); ESI-MS: m/z 460.1 (M+H)+.
Example 4-39: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-l,2,3,4-tetrahydroisoquinoline- 7-sulfonamide
[0379] The title compound was prepared as described for Example 4-15 (TFA salt). IH NMR (400 MHz, DMSO-D6) δ ppm 0.65 (t, 7=7.33 Hz, 6 H) 1.53 - 1.71 (m, 4 H) 3.02 (t, 7=6.44 Hz, 2 H) 3.39 (t, 7=5.94 Hz, 2 H) 4.35 (s, 2 H) 4.97 (s, 1 H) 6.44 (s, 1 H) 7.39 (d, 7=7.83 Hz, 1 H) 7.66 (dd, 7=7.83, 1.77 Hz, 1 H) 7.69 (d, 7=1.52 Hz, 1 H) 8.98 (s, 2 H) 12.52 (s, 1 H); ESI-MS: m/z 382.1 (M+H)+. Example 4-40: 2-fluoro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-5- methylbenzenesulfonamide
[0380] The title compound was prepared as described for Example 4-15. ESI-MS: m/z 359.1 (M+H)+.
Example 4-41 : 3-cyano-N-(4-(3 -hydroxypentan-3 -yl)thiazol-2-yl)benzenesulfonamide
[0381] The title compound was prepared as described for Example 4-15. IH NMR (400 MHz, DMSO-D6) δ ppm 0.65 (t, 7=7.33 Hz, 6 H) 1.54 - 1.71 (m, 4 H) 5.00 (s, 1 H) 6.50 (s, 1 H) 7.76 (t, 7=7.96 Hz, 1 H) 8.06 - 8.11 (m, 2 H) 8.15 (s, 1 H) 12.70 (s, 1 H); ESI-MS: m/z 352.1 (M+H)+.
Example 4-42: 4-bromo-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0382] The title compound was prepared as described for Example 4-15. IH NMR (400 MHz, DMSO-D6) δ ppm 0.66 (t, 7=7.45 Hz, 6 H) 1.54 - 1.72 (m, 4 H) 2.55 (s, 3 H) 4.98 (s, 1 H) 6.43 (d, 7=1.77 Hz, 1 H) 7.56 (ddd, 7=8.40, 2.08, 0.63 Hz, 1 H) 7.60 - 7.64 (m, 1 H) 7.79 (d, 7=8.34 Hz, 1 H) 12.54 (s, 1 H); ESI-MS: m/z 419.0 (M+H)+. Example 4-43: 4-bromo-2-chloro-N-(4-(3-hydroxyρentan-3-yl)thiazol-2- yl)benzenesulfonamide
[0383] The title compound was prepared as described for Example 4-15. IH NMR (400 MHz, DMSO-D6) δ ppm 0.66 (t, 7=7.33 Hz, 6 H) 1.55 - 1.74 (m, 4 H) 4.99 (s, 1 H) 6.48 (s, 1 H) 7.74 (dd, /=8.34, 2.02 Hz, 1 H) 7.92 (d, 7=2.02 Hz, 1 H) 7.95 (d, 7=8.34 Hz, 1 H) 12.70 (s, 1 H) ESI-MS: m/z 439.0 (MH-H)+.
Example 4-44: 4-bromo-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2-(trifluoromethyl) benzenesulfonamide
[0384] The title compound was prepared as described for Example 4-15. ESI-MS: m/z
472.9 (M+H)+.
Example 4-45: 4-bromo-5-chloro-N-(4-(3-hydroxypentan-3-yl)miazol-2-yl)thiophene-2- sulfonamide
[0385] The title compound was prepared as described for Example 4-15. ESI-MS: m/z 445.0 (M+H)+. Example 4-46: 4-cyano-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide
[0386] The title compound was prepared as described for Example 4-15. ESI-MS: m/z
352.2 (M+H)+.
Example 4-47: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3-nitrobenzenesulfonamide
[0387] The title compound was prepared as described for Example 4-15. ESI-MS: m/z 372.1 (M+H)+.
Example 4-48: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4-nitrobenzenesulfonamide
[0388] The title compound was prepared as described for Example 4-15. ESI-MS: m/z
372.1 (M+H)+.
Example 4-49: 2-chloro-4-cyano-N-(4-(3-hydroxypentan-3-yl)thiazol-2- yl)benzenesulfonamide
[0389] The title compound was prepared as described for Example 4-15. ESI-MS: m/z
386.1 (M+H)+. Example 4-50: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4-(methylsulfonyl) benzenesulfonamide
[0390] The title compound was prepared as described for Example 4-15. ESI-MS: m/z
405.2 (M+H)+.
Example 4-51 : N-(4-(3 -hydroxypentan-3 -yl)thiazol-2-yl)-4-methoxybenzenesulf onamide
[0391] The title compound was prepared as described for Example 4-15. ESI-MS: m/z
357.3 (M+H)+.
Example 4-52: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4-isopropylbenzenesulfonamide
[0392] The title compound was prepared as described for Example 4-15. ESI-MS: m/z 369.3 (M+H)+.
Example 4-53: 4-(difluoromethoxy)-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl) benzenesulfonamide
[0393] The title compound was prepared as described for Example 4-15. ESI-MS: m/z 393.3 (M+H)+. Example 4-54: 3-(difluoromethoxy)-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl) benzenesulfonamide
[0394] The title compound was prepared as described for Example 4-15. ESI-MS: m/z 393.3 (M+H)+.
Example 4-55: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4- isopropoxybenzenesulfonamide
[0395] The title compound was prepared as described for Example 4-15. ESI-MS: m/z
385.3 (M+H)+.
Example 4-56: 2-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4-(trifluoromethyl) benzenesulfonamide
[0396] The title compound was prepared as described for Example 4-15. IH NMR (400 MHz, DMSO-D6) δ ppm 0.66 (t, 7=7.33 Hz, 6 H) 1.55 - 1.75 (m, 4 H) 5.01 (s, 1 H) 6.52 (d, 7=1.52 Hz, 1 H) 7.91 (d, 7=8.34 Hz, 1 H) 8.06 (s, 1 H) 8.24 (d, 7=8.34 Hz, 1 H) 12.78 (s, 1 H); ESI-MS: m/z 429.2 (M+H)+. Example 4-57: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3-methoxybenzenesulfonamide
[0397] The title compound was prepared as described for Example 4-15. ESI-MS: m/z
357.3 (M+H)+.
Example 4-58: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzo[d][l,3]dioxole-5- sulfonamide
[0398] The title compound was prepared as described for Example 4-15. IH NMR (400 MHz, DMSO-D6) δ ppm 0.65 (t, 7=7.33 Hz, 6 H) 1.53 - 1.70 (m, 4 H) 4.96 (s, 1 H) 6.12 (s, 2 H) 6.42 (s, 1 H) 7.02 (d, 7=8.34 Hz, 1 H) 7.19 (d, 7=1.77 Hz, 1 H) 7.32 - 7.36 (m, 1 H) 12.47 (s, 1 H); ESI-MS: m/z 371.3 (M+H)+.
Example 4-59: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3-oxo-3,4-dihydro-2H- benzo[b][l,4] oxazine-6-sulfonamide
[0399] The title compound was prepared as described for Example 4-15. ESI-MS: m/z 398.3 (M+H)+.
Example 4-60: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4-methyl-3- nitrobenzenesulfonamide
[0400] The title compound was prepared as described for Example 4-15. ESI-MS: m/z 386.3 (M+H)+.
Example 4-61: 4-acetyl-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide
[0401] The title compound was prepared as described for Example 4-15. IH NMR (400 MHz, DMS0-D6) δ ppm 0.64 (t, 7=7.45 Hz, 6 H) 1.53 - 1.70 (m, 4 H) 2.60 (s, 3 H) 4.98 (s, 1 H) 6.47 (s, 1 H) 7.91 (d, 7=8.59 Hz, 2 H) 8.08 (d, 7=8.34 Hz, 2 H) 12.64 (s, 1 H); ESI-MS: m/z 369.3 (M+H)+.
Example 4-62: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2-methyl-5- nitrobenzenesulfonamide
[0402] The title compound was prepared as described for Example 4-15. IH NMR (400 MHz, DMSO-D6) δ ppm 0.66 (t, 7=7.45 Hz, 6 H) 1.54 - 1.72 (m, 4 H) 2.70 (s, 3 H) 5.01 (s, 1 H) 6.48 (s, 1 H) 7.67 (d, 7=8.59 Hz, 1 H) 8.31 (dd, 7=8.46, 2.40 Hz, 1 H) 8.60 (d, 7=2.27 Hz, 1 H) 12.73 (s, 1 H); ESI-MS: m/z 386.3 (M+H)+. Example 4-63: 3-acetyl-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide
[0403] The title compound was prepared as described for Example 4-15. ESI-MS: m/z 369.3 (M+H)+.
Example 4-64: N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3-(methylsulfonyl) benzenesulfonamide
[0404] The title compound was prepared as described for Example 4-15. ESI-MS: m/z 405.2 (M+H)+.
Example 4-65: N-(2-chloro-4-(N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)sulfamoyl) phenyl)acetamide
[0405] The title compound was prepared as described for Example 4-15. ESI-MS: m/z 418.1 (M+H)+.
Example 5-1: 3-chloro-N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0406] Ethyl 2-(2-(3-chloro-2-methylρhenylsulfonamido)thiazol-4-yl)acetate (1.51 g, 4.03 mmol) was dissolved in THF (8 mL) and treated with ethylmagnesium chloride (2M in ethyl ether, 8 mL, 16 mmol). The reaction mixture was stirred for 5 min, cooled to 0°C and quenched carefully with a cold (0°C) NH4Cl (sat. aq. 5 mL)-water (5 mL) mixture, stirred vigorously for 5 min and extracted with ethyl acetate (15 mL). The organic extract was dried (MgSO4), filtered and concentrated in vacuo. Flash column chromatography (250 mL SiO2, hexanes-ethyl acetate 1:1, IL) afforded the title compound as an off-white solid (0.210 mg, 13%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.87 (t, 7=7.45 Hz, 6 H) 1.43 - 1.54 (m, 4 H) 2.66 (s, 2 H) 2.71 (s, 3 H) 6.08 (s, 1 H) 7.22 (t, 7=8.08 Hz, 1 H) 7.53 (d, 7=7.33 Hz, 1 H) 8.03 (d, 7=8.08 Hz, 1 H) ESI-MS: m/z 389.1 (M+H)+
Example 5-2: 3-Chloro-N-(4-(2-hydroxy-2-propylpentyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0407] The title compound was prepare descri ObeHd for Example 5-1. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.90 (t, 7=7.20 Hz, 6 H) 1.23 - 1.35 (m, 4 H) 1.37 - 1.44 (m, 4 H) 2.18 (br s, 1 H) 2.64 (s, 2 H) 2.70 (s, 3 H) 6.04 (s, 1 H) 7.21 (t, 7=7.96 Hz, 1 H) 7.52 (d, 7=8.08 Hz, 1 H) 8.02 (d, 7=8.08 Hz, 1 H) 10.54 (s, 1 H). ESI-MS: m/z 417.2 (M+H)+.
Example 5-3: 3-chloro-N-(4-(( 1 -hydroxycyclobutyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
Step A: 3-chloro-N-(4-(chloromethyl)thiazol-2-yl)-2-methylbenzenesulfonamide
[0408] 4-(Chloromethyl)thiazol-2-amine hydrochloride (2.0 g, 11 mmol) was suspended in CH2Cl2 at 00C and was neutralized with ice-cold saturated NaHCO3. The mixture was extracted twice with CH2Cl2. The combined organic layers were then dried over MgSO4, filtered and concentrated to about 30 ml. To this solution was added 3- chloro-2-methylbenzene-l-sulfonyl chloride (2.4 g, 11 mmol), dimethylaminopyridine (66 mg, 0.54 mmol), and triethylamine (2.3 ml, 16 mmol). The reaction mixture was stirred at room temperature for 18 h. Saturated NaHCO3 was added and the mixture was extracted three times with EtOAc. Combined organic layers were washed with IN HCl and then with brine. The crude product was purified by column on SiO2 eluted with EtOAc/hexanes (1:1) to yield a yellow solid. The product was further purified by trituration with Et2O; filtration afforded 1.1 g (30 %) of the title compound as a yellow solid. 1H NMR (400 MHz, J6-DMSO) 6, ppm: 2.62 (s, 3 H), 4.24 (d, 7=3.5 Hz, 2 H), 5.38 (s, 1 H), 6.58 (s, 1 H), 7.36 (t, 7=8.0 Hz, 1 H), 7.65 (d, 7=7.8 Hz, 1 H), 7.88 (d, 7=8.1 Hz, 1 H), 12.84 (s, 1 H); ESI-MS: m/z 337.2 (M+H)+.
Step B: 3-chloro-N-(4-((l-hydroxycyclobutyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0409] To a solution of cyclobutanone (22 μl, 0.30 mmol) and 3-chloro-N-(4- (chloromethyl)thiazol-2-yl)-2-methylbenzenesulfonamide (100 mg, 0.30 mmol) in tetrahydrofuran (3 ml) was added sodium iodide (8 mg, 0.06 mmol). To this mixture at room temperature was added dropwise a 0.05 M solution of samarium(II) iodide in THF (ca. 3 ml) until a deep blue color persisted. Another 18 ml of the SmI2ZTHF solution (0.90 mmol) was then added portionwise. The reaction mixture was stirred at room temperature for about 30 min, until the blue mixture has turned yellow. A 1.0 M aqueous solution of potassium sodium tartrate was added and the bilayer was stirred vigorously for 30 min. Brine was added and the aqueous phase was extracted twice with EtOAc. Combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by HPLC (C-18, isocratic, 45% ACN/H2O), to give 15 mg of the title compound (14 %). 1H NMR (400 MHz, CDCl3) δ, ppm: 1.56 (m, 1 H), 1.79 (m, 1 H), 2.06 (m, 4 H), 2.67 (s, 3 H), 2.86 (s, 2 H), 6.17 (s, 1 H), 7.22 (t, 7=8.0 Hz, 1 H), 7.53 (d, 7=8.1 Hz, 1 H), 8.01 (d, 7=7.8 Hz, 1 H); ESI-MS: m/z 373.2 (M+H)+.
Example 5-4: 3-chloro-N-(4-((l-hydroxycyclopentyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0410] The title compound was prepared from cyclopentanone and 3-chloro-N-(4- (chloromethyl)thiazol-2-yl)-2-methylbenzenesulfonamide according to the procedure described for Example 5-3. The crude product was purified by HPLC (C-18, gradient, 45- 60% ACN/H2O) to give the title compound. 1H NMR (400 MHz, CDCl3) δ, ppm: 1.58- 1.69 (m, 6 H), 1.81 (m, 1 H), 2.67 (s, 3 H), 2.84 (s, 2 H), 6.11 (s, 1 H), 7.22 (t, 7=7.8 Hz, 1 H), 7.54 (d, 7=8.1 Hz, 1 H), 8.01 (d, J=7.8 Hz, 1 H); ESI-MS: m/z 387.2 (M+H)+.
Example 5-5 : N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-4-fluoro-2- methylbenzenesulfonamide
[0411] The title compound was prepared from ethyl 2-(2-(4-fluoro-2- methylphenylsulfonamido)thiazol-4-yl)acetate (Example 2-21-A) as described in Example 5-1. 1H NMR (400 MHz, Chloroform-d) δ ppm: 0.86 (t, J=7.45 Hz, 6 H), 1.46 (td, J=7.45, 3.28 Hz, 4 H), 2.62 (s, 2 H), 2.66 (s, 3 H), 6.07 (s, 1 H), 6.90 - 6.99 (m, 2 H), 8.06 (dd, J=8.59, 5.56 Hz, 1 H); ESI-MS: m/z 373.2 (M+H)+. Example 5-6: 4-(2-(dimethylamino)ethoxy)-N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0412] N, N-dimethylethanolamine (122 μL, 1.21 mmol) was added to a stirring solution of sodium hydride (0.031 g, 95 % dry, 1.21 mmol) in 2 niL of tetrahydrofuran at 0 0C. After stirring for 0.5 h, the resulting solution was added to N-(4-(2-ethyl-2- hydroxybutyl)thiazol-2-yl)-4-fluoro-2-methylbenzenesulfonamide (Example 5-5, 0.075 g, 0.20 mmol) in THF (2 mL). The resulting reaction mixture was microwaved at 1500C. After 45 minutes the reaction was concentrated and the resulting residue was purified by column chromatography on SiO2 eluted with methylene chloride/methanol (9: 1) to yield 0.065 g (74 %)of the title compound as a white foam. 1H NMR (400 MHz, Methanol-d4) δ ppm: 0.86 (t, J=7.58 Hz, 6 H), 1.44 (q, J=7.58 Hz, 4 H), 2.40 (s, 6 H), 2.59 (s, 2 H), 2.61 (s, 3 H), 2.85 (t, J=5.31 Hz, 2 H) 4.16 (t, J=5.31 Hz, 2 H), 6.30 (s, 1 H), 6.82 - 6.91 (m, 2 H), 7.93 (d, J=8.59 Hz, 1 H); ESI-MS: m/z 442.3 (M+H)+.
Example 5-7: N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-2-methyl-4-(2- morpholinoethoxy)benzenesulfonamide
[0413] The title compound was prepared from commercially available N-(2- hydroxyethyl)morpholine and Λf-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-4-fluoro-2- methylbenzenesulfonamide Example 5-5 as described in Example 5-6. 1H NMR (400 MHz, Chloroform-d) δ ppm: 0.80 (t, J=6.82 Hz, 6 H), 1.37 - 1.49 (m, 4 H), 2.48 (s, 3 H), 2.54 (s, 4 H), 2.67 (s, 2 H), 2.77 (s, 2 H), 3.69 (s, 4 H), 4.10 (s, 2 H), 6.01 (s, 1 H), 6.68 - 6.75 (m, 2 H), 7.95 (d, J=8.34 Hz, 1 H); ESI-MS: m/z 484.3 (M+H)+. Example 5-8: 4-(3-(dimethylamino)propoxy)-N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)- 2-methylbenzenesulfonamide
[0414] The title compound was prepared from commercially available 3- dimethylamino- 1 -propanol and N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-4-fluoro-2- methylbenzenesulfonamide Example 5-5. 1H NMR (400 MHz, Chloroform-d) δ ppm: 0.80 (t, J=7.45 Hz, 6 H), 1.35 - 1.46 (m, J=14.72, 14.72, 7.20, 7.07 Hz,4 H), 1.94 - 2.04 (m, 2 H), 2.36 (s, 6 H), 2.51 (s, 3 H), 2.56 - 2.66 (m, 4 H), 4.01 (t, J=6.32 Hz, 2 H), 6.01 (s, 1 H), 6.65 - 6.75 (m, 2 H), 7.94 (d, J=8.59 Hz, 1 H); ESI-MS: m/z 456.3 (M+H)+.
Example 5-9: 3-chloro-N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-4- fluorobenzenesulfonamide
Step A: Ethyl 2-(2-(3-chloro-4-fluorophenylsulfonamido)thiazol-4-yl)acetate
[0415] The title compound was prepared as described in Example 2-1-A. 1H NMR (400 MHz, DMSO-d6) 5 ppm: 1.18 (t, J=7.20 Hz, 3 H), 3.65 (s, 2 H), 4.02 - 4.13 (m, 2 H), 6.68 (s, 1 H), 7.60 (t, J=8.84 Hz, 1 H), 7.81 (dd, J=7.20, 5.43 Hz, 1 H), 7.92 (d, J=7.07 Hz, 1 H), 12.88 (s, 1 H); ESI-MS: m/z 379.1 (M+H)+.
Step B : 3-chloro-N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-4-fluorobenzenesulfonamide [0416] The title compound was prepared as described in Example 5-1. 1H NMR (400 MHz, DMSO-d6) δ ppm: 0.78 (t, 7=7.33 Hz, 6 H), 1.26 - 1.38 (m, 4 H), 4.26 (s, 2 H), 6.48 (s, 1 H), 7.59 (t, 7=9.09 Hz, 1 H), 7.77 - 7.85 (m, 1 H), 7.91 (dd, 7=6.69, 1.89 Hz, 1 H), 12.46 (s, 1 H); ESI-MS: m/z 393.2 (M+H)+. Example 5-10: 3-chloro-4-(2-(dimethylamino)ethoxy)-iV-(4-(2-ethyl-2- hydroxybutyl)thiazol-2-yl)benzenesulfonamide
• [0417] The title compound was prepared from 3-chloro-N-(4-(2-ethyl-2- hydroxybutyl)thiazol-2-yl)-4-fluorobenzenesulfonamide Example 5-9 as described in Example 5-6. 1H NMR (400 MHz, Chloroform-d) δ ppm: 0.85 (t, J=7.58 Hz, 6 H), 1.41 - 1.52 (m, 4 H), 2.52 (s, 6 H), 2.61 (s, 2 H), 3.01 (t, J=5.56 Hz, 2 H), 4.27 (t, J=5.43 Hz, 2 H), 6.04 (s, 1 H), 6.90 (d, J=8.59 Hz, 1 H), 7.78 (dd, J=8.59, 2.27 Hz, 1 H), 7.94 (d, J=2.27 Hz, 1 H); ESI-MS: m/z 462.2 (M+H)+.
Example 5-11: 3-chloro-iV-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-4-(2- morpholinoethoxy)benzenesulfbnamide
[0418] The title compound was prepared from commercially available N-(2- hydroxyethyl)morpholine and 3-chloro-N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-4- fluorobenzenesulfonamide Example 5-9 as described in Example 5-6. 1H NMR (400 MHz, Chloroform-d) δ ppm: 0.81 (t, J=6.69 Hz, 6 H), 1.43 (dd, J=14.53, 7.20 Hz, 4 H), 2.59 (s, 4 H), 2.65 (s, 2 H), 2.83 (s, 2 H), 3.67 (s, 4 H), 4.17 (s, 2 H), 6.07 (s, 1 H), 6.89 (d, J=8.59 Hz, 1 H), 7.72 (d, J=8.34 Hz, 1 H), 7.86 (s, 1 H); ESI-MS: m/z 504.2 (M+H)+.
Example 5-12: 3-chloro-iV-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-4-(3- morpholinopropoxy)benzenesulfonamide
[0419] The title compound was prepared from commercially available 3- morpholinopropanol and 3-chloro-N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-4- fluorobenzenesulfonamide Example 5-9 as described in Example 5-6. 1H NMR (400 MHz, Chloroform-d) δ ppm: 0.83 (t, J=7.45 Hz, 6 H), 1.17 - 1.28 (m, 2 H), 1.39 - 1.50 (m, 4 H), 2.01 (m, 2 H), 2.45 (m, 4 H), 2.54 (t, J=7.07 Hz, 2 H), 2.66 (s, 2 H), 3.64 - 3.72 (m, 4 H), 4.12 (t, J=6.19 Hz, 2 H), 6.06 (s, 1 H), 6.92 (d, J=8.59 Hz, 1 H), 7.74 (d, J=10.86 Hz, 1 H), 7.87 (s, 1 H); ESI-MS: m/z 518.3 (M+H)+.
Example 5-13: 3-chloro-4-(3-(dimethylaniino)propoxy)-/V-(4-(2-ethyl-2- hydroxybutyl)thiazol-2-yl)benzenesulfonamide
[0420] The title compound was prepared from commercially available 3- dimethylamino- 1-propanol and 3-chloro-./V-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-4- fluorobenzenesulfonamide Example 5-9 as described in Example 5-6. 1H NMR (400 MHz, Chloroform-d) 5 ppm: 0.86 (t, J=7.45 Hz, 6 H), 1.40 - 1.51 (m, J=14.68, 10.39, 7.14, 6.95 Hz, 4 H), 2.10 - 2.18 (m, 2 H), 2.45 (s, 6 H) 2.61 (s, 2 H), 2.70 - 2.80 (m, 2 H), 4.13 (t, J=6.06 Hz, 2 H), 6.04 (s, 1 H), 6.89 (d, J=8.59 Hz, 1 H), 7.77 (dd, J=8.59, 2.27 Hz,
1 H), 7.93 (d, J=2.27 Hz, 1 H); ESI-MS: m/z 476.3 (M+H)+.
Example 5-14: Λf-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-2-methyl-4-(3- morpholinopropoxy)benzenesulfonamide
[0421] The title compound was prepared from commercially available 3- morpholinopropanol and N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-4-fluoro-2- methylbenzenesulfonamide Example 5-5. 1H NMR (400 MHz, Chloroform-d) δ ppm: 0.81 (t, J=7.45 Hz, 6 H), 1.39 - 1.49 (m, 4 H), 1.90 - 1.99 (m, J=6.82, 6.82, 6.69, 6.44 Hz,
2 H), 2.44 (s, 3 H), 2.46 - 2.51 (m, 4 H), 2.67 (s, 2 H), 3.66 - 3.73 (m, 4 H), 4.02 (t, J=6.32 Hz, 2 H), 6.01 (s, 1 H), 6.68 - 6.75 (m, 2 H), 7.95 (d, J=8.34 Hz, 1 H); ESI-MS: m/z 498.3 (M+H)+. Example 5-15: N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-4-fluorobenzenesulfonamide
[0422] The title compound was prepared as described in Example 5-1. 1H NMR (400 MHz, Chloroform-d) δ ppm: 0.85 (t, J=7.45 Hz, 6 H) 1.47 (ddd, J=19.83, 14.53, 6.82 Hz, 4 H) 2.63 (s, 2 H) 6.07 (s, 1 H) 7.11 (t, J=8.46 Hz, 2 H) 7.93 (dd, J=8.59, 5.05 Hz, 2 H); ESI-MS: m/z 359.2 (M+H)+.
Example 5-16: N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-3-fluorobenzenesulfonamide
[0423] The title compound was prepared as described in Example 5-1. 1H NMR (400 MHz, Chloroform-d) δ ppm: 0.86 (t, J=7.58 Hz, 6 H) 1.40 - 1.52 (m, 4 H) 2.63 (s, 2 H) 6.08 (s, 1 H) 7.20 (td, J=8.46, 2.53 Hz, 1 H) 7.42 (td, J=8.08, 5.31 Hz, 1 H) 7.63 (dt, J=8.34, 2.15 Hz, 1 H) 7.73 (d, J=7.83 Hz, 1 H); ESI-MS: m/z 359.2 (M+H)+.
Example 5-17: N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-3-(3-morpholinopropoxy) benzenesulfonamide
[0424] The title compound was prepared from commercially available 3- morpholinopropanol and N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-3- fluorobenzenesulfonamide Example 5-16 as described in Example 5-6. 1H NMR (400 MHz, Chloroform-d) δ ppm: 0.85 (t, J=7.58 Hz, 6 H) 1.41 - 1.52 (m, 4 H) 1.93 - 2.03 (m, 2 H) 2.50 (s, 4 H) 2.62 (s, 2 H) 3.68 - 3.79 (m,4 H) 4.03 (t, J=6.19 Hz, 2 H) 6.03 (s, 1 H) 7.02 (dd, J=8.34, 2.53 Hz, 1 H) 7.31 (t, J=7.96 Hz, 1 H) 7.43 - 7.55 (m, 2 H); ESI-MS: m/z 484.3 (M+H)+. Example 5-18: iV-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-4-(3-morpholinopropoxy) benzenesulfonamide
[0425] The title compound was prepared from commercially available 3- morpholinopropanol and N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-4- fluorobenzenesulfonamide Example 5-15 as described in Example 5-6. 1H NMR (400 MHz, Chloroform-d) δ ppm: 0.85 (t, J=7.45 Hz, 6 H) 1.41 - 1.52 (m, 4 H) 1.96 - 2.03 (m, 2 H) 2.50 (m, 4 H) 2.55 (m, 2 H) 2.62 (s, 2 H) 3.69 - 3.78 (m, 4 H) 4.05 (t, J=6.19 Hz, 2 H) 6.01 (s, 1 H) 6.89 (d, J=8.84 Hz, 2 H) 7.84 (d, J=8.84 Hz, 2 H); ESI-MS: m/z 484.4 (M+H)+.
Example 5-19: 4-(3-(dimethylamino)propoxy)-N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl) benzenesulfonamide
[0426] The title compound was prepared from commercially available 3- dimethylamino- 1 -propanol and Λf-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-4- fluorobenzenesulfonamide Example 5-15 as described in Example 5-6. 1H NMR (400 MHz, Chloroform-d) 6 ppm: 0.85 (t, J=7.45 Hz, 6 H) 1.39 - 1.50 (m, 6 H) 1.96 - 2.07 (m, 2 H) 2.35 (s, 6 H) 2.54 - 2.63 (m, 4 H) 4.03 (t, J=6.32 Hz, 2 H) 6.01 (s, 1 H) 6.87 (d, J=8.84 Hz, 2 H) 7.84 (d, J=8.84 Hz, 2 H); ESI-MS: m/z 442.3 (M+H)+.
Example 5-20: 3-(3-(dimethylamino)propoxy)-N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl) benzenesulfonamide
[0427] The title compound was prepared from commercially available 3- dimethylamino- 1 -propanol and N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-3- fluorobenzenesulfonamide Example 5-16 as described in Example 5-6. 1H NMR (400 MHz, Chloroform-d) δ ppm: 0.84 (t, J=7.45 Hz, 6 H) 1.38 - 1.50 (m, 4 H) 1.95 - 2.06 (m, 2 H) 2.37 (s, 6 H) 2.55 - 2.63 (m, 4 H) 4.03 (t, J=6.32 Hz, 2 H) 6.04 (s, 1 H) 7.00 (dd, J=7.83, 2.27 Hz, 1 H) 7.31 (t, J=7.96 Hz, 1 H) 7.41 - 7.46 (m, 1 H) 7.52 (d, J=7.58 Hz, 1 H); ESI-MS: m/z 442.3 (M+H)+.
Example 5-21: 3-chloro-N-(4-((4-hydroxy-tetrahydro-2H-pyran-4-yl)methyl)thiazol-2- yl)-2-methylbenzenesulfonamide
[0428] The title compound was prepared from tetrahydropyran-4-one and 3-chloro-N- (4-(chloromethyl)thiazol-2-yl)-2-methylbenzenesulfonamide according to the procedure described for Example 5-3. The crude product was purified by column chromatography (SiO2, gradient, 0-0.5% MeOH/EtOAc) to give the title compound (24%). IH NMR (400 MHz, CHLOROFORM-D) δ ppm 1.56 - 1.68 (m, 4 H) 2.65 (s, 3 H) 2.81 (s, 2 H) 3.33 (s, 1 H) 3.72 (dd, 7=6.44, 2.40 Hz, 4 H) 6.14 (s, 1 H) 7.24 (t, 7=7.96 Hz, 1 H) 7.57 (dd, 7=8.10, 1.30Hz, 1 H) 8.00 (dd, 7=7.83, 1.01 Hz, 1 H) 11.66 (s, 1 H) ); ESI-MS: m/z 403.1 (M+H)+
Example 5-22: 4-bromo-N-(4-((l-hydroxycyclobutyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
Step A: tert-butyl 4-(chloromethyl)thiazol-2-ylcarbamate
[0429] 4-(Chloromethyl)thiazol-2-amine hydrochloride (2.7 g, 15 mmol) was suspended in CH2Cl2 (150 ml) at 00C and was neutralized with ice-cold saturated NaHCO3. The mixture was extracted twice with CH2Cl2. The combined organic layers were then dried over MgSO4, filtered and concentrated to about 150 ml. To this solution was added di-tert-butyl dicarbonate (3.2 g, 15 mmol) and 4-dimethylaminopyridine (89 mg, 0.73 mmol). The mixture was stirred at room temperature for 18 h. Dilute HCl (0.1 M) was added before CH2Cl2 was removed in vacuo. The aqueous residue was extracted three times with EtOAc. Combined organic layers were washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, 30% EtOAc/hexanes) to give the title compound as a white solid (1.7 g, 45%)
Step B: tert-butyl 4-((l-hydroxycyclobutyl)methyl)thiazol-2-ylcarbamate
[0430] To a solution of cyclobutanone (1.0 ml, 13 mmol) and tert-butyl 4- (chloromethyl)thiazol-2-ylcarbamate Example 5-22-A (1.1 g , 13 mmol) in tetrahydrofuran (20 ml) was added samarium(II) iodide solution (0.1 M in THF, 88 ml, 8.8 mmol). The reaction mixture was stirred at room temperature for about 30 min, until the blue mixture had turned yellow. A 0.1 M HCl solution was added and THF was removed in vacuo. The aqueous residue was extracted three times with EtOAc. Combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, gradient, 5-10% Et2O/CH2Cl2) to give the title compound as a white solid (790 mg, 63%). IH NMR (400 MHz, CHLOROFORM-D) 6 ppm 1.47 - 1.58 (m, 1 H) 1.54 (s, 9 H) 1.89 - 1.92 (m, 1 H) 1.92 - 1.98 (m, 2 H) 2.14 - 2.22 (m, 2 H) 2.91 (s, 2 H) 6.55 (s, 1 H); ESI-MS: m/z 285.3 (M+H)+. Step C: l-((2-aminothiazol-4-yl)methyl)cyclobutanol
[0431] To a solution of tert-butyl 4-(( 1 -hydroxycyclobutyl)methyl)thiazol-2- ylcarbamate Example 5-22-B (600 mg , 2.1 mmol) in CH2Cl2 (15 ml) was added trifluoroacetic acid (5 ml) at room temperature. The reaction mixture was stirred for 5 h at room temperature. AU the volatiles were then removed in vacuo. The residue was then re-diluted in saturated NaHCO3, and was extracted twice into EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a beige solid (400 mg, 90%).
Step D: 4-bromo-N-(4-(( 1 -hydroxycyclobutyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0432] To a solution of l-((2-aminothiazol-4-yl)methyl)cyclobutanol Example 5-22-C (100 mg, 0.54 mmol) in pyridine (5 ml) was added 4-dimethylaminopyridine (catalytic amount) and 2-bromo-4-methylphenyl sulfonyl chloride (146 mg, 0.54 mmol). The yellow solution was stirred at room temperature for 18 h. Pyridine was then removed in vacuo. The residue was diluted in 1 N HCl, and extracted three times with EtOAc. Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, gradient, 50-60 % EtOAc/hexanes) to give the title compound as a pink solid (135 mg, 60%). IH NMR (400 MHz, CHLOROFORM-D) δ ppm 1.53 - 1.58 (m, 2H) 1.77 - 1.79 (m, 2 H) 2.03 - 2.07 (m, 4 H) 2.58 (s, 3 H) 2.83 (s, 2 H) 6.14 (s, 1 H) 7.41 (d, 7=8.1 Hz, 1 H) 7.42 (s, 1 H) 7.91 (d, 7=8.1 Hz, 1 H); ESI-MS: m/z 417.3 (M+H)+.
Example 6-1: N-(4-(4-fluorobenzyl)thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide
[0433] Triethylsilane (0.270 mL, 1.69 mmol) was added to a solution of 3-chloro-N-(4- ((4-fluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2-methylbenzenesulfonamide Example 1- 16 (0.070 g, 0.170 mmol) in trifluoroacetic acid (1 mL). After stirring overnight the reaction mixture was concentrated in vacuo, dissolved in dichloromethane (5 mL) and washed with saturated aqueous NaHCO3. The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by column chromatography on SiO2 eluted with hexanes/ethyl acetate (2:1) to yield 0.052 g (77 %)of the title compound as a white foam. 1H NMR (400 MHz, DMSO-d6) δ, ppm: 2.62 (s, 3 H), 3.76 (s, 2 H), 6.32 (s, 1 H), 7.13 (t, 7=8.97 Hz, 2 H), 7.28 (dd, 7=8.34, 5.81 Hz, 2 H), 7.37 (t, 7=8.08 Hz, 1 H), 7.66 (d, 7=7.83 Hz, 1 H), 7.87 (d, 7=7.83 Hz, 1 H), 12.89 (s, 1 H); ESI-MS: m/z 397.2 (M+H)+.
Example 6-2: N-(4-benzylthiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide
[0434] The title compound was prepared from 3-chloro-N-(4- (hydroxy(phenyl)methyl)thiazol-2-yl)-2-methylbenzenesulfonamide Example 1-17 according to the procedure described in Example 6-1. 1H NMR (400 MHz, DMSO-d6) 6, ppm: 2.62 (s, 3 H), 3.77 (s, 2 H,) 6.33 (s, 1 H), 7.23 (d, 7=3.28 Hz, 1 H), 7.24 (s, 2 H), 7.28 - 7.39 (m, 3 H), 7.65 (d, 7=8.08 Hz, 1 H), 7.87 (d, 7=7.83 Hz, 1 H), 12.90 (s, 1 H); ESI-MS: m/z 379.1 (M+H)+.
Example 6-3: N-(4-(4-chlorobenzyl)thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide
[0435] The title compound was prepared from 3-chloro-N-(4-((4- chlorophenyl)(hydroxy)methyl)thiazol-2-yl)-2-methylbenzenesulfonamide Example 1-18 according to the procedure described in Example 6-1. 1H NMR (400 MHz, DMSO-d6) δ, ppm; 2.62 (s, 3 H), 3.77 (s, 2 H), 6.35 (s, 1 H), 7.25 - 7.30 (m, 2 H), 7.34 - 7.43 (m, 3 H), 7.66 (d, 7=8.08 Hz, 1 H), 7.87 (d, 7=7.83 Hz, 1 H), 12.90 (s, 1 H); ESI-MS: m/z 413.1
(M+H)+.
Example 6-4: N-(4-(3-chlorobenzyl)thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide
[0436] The title compound was prepared from 3-chloro-N-(4-((3- chlorophenyl)(hydroxy)methyl)thiazol-2-yl)-2-methylbenzenesulfonamide Example 1-19 according to the procedure described in Example 6-1. 1H NMR (400 MHz, DMSO-d6) 6, ppm: 2.62 (s, 3 H), 3.79 (s, 2 H), 6.39 (s, 1 H,) 7.21 (d, 7=8.84 Hz, 1 H), 7.29 - 7.41 (m, 4 H), 7.66 (d, 7=7.58 Hz, 1 H), 7.87 (d, 7=7.58 Hz, 1 H), 12.90 (s, 1 H); ESI-MS: m/z 413.1 (M+H)+.
Example 6-5: N-(4-(3-chloro-4-fluorobenzyl)thiazol-2-yl)-3-chloro-2- methylbenzenesulfonamide
[0437] The title compound was prepared from 3-chloro-N-(4-((3-chloro-4- fluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2-methylbenzenesulfonamide Example 1-20 according to the procedure described in Example 6-1. 1H NMR (400 MHz, DMSO-d6) δ, ppm: 2.62 (s, 3 H), 3.78 (s, 2 H), 6.37 (s, 1 H), 7.20 - 7.31 (m, 1 H), 7.32 - 7.41 (m, 2 H), 7.51 (d, 7=5.56 Hz, 1 H), 7.66 (d, 7=8.34 Hz, 1 H), 7.87 (d, 7=8.08 Hz, 1 H), 12.89 (s, 1 H); ESI-MS: m/z 431.1 (M+H)+.
Example 6-6: N-(4-(3,5-difluorobenzyl)thiazol-2-yl)-3-chloro-2- methylbenzenesulfonamide
[0438] The title compound was prepared from 3-chloro-N-(4-((3,5- difluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2-methylbenzenesulfonamide Example 1- 21 according to the procedure described in Example 6-1. 1H NMR (400 MHz, DMSO- d6) 6, ppm: 2.62 (s, 3 H), 3.81 (s, 2 H), 6.41 (s, 1 H), 7.02 (d, 7=8.59 Hz, 2 H), 7.08 - 7.18 (m, 1 H), 7.37 (t, 7=7.96 Hz, 1 H), 7.66 (d, 7=8.08 Hz, 1 H), 7.88 (d, 7=6.57 Hz, 1 H), 12.90 (s, 1 H); ESI-MS: m/z 415.1 (M+H)+.
Example 6-7: 3-chloro-N-(((m-tolyl)methyl)thiazol-2-yl)-2-methylbenzenesulfonamide
[0439] The title compound was prepared from 3-chloro-N-(4-(hydroxy(m- tolyl)methyl)thiazol-2-yl)-2-methylbenzenesulfonamide Example 1-22 according to the procedure described in Example 6-1. 1H NMR (400 MHz, DMSO-d6) δ, ppm: 2.25 (s, 3 H), 2.61 (s, 3 H), 3.72 (s, 2 H), 6.32 (s, 1 H), 6.99 - 7.08 (m, 3 H), 7.18 (t, 7=7.83 Hz, 1 H), 7.36 (t, 7=7.96 Hz, 1 H), 7.65 (d, 7=8.08 Hz, 1 H), 7.87 (d, 7=7.07 Hz, 1 H), 12.87 (s, 1 H); ESI-MS: m/z 393.2 (M+H)+.
Example 6-8: 3-chloro-N-(4-((2,5-dimethylphenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide
[0440] The title compound was prepared from commercially available 2,5- dimethylphenylmagnesium bromide (0.5 M in THF) and 3-chloro-N-(4-formylthiazol-2- yl)-2-methylbenzenesulfonamide Example 1-1-C according to the procedure described in Example 1-16. 1H NMR (400 MHz, Chloroform-d) δ, ppm: 2.09 (s, 3 H), 2.28 (s, 3 H), 2.69 (s, 3 H), 4.84 (s, 1 H), 5.69 (s, 1 H), 6.02 (s, 1 H), 7.14 (d, J=4.29 Hz, 2 H), 7.20 - 7.25 (m, 1 H), 7.37 - 7.45 (m, 1 H), 7.57 (d, J=7.83 Hz, 1 H), 7.98 (d, J=7.83 Hz, 1 H), 12.31 (s, 1 H); ESI-MS: m/z 423.2 (M+H)+.
Example 6-9: 3-chloro-N-(((o-tolyl)methyl)thiazol-2-yl)-2-methylbenzenesulfonamide
[0441] The title compound was prepared from 3-chloro-N-(4-(hydroxy(o- tolyl)methyl)thiazol-2-yl)-2-methylbenzenesulfonamide Example 1-10 according to the procedure described in Example 6-1. 1H NMR (400 MHz, DMSO-d6) δ, ppm: 2.21 (s, 3 H), 2.63 (s, 3 H), 3.75 (s, 2 H), 6.11 (s, 1 H), 7.08 - 7.19 (m, 4 H), 7.37 (t, 7=7.96 Hz, 1 H), 7.66 (d, 7=7.33 Hz, 1 H), 7.88 (d, 7=7.33 Hz, 1 H), 12.88 (s, 1 H); ESI-MS: m/z 393.2 (M+H)+.
Example 6-10: N-(4-(4-cyanobenzyl)thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide
[0442] The title compound was prepared from 3-chloro-N-(4-((4- cyanophenyl)(hydroxy)methyl)thiazol-2-yl)-2-methylbenzenesulfonamide Example 1-25 according to the procedure described in Example 6-1. 1H NMR (400 MHz, DMSO-d6) δ, ppm: 2.61 (s, 3 H), 3.88 (s, 2 H), 6.41 (s, 1 H), 7.37 (t, 7=7.96 Hz, 1 H), 7.44 (d, 7=8.08 Hz, 2 H), 7.66 (d, 7=7.83 Hz, 1 H), 7.79 (d, 7=8.34 Hz, 2 H), 7.86 (d, 7=1.26 Hz, 1 H), 12.93 (s, 1 H); ESI-MS: m/z 404.2 (M+H)+. Example 6-11: 4-((2-(3-chloro-2-methyrphenylsulfonamido)fhiazol-4- yl)methyl)benzamide
[0443] Potassium carbonate (0.109 g, 0.79 mmol) was added to a solution of N-(4-(4- cyanobenzyl)thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide Example 6-10 (0.040 g, 0.1 mmol) in dimethylsulfoxide (0.250 mL) and cooled to 10 0C. Hydrogen peroxide (0.341 mL, 35 % wt solution in water, 3.9 mmol) was added drop wise and the resulting reaction was allowed to stir for Ih at 10 0C, and then warmed to ambient temperature. After 2 h, the reaction mixture was poured into brine (1 mL). The resulting solution was extracted with ethyl acetate (2 x 2 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give 0.010 g (24 %) of the title compound as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ, ppm: 2.61 (s, 5 H), 3.76 (s, 3 H), 6.16 (s, 2 H), 7.25 - 7.34 (m, 6 H), 7.55 (d, 7=8.34 Hz, 2 H), 7.77 (d, 7=7.83 Hz, 3 H), 7.83 - 7.94 (m, 4 H), 12.92 (s, 1 H); ESI-MS: m/z 422.1 (M+H)+.
Example 6-12: N-(4-(3-cyanobenzyl)thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide
[0444] The title compound was prepared from 3-chloro-N-(4-((3- cyanophenyl)(hydroxy)methyl)thiazol-2-yl)-2-methylbenzenesulfonamide Example 1-13 according to the procedure described in Example 6-1. 1H NMR (400 MHz, DMSO-d6) δ, ppm: 2.62 (s, 3 H), 3.85 (s, 2 H), 6.38 (s, 1 H), 7.37 (t, J=7.96 Hz, 1 H), 7.53 (t, J=7.58 Hz, 1 H), 7.57 - 7.63 (m, 1 H), 7.66 (d, J=7.83 Hz, 1 H), 7.71 - 7.78 (m, 2 H), 7.87 (d, J=8.O8 Hz, 1 H), 12.90 (s, 1 H); ESI-MS: m/z 404.1 (M+H)+. Example 6-13: 3-((2-(3-chloro-2-methylphenylsulfonamido)thiazol-4- yl)methyl)benzamide
[0445] The title compound was prepared from N-(4-(3-cyanobenzyl)thiazol-2-yl)-3- chloro-2-methylbenzenesulfonamide Example 6-12 according to the procedure described in Example 6-11. 1H NMR (400 MHz, DMSO-d6) 5, ppm: 2.60 (s, 3 H), 3.72 (s, 2 H), 6.02 (s, 1 H), 7.23 (t, J=7.96 Hz, 1 H), 7.27 - 7.34 (m, 3 H), 7.48 (d, J=8.08 Hz, 1 H), 7.67 (td, J=4.11, 1.89 Hz, 1 H), 7.72 (s, 1 H), 7.83 (d, J=7.58 Hz, 1 H), 7.89 (s, 1 H); ESI-MS: m/z 422.1 (M+H)+.
Example 6-14: N-(4-(3-(trifluoromethyl)benzyl)thiazol-2-yl)-3-chloro-2- methylbenzenesulfonamide
[0446] The title compound was prepared from 3~chloro-N-(4-(hydroxy(3- (trifluoromethyl)phenyl)methyl)thiazol-2-yl)-2-methylbenzenesulfonamide Example 1-26 according to the procedure described in Example 6-1. 1H NMR (400 MHz, DMSO-d6) δ, ppm: 2.61 (s, 3 H), 3.89 (s, 2 H), 6.39 (s, 1 H), 7.36 (t, 7=7.96 Hz, 1 H), 7.54 - 7.57 (m, 2 H), 7.59 - 7.67 (m, 3 H), 7.87 (d, 7=7.83 Hz, 1 H), 12.93 (s, 1 H); ESI-MS: m/z 447.2 (M+H)+.
Example 6-15: 3-chloro-2-methyl-N-(4-((2-oxopyridin- 1 (2H)-yl)methyl)thiazol-2- yl)benzenesulfonamide
[0447] Sodium hydride (0.022 g, 95 % dry 0.920 mmol) was added to a stirring solution of 2-hydroxypyridine (0.085 g, 0.89 mmol) in 2 niL of DME and 0.5 mL of DMF at 0 0C. After 10 min, 3-chloro-N-(4-(chloromethyl)thiazol-2-yl)-2- methylbenzenesulfonamide Example 5-3-A (0.100 g, 0.297 mmol) was added and the resulting reaction mixture was stirred at room temperature for 15 min and then refluxed overnight. The reaction was quenched by addition to a cold brine solution (10 mL). The resulting solution was extracted with ethyl acetate (2 x 5 mL). The combined organic fractions were dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude residue was treated with dichloromethane to give a white precipitate that was filtered to yield 0.087 g (74 %) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-dβ) δ, ppm: 2.60 (s, 3 H), 4.77 (s, 2 H), 6.10 (s, 1 H), 6.15 (t, 7=5.94 Hz, 1 H), 6.33 (d, 7=8.84 Hz, 1 H), 7.20 (t, 7=7.83 Hz, 1 H), 7.33 - 7.39 (m, 1 H), 7.44 (d, 7=7.58 Hz, 1 H), 7.57 (dd, 7=6.82, 2.02 Hz, 1 H), 7.82 (d, 7=7.58 Hz, 1 H); ESI-MS: m/z 396.2 (M+H)+.
Example 6-16: N-(4-(3-methoxybenzyl)thiazol-2-yl)-3-chloro-2- methylbenzenesulfonamide
[0448] The title compound was prepared from EXAMPLE 1-33 according to the procedure described in Example 6-1. The crude product was purified by column chromatography on SiO2 eluted with EtOAc/hexanes (1:1) to yield 0.089 g (60 %) of the title compound. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.63 (s, 3 H), 3.76 (s, 3 H), 3.97 (s, 2 H), 5.91 (s, 1 H), 6.75 - 6.84 (m, 3 H), 7.21 (t, 7=8.0, 1 H), 7.21 (t, 7=8.0, 1 H), 7.21 (t, 7=8.1, 1 H), 7.53 (d, 7=8.1 Hz, 2 H), 8.00 (d, 7=7.9 Hz, 1 H); 13C NMR (100 MHz, CHLOROFORM-D) δ ppm 14.2, 17.2, 21.1, 34.2, 55.2, 60.5, 103.6, 112.9, 114.8, 121.4, 126.2, 127.6, 129.8, 133.3, 135.2, 136.9, 137.2, 138.8, 141.0, 159.9, 170.6; ESI- MS: m/z 409.2 (M+H)+. Biological Testing
[0449] The activity of compounds as 1 Ib-HSDl inhibitors may be assayed in vitro, in vivo or in a cell line. Provided below is an in vitro enzymatic 1 Ib-HSDl dehydrogenase activity assay for activity against 1 Ib-HSDl.
[0100] It should be noted that a variety of other expression systems and hosts are also suitable for the expression of 1 Ib-HSDl, as would be readily appreciated by one of skill in the art.
[0101] Purified 1 Ib-HSDl may be obtained as follows: Residues 24 to 292 of 11-β- hydroxysteroid dehydrogenase isoform 1 was amplified from IMAGE clone 5193867 (ATCC clone 7277078) using PCR with the primers hsdl_24-f: 5'- AACGAGGAATTC AGACCAGAGATG-S' (SEQ. JD NO. 1) and hsdl-292-r: 5'- TTACTTGTTTATGAATCTGTCC AT-3' (SEQ. ID No. 2). The resulting PCR product was topocloned into the pBAD-ThioE vector (Invitrogen) that was modified by inserting a DNA sequence that codes for MKHQHQHQHQHQHQQPL at the cloning site and adapted for TOPOcloning PCR (Invitrogen). Residues 24-292 of 11-β-hydroxysteroid dehydrogenase isoform 1 were generated fused with MKHQHQHQHQHQHQQPL at the N-terminus under control of an ara promoter. One point mutation C272S was made in the final construct by quick change PCR mutagenesis using the primers hsdC272Sqcf: 5'- TCAGAAATCCATCCAGGAAGATC-3' (SEQ. ID No. 3) and hsdC272Sqcr: 5'- GATCTTCCTGGATGGATTTCTG A-3' (SEQ. ID No. 4).
[0102] E. coli DHlOb-Tir (Invitrogen), harboring the 1 Ib-HSDl expression plasmid, were grown overnight at 37°C, in Luria broth (LB) supplemented to 0.05 mg/ml kanamycin (Km). 15 mis of saturated culture was then used to inoculate one liter of fresh LB (0.05 mg/ml Km). When this culture reached an optical density of 0.4 (λ = 600 nm), the growth temperature was shifted from 37°C to 25°C. After an additional 2 hours of growth, arabinose and coiticosterone were added to a final concentration of 0.2% (w/w), and 0.25 mM, respectively. Cells were harvested approximately 14 hours following induction, and were immediately frozen at -800C. The cell pellets from each liter of cell culture were thawed and resuspended in 50 mis of lysis buffer (30 mM CHAPS, 50 mM Tris-HCl, pH 7.9, 0.15 M NaCl, 0.5 μl/ml benzonase, 1 μl/ml ReadyLyse). Following a 30-minute incubation at room temperature, the lysates were clarified by centrifugation. The resulting supernatant was loaded on 6 mis of Probond resin (Invitrogen), previously equilibrated with wash buffer (4 mM CHAPS, 50 mM Tris-HCl, pH 7.9, 0.25 M NaCl, 40 mM imidazole), and then washed with 10 column volumes of wash buffer. 1 Ib-HSDl was then eluted with 3 column volumes of wash buffer supplemented to 0.2 M imidazole. The eluate of purified 1 Ib-HSDl was extensively dialysed against 4 mM CHAPS, 25 mM Tris-HCl, pH 7.9, 0.25 M NaCl, and concentrated to 10 mg/ml. Size exclusion chromatography demonstrated that this method of purification yields monodispersive 1 Ib- HSDl.
[0103] It should be noted that a variety of other expression systems and hosts are also suitable for the expression of 1 Ib-HSDl, as would be readily appreciated by one of skill in the art.
[0450] The inhibitory properties of compounds relative to 1 Ib-HSDl may be determined using a white 384- well-plate format under the following reaction conditions: 50 mM Tris pH 7.5, 150 mM NaCl, 0.1 mM EDTA, 0.01% Brij35, 10 μM each of Cortisol and NADP+, 1% DMSO. Reaction product may be determined quantitatively by fluorescence intensity using a fluorescence plate reader (Molecular Devices Gemini) with a 340 nm excitation wavelength and a 460 nm emission wavelength. [0451] The assay reaction may be initiated as follows: 4 μl buffer containing 25 μM Cortisol and 25 μM NADP+ was added to each well of the plate, followed by the addition of 2 μl of inhibitor (2 fold serial dilutions for 11 data points for each inhibitor) containing 5% DMSO. 4 μl of 125 nM 1 Ib-HSDl enzyme solution may be added to initiate the reaction (final enzyme concentrations was 50 nM). Fluorescence intensities of the resulting reaction mixtures may be measured after 60 minutes incubation at room temperature.
[0452] IC50 values may be calculated by non-linear curve fitting of the compound concentrations and fluorescence intensities to the standard IC50 equation. As a reference point for this assay, carbenoxolone and BVT14225 showed IC50s of 100 nM and 500 nM, respectively, for the 1 Ib-HSDl dehydrogenase assay. [0453] The following abbreviations have been used:
ATP Adenosine Triphosphate
BSA Bovine Serum Albumin EDTA Ethylenediaminetetraacetic acid MOPS Moφholinepropanesulfonic acid SPA Scintillation Proximity Assay
[0454] It will be apparent to those skilled in the art that various modifications and variations can be made in the compounds, compositions, kits, and methods of the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.

Claims

What is claimed is:
1. A compound comprising:
wherein:
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NR15;
R1 is selected from the group consisting of (C1.10)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R2 is selected from the group consisting of
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-10)alkyl, heteroaryl(C1-5)alkyl, (C3-i2)cycloalkyl(Ci.,o)alkyl, halo(C1-io)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1.3)alkyl, sulfinyl(Ci_3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4.12)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Cι-Io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-5)alkyl, (C3.i2)cycloalkyl(Ci.io)alkyl, halo(C1-10)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, imino(C1_3)alkyl, aryl, heteroaryl, and hetero(C4_i2)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-Io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Cι-5)alkyl, perhalo(Ci-io)alkyl, (C3_i2)cycloalkyl(C1-1o)alkyl, halo(C1-1o)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, amino (C1-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3.i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci_1o)alkyl, heteroaryl(Ci_5)alkyl, perhalo(Ci-io)alkyl, (C3_i2)cycloalkyl(Ci-i0)alkyl, halo(Ci_io)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(C1-io)alkyl, heteroaryl (C i.5)alkyl, perhalo(Ci_io)alkyl, (C3-i2)cycloalkyl(Ci-)0)alkyl, halo(C1-10)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci_1o)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4_i2)bicycloaryl, each substituted or unsubstituted;
R9, Rio, Rn and Ri2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci_io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci_io)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(C1.10)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci.3)alkyl, amino (Ci-io)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, or any two of R7, Rg, R9, Rio, Ri 1 and Ri2 are taken together to form a ring;
R13 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3.]2)bicycloalkyl, aryl(Ci_io)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci_io)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(Ci.io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(Ci_3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or Ri3 and any one of R7, R9 and Rn are taken together to form a ring; Ri5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-)2)bicycloalkyl, aryl(Ci.iO)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(Ci-10)alkyl, halo(Ci-10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4.12)bicycloaryl, each substituted or unsubstituted;
X is selected from the group consisting of unsubstituted and substituted C1-6 alkylenes; and
Y is selected from the group consisting of (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl, heteroaryl, (Cc1-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted.
2. The compound according to claim 1 comprising:
wherein: n is selected from the group consisting of 0, 1, 2,3, 4 and 5;
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond; M is selected from the group consisting of S, O and NR15; R2 is selected from the group consisting of
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci-ιo)alkyl, heteroaryl(C1-5)alkyl, (C3-i2)cycloalkyl(C1-1o)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci_3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-io)alkyl, heteroaryl(C1-5)alkyl, (C3-i2)cycloalkyl(C1-io)alkyl, halo(C].io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C1-5)alkyl, perhalo(C1-10)alkyl, (C3-i2)cycloalkyl(C1-i0)alkyl, halo(Ci.i0)alkyl, carbonyl(Cj-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C]-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
Re is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (CMo)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9.)2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-5)alkyl, perhalo(C1-1o)alkyl, (C3-12)cycloalkyl(C1-i0)alkyl, halo(C1-1o)alkyl, carbonyl(C]-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci.3)alkyl, amino (Ci-Io)alkyl, UrUnO(C1 -3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3-i2)cycloalkyl, hetero(C3.[2)cycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci-io)alkyl, (C3-i2)cycloalkyl(Ci_io)alkyl, halo(C1.1o)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, and hetero(C4-ι2)bicycloaryl, each substituted or unsubstituted;
R9, Rio, Rn and Ri2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-Io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3.i2)cycloalkyl, (Cg.^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci_io)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci-io)alkyl, (C3.i2)cycloalkyl(Ci.io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C).3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci.3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9, Rio> Ri 1 and R12 are taken together to form a ring;
Ri3 is selected from the group consisting of hydrogen, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-i0)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-10)alkyl, heteroaryl(Ci_5)alkyl, perhalo(Ci.io)alkyl, (C3-12)cycloalkyl(C 1. !o)alkyl, halo(C 1.1 o)alkyl, carbonyl(C 1 _3)alkyl, thiocarbonyl(Ci_3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, amino (C1-1o)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or Ri3 and any one of R7, R9 and Rn are taken together to form a ring; each Ri4 is independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3.i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(Ci_io)alkyl, heteroaryl(Ci_5)alkyl, perhalo(Ci-io)alkyl, (C3- 12)cycloalkyl(Ci . io)alkyl, halo(C 1. io)alkyl, carbonyl(C 1 -3)alkyl, thiocarbonyl(C]-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
Ri5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3_i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3_i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
X is selected from the group consisting of unsubstituted and substituted Ci-6 alkylenes; and Y is selected from the group consisting of (C3-12)cycloalkyl, hetero(C3.i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted.
3. The compound according to claim 1 comprising:
wherein:
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NR15; R2 is selected from the group consisting of
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3_i2)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci_io)alkyl, heteroaryl(C1.5)alkyl, (C3.i2)cycloalkyl(Ci.io)alkyl, halo(C1-10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(Ci.3)alkyl, imino(C]-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4_i2)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3.12)cycloalkyl, hetero(C3.12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(Ci.5)alkyl, (C3-12)cycloalkyl(C1-1o)alkyl, halo(Ci.10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3.12)bicycloalkyl, aryl(Ci-1o)alkyl, heteroaryl (C 1 -5)alkyl, perhalo(C 1 -Io)alkyl, (C3.12)cycloalkyl(C i_io)alkyl, halo(Ci_io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1.3)alkyl, amino (Ci-io)alkyl, imino(C 1-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(C 1.5)alkyl, perhalo(C 1. io)alkyl, (C3.12)cycloalkyl(C 1. \ o)alkyl, halo(Ci.io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-10)alkyl, imino(C1.3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4.12)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci_i0)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9- 12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-iO)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-1o)alkyl, (C3.i2)cycloalkyl(C1.io)alkyl, halo(C1-I0)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C|.3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci.3)alkyl, amino (Ci.io)alkyl, UrUnO(C1.3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4_12)bicycloaryl, each substituted or unsubstituted;
R9, Ri0, Rn and Ri2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3.]2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci.io)alkyl, (C3-12)cycloalkyl(C 1 _i o)alkyl, 1IaIo(C1.1 o)alkyl, carbonyl(C 1.3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci.3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9, Rio, Rn and Ri2 are taken together to form a ring;
Ri3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3_i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-io)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C]-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-] 2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or Ri3 and any one of R7, R9 and Rn are taken together to form a ring; R1S is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3.12)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-5)alkyl, (C3-12)cycloalkyl(C1-io)alkyl, halo(C1-io)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
X is selected from the group consisting of unsubstituted and substituted C1-6 alkylenes; and
Y is selected from the group consisting of (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted.
4. The compound according to claim 1 comprising:
wherein:
R2 is selected from the group consisting of
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-1O)OIlCyI, (C3_12)cycloalkyl, hetero(C3-ι2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(C1-5)alkyl, (C3-12)cycloalkyl(C1-10)alkyl, halo(C1-10)alkyl, carbonyl(C]-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Cι_3)alkyl, sulfinyl(C1-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1.1o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-10)alkyl, heteroaryl(Ci-5)alkyl, perhalo(C1-1o)alkyl, (C3-12)cycloalkyl(C1-i0)alkyl, halo(Ci_io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (C1-io)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci_io)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl) halo(Ci-10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci_3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R9, Rio, Rn and R)2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-Io)alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-io)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(Ci.io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9, R1O, Ri 1 and R12 are taken together to form a ring;
Ri3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci_io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-io)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl, halo(Ci.io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or Ri3 and any one of R7, R9 and Rn are taken together to form a ring;
X is selected from the group consisting of unsubstituted and substituted C]-6 alkylenes; and
Y is selected from the group consisting of (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted.
5. The compound according to claim 1 comprising:
wherein:
R2 is selected from the group consisting of
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-1o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(Ci-5)alkyl, perhalo(C1-1o)alkyl, (C3-12)cycloalkyl(C1-io)alkyl, halo(Ci.io)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci_3)alkyl, amino (C1-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4-ι2)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Cι-io)alkyl, (C3-i2)cycloalkyl, hetero(C3.i2)cycloalkyl, (C^i^bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(Ci_io)alkyl, heteroaryl(d-5)alkyl, perhalo(Ci-io)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(CM0)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted; and
Rg, R1O, Rn and Ru are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci.10)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci.io)alkyl, (C3.i2)cycloalkyl(Ci.io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci_3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci.io)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or any two of R7, Rg, Rg, Rio, Rn and Ri2 are taken together to form a ring.
6. The compound according to claim 1 comprising:
wherein:
R2 is selected from the group consisting of
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-1o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci_1o)alkyl, (C3-i2)cycloalkyl(C1-1o)alkyl, halo(C1-1o)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C]-3)alkyl, amino (Ci-io)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1.1o)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3_i2)bicycloalkyl, aryl(C1-io)alkyl, heteroaryl(Ci_5)alkyl, perhalo(C1-1o)alkyl, (C3-12)cycloalkyl(C 1 -10)alkyl, halo(C 1.1 o)alkyl, carbonyl(C 1.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C].3)alkyl, sulfinyl(C1-3)alkyl, amino (C1-1o)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted; and
R9, Rio, Rn and R]2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-]2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci_io)alkyl, (C3-i2)cycloalkyl(CM0)alkyl, halo(C,.10)alkyl, carbonyl(C,-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9, Rio, Ri 1 and R12 are taken together to form a ring.
7. The compound according to claim 1 comprising:
wherein:
R1 is selected from the group consisting of (Ci-10)alkyl, (C3.i2)cycloalkyl, hetero(C3.12)cycloalkyl, (Cc)-12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl, heteroaryl, (C9_12)bicycloaryl, hetero(C4-]2)bicycloaryl, each substituted or unsubstituted;
R2 is selected from the group consisting of
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C)-3)alkyl, sulfinyl(Ci-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-Io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-12)cycloalkyl, hetero(C3.i2)cycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(C1-i0)alkyl, (C3-12)cycloalkyl(Ci.i0)alkyl, halo(Ci.io)alkyl, carbonyl(Ci_3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-ιo)alkyl, imino(C).3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-1o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci_ιo)alkyl, heteroaryl(C1-5)alkyl, perhalo(C1-io)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(C)-io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1.3)alkyl, sulfinyl(Ci.3)alkyl, amino (C1-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R9, R10, Rj1 and R12 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-i^alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3.i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3.12)bicycloalkyl, aryl(C1.io)alkyl, heteroaryl(C1-5)alkyl, perhalo(Ci-i0)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(Ci.io)alkyl, carbonyl(Ci_3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-Io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4.12)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9, Rio, Ru and Ri2 are taken together to form a ring; RB is selected from the group consisting of hydrogen, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3.12)cycloalkyl, hetero(C3.i 2)cycloalkyl, (Cg- 12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-10)alkyl, heteroaryl(C1-5)alkyl, perhalo(Ci-1o)alkyl, (C3.12)cycloalkyl(C1-10)alkyl, halo(Ci-1o)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (C1-1o)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_12)bicycloaryl, and hetero(C4.i2)bicycloaryl, each substituted or unsubstituted, or R13 and any one of R7, R9 and Rn are taken together to form a ring;
X is selected from the group consisting of unsubstituted and substituted Ci-6 alkylenes; and
Y is selected from the group consisting of (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted.
8. The compound according to claim 1 comprising:
wherein:
Ri is selected from the group consisting of (Ci.nOalkyl, (C3_i2)cycloalkyl, hetero(C3.i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R2 is selected from the group consisting of
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3.]2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3.12)bicycloalkyl, aryl(C1-io)alkyl, heteroaryl(C1-5)alkyl, perhalo(Ci-10)alkyl, (C3-12)cycloalkyl(C1-10)alkyl, halo(Ci-1o)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C]_3)alkyl, sulfinyl(Ci-3)alkyl, amino (C1-10)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4_i2)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-10)alkyl, heteroaryl(Ci.5)alkyl, perhalo(C1-1o)alkyl, (C3-ι2)cycloalkyl(C1-1o)alkyl, halo(C1.io)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-io)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted; and
R9, R10, Rn and Ri2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3.i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci_io)alkyl, (C3-i2)cycloalkyl(CMo)alkyl, halo(Ci-10)alkyl, carbonyl(C,-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci.3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9, Rio, Rn and Ri2 are taken together to form a ring.
9. The compound according to claim 1 comprising:
wherein:
Ri is selected from the group consisting of (Ci-Io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R2 is selected from the group consisting of
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci_1o)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl (C 1 ^alkyl, perhalo(C 1.1 o)alkyl, (C3.12)cycloalkyl(C 1.1 o)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C) -3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9.12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci.io)alkyl, (C3- 12)cycloalkyl(C i -i o)alkyl, halo(C i . ( o)alkyl, carbonyl (C i -3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-10)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted; and
Rg, Rio, Rn and Ri2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1.1o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-Io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci_io)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci-io)alkyl, (C3-12)cycloalkyl(Ci.io)alkyl, halo(Ci_io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(Ci-3)alkyl, amino (C1-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C^i^bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9, R1O, Rn and Ri2 are taken together to form a ring.
10. The compound according to claim 1 comprising:
wherein: J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NRi 5;
Ri is selected from the group consisting of (Ci.io)alkyl, (C3-12)cycloalkyl, hetero(C3_i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, hetero(C4_i2)bicycloaryl, each substituted or unsubstituted;
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(C1.10)alkyl, halo(C1-10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (Cc>-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(Ci-5)alkyl, (C3-12)cycloalkyl(C1-io)alkyl, halo(Ci.10)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci.3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci_io)alkyl, (C3-i2)cycloalkyl(Ci-1o)alkyl, halo(Ci-10)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C]-3)alkyl, amino (C1.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4.i2)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3.12)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-5)alkyl, perhalo(C1.1o)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(Ci-1o)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Cι-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-10)alkyl, imino(Cι.3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4.12)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.ιo)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3.12)bicycloalkyl, aryl(C1.io)alkyl, heteroaryl(Ci.5)alkyl, perhalo(C1-io)alkyl, (C3-12)cycloalkyl(C1-1o)alkyl, halo(C1-10)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, amino (C1-1o)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, or R7 and R8 are taken together to form a ring;
R13 is selected from the group consisting of hydrogen, carbonyl, amino, (C1_io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci-iO)alkyl, heteroaryl(C1-5)alkyl, perhalo(C1-io)alkyl, (C3-i2)cycloalkyl(C].io)alkyl, halo(Ci.i0)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci_3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or R13 and R7 are taken together to form a ring; and R15 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-]2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C i -5)alkyl, (C3-12)cycloalkyl(C i .10)alkyl, halo(C i .10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted.
11. The compound according to claim 1 comprising:
wherein:
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NRi5;
R1 is selected from the group consisting of (Ci.io)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, hetero(C4.]2)bicycloaryl, each substituted or unsubstituted;
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3.12)cycloalkyl, hetero(C3.12)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(C1-io)alkyl, halo(Ci-1o)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(Ci.iO)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C].3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-j2)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-1o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-10)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C1-5)alkyl, perhalo(C(.1o)alkyl, (C3_i2)cycloalkyl(C1-io)alkyl, halo(C1-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-Io)alkyl, imino(C]-3)alkyl, aryl, heteroaryl, (Cc,-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-1o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-Io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci_10)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci-io)alkyl, (C3-]2)cycloalkyl(Ci-1o)alkyl, halo(Ci.io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl (C i-3)alkyl, amino (Ci-10)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-i0)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-10)alkyl, heteroaryl(C1-5)alkyl, perhalo(C1-i0)alkyl, (C3-12)cycloalkyl(C , .10)alkyl, halo(C i . )0)alkyl, carbonyl(C i .3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci.io)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, or R7 and R8 are taken together to form a ring;
Ri3 is selected from the group consisting of hydrogen, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1.1o)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-10)alkyl, heteroaryl(C1-5)alkyl, perhalo(C1-1o)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(C1-1o)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, amino (C1-1o)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, or Ri3 and R7 are taken together to form a ring; and
Ri5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, (C3-)2)cycloalkyl(Ci-10)alkyl, halo(Ci_io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted.
12. The compound according to claim 1 comprising:
wherein: J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NRi 5;
Ri is selected from the group consisting of (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-12)cycloalkyl, hetero(C3-j2)cycloalkyl, (C9.12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-ιo)alkyl, heteroaryl(Ci-5)alkyl, (C3-12)cycloalkyl(Ci-1o)alkyl, halo(Ci-1o)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci.5)alkyl, (C3-12)cycloalkyl(Ci.io)alkyl, halo(C1-10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C].3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-io)alkyl, heteroaryl(C1-5)alkyl, perhalo(Ci.io)alkyl, (C3-i2)cycloalkyl(C1-io)alkyl, halo(Ci.io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, amino (C1-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.]o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3.12)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-5)alkyl, (C3-12)cycloalkyl(Ci-i0)alkyl, halo(C1-io)alkyl, carbonyl(Ci_3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C].3)alkyl, sulfinyl(C]-3)alkyl, amino (Ci.10)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3_i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Ccι_12)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-io)alkyl, halo(Ci.1o)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-Io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R9 and R1O are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3.i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg-i^bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-i0)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci.io)alkyl, (C3- 12)cycloalkyl(C 1.1 o)alkyl, halo(C 1-1o)alkyl, carbonyl (C 1 -3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(C|.3)alkyl, sulfinyl(Ci_3)alkyl, amino (C1-1o)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9 and R10 are taken together to form a ring;
Ri3 is selected from the group consisting of hydrogen, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3_i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci.io)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4.12)bicycloaryl, each substituted or unsubstituted, or Ri3 and any one of R7 and R9 are taken together to form a ring; and
R15 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3.i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci.iO)alkyl, heteroaryl(Ci_5)alkyl, (C3-12)cycloalkyl(Ci-io)alkyl, halo(Ci_io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci_3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted.
13. The compound according to claim 1 comprising:
wherein:
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond; L is selected from the group consisting of CR6 and N, with the proviso that L is CR.6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NRj5;
Ri is selected from the group consisting of (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3.12)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3.12)bicycloalkyl, aryl, heteroaryl, (C^i^bicycloaryl, hetero(C4_i2)bicycloaryl, each substituted or unsubstituted;
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (d.io)alkyl, (C3.12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.10)alkyl, heteroaryl(C1-5)alkyl, (C3.12)cycloalkyl(Ci-io)alkyl, halo(C1-1o)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, imino(Ci_3)alkyl, aryl, heteroaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.^bicycloalkyl, hetero(C3_i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C1-5)alkyl, (C3-12)cycloalkyl(CMo)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(C1_3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-10)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci_io)alkyl, (C3-i2)cycloalkyl(Ci.i0)alkyl, halo(Ci_io)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted; R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-]0)alkyl, heteroaryl(C i -5)alkyl, perhalo(C i .10)alkyl, (C3- 12)cycloalkyl(C i . i o)alkyl, halo(Ci-1o)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3.12)cycloalkyl, hetero(C3.i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-10)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci.io)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(C1-10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci.3)alkyl, amino (Ci,io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R9 and R10 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C3.i2)cycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci_iO)alkyl, heteroaryl (C i^alkyl, perhalo(C1-io)alkyl, (C3-i2)cycloalkyl(C1-io)alkyl, halo(Ci-1o)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C]-3)alkyl, amino (Cι.iO)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (Cg-12)bicycloaryl, and hetero(C4.12)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9 and Rj0 are taken together to form a ring;
R13 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3.i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3.12)bicycloalkyl, OTyI(C1-I0)OIlCyI, heterooryl(C1-5)olkyl, perholo(Ci.i0)olkyl, (C3-i2)cycloolkyl(C1-10)olkyl, holo(Ci-10)olkyl, corbonyl(C)-3)olkyl, thiocorbonyl(Ci-3)olkyl, sulfonyl(Ci-3)olkyl, sulfinyl(C1-3)olkyl, omino (C1.10)olkyl, imino(Ci-3)olkyl, oryl, heterooryl, and 11CtCrO(C4-12)bicyclooryl, each substituted or unsubstituted, or R13 and any one of R7 and R9 are taken together to form a ring; ond
R15 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-12)bicycloalkyl, oryl(C1-io)olkyl, heterooryl(C ] -5)alkyl, (C3- 12)cycloalkyl(C 1.10)alkyl, halo(C \ . io)alkyl, carbonyl(C1-3)alkyl, thiocorbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, imino(Ci-3)olkyl, oryl, heteroaryl, (C^i^bicycloaryl, and hetero(C4.12)bicyclooryl, each substituted or unsubstituted.
14. The compound according to claim 1 comprising:
wherein:
J is selected from the group consisting of CR6 and N, with the proviso thot J is CR6 ond R6 is obsent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 ond R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso thot L is CR6 ond R6 is obsent when L forms part of a double bond;
M is selected from the group consisting of S, O and NR15; Ri is selected from the group consisting of (Ci-io)alkyl, (C3.i2)cycloalkyl, hetero(C3-12)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3_12)bicycloalkyl, aryl, heteroaryl, (C9-12)bicycloaryl, hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3.i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3_i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, (C3-12)cycloalkyl(Ci.io)alkyl, halo(Ci.io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1.i0)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (Cg.^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(C1-5)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl, halo(Ci-i0)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C].3)alkyl, sulfinyl(C1_3)alkyl, imino(C].3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-1o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3_i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(C1-5)alkyl, perhalo(C1-io)alkyl, (C3-i2)cycloalkyl(C1-1o)alkyl, halo(Ci.io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3.12)bicycloalkyl, aryl(Ci-i0)alkyl, heteroaryl(Ci-5)alkyl> perhalo(Ci-io)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl, halo(Ci-1o)alkyl, carbonyl(C1.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C]-3)alkyl, amino (Ci.]o)alkyl, InUnO(C1 -3)alkyl, aryl, heteroaryl, (C9_12)bicycloaryl, and hetero(C4.12)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-Io)alkyl, (C3-] 2)cycloalkyl, hetero(C3.12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3.12)bicycloalkyl, aryl(Ci_1o)alkyl, heteroaryl(Ci-5)alkyl, perhalo(C1-1o)alkyl, (C3-i2)cycloalkyl(CMo)alkyl, halo(C1-10)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, amino (C1-1o)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R9, Rio, Rn and Ri2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3_i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci-io)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(Ci.io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9, Ri0, Ru and Ri2 are taken together to form a ring;
Ri3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3.i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci-io)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(C]_io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci.3)alkyl, amino (Ci.io)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, or R]3 and any one of R7, R9 and Rj 1 are taken together to form a ring; and
Ri5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3_i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(Ci_io)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(C1.io)alkyl, halo(Ci.io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted.
15. The compound according to claim 1 comprising:
wherein:
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NRi5;
Ri is selected from the group consisting of (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, hetero(C4-i2)bicycloaryl, each substituted or unsubstituted; R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Cι-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(C i .5)alkyl, (C3-12)cycloalkyl(C i .i 0)alkyl, halo(C i . io)alkyl, carbonyl(C]-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and heterp(C4-)2)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C3.12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3.12)bicycloalkyl, aryl(Ci-10)alkyl, heteroaryl(C1-5)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl, halo(C1-1o)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3_12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-5)alkyl, perhalo(C1-1o)alkyl, (C3-i2)cycloalkyl(C1-i0)alkyl, halo(Ci-1o)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, amino (C1-1o)alkyl, InUnO(C1 -3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-i0)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(C1-io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-1o)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(Ci-io)alkyl, carbonyl(C]-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C].3)alkyl, sulfinyl(Ci.3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci_io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci.io)alkyl, (C3-12)cycloalkyl(C1-io)alkyl, halo(C1-io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, amino (C1-1o)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R9, Rio, Rn and Ri2 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-Io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci.io)alkyl, (C3.12)cycloalkyl(Ci.,o)alkyl, halo(C1-io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9, Rio, Rn and R12 are taken together to form a ring;
Ri3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci_io)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci-io)alkyl, (C3-i2)cycloalkyl(Ci.io)alkyl, halo(C].io)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or Ri3 and any one of R7, R9 and Ri 1 are taken together to form a ring; and R15 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-iO)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(C1-io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C]-3)alkyl, sulfinyl(Ci.3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted.
16. The compound according to claim 1 comprising:
wherein:
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NRi5;
Ri is selected from the group consisting of (Ci-io)alkyl, (C3-]2)cycloalkyl, hetero(C3.i2)cycloalkyl, hetero(C3-i2)bicycloalkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3.]2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(C1-io)alkyl, halo(Ci-io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4.]2)bicycloaryl, each substituted or unsubstituted;
Bi4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-1o)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(C1-io)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C1.3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4.12)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3.i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9_12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-10)alkyl, heteroaryl(C1-5)alkyl, perhalo(C1.1o)alkyl, (C3-12)cycloalkyl(C1.1o)alkyl, halo(Ci-io)alkyl, carbonyl(Ci_3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (C1-1o)alkyl, imino(C].3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-Io)alkyl, (C3.i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9.12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-io)alkyl, heteroaryl(Ci.5)alkyl, perhalo(C1-io)alkyl, (C3-12)cycloalkyl(Ci-1o)alkyl, halo(Ci-io)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, amino (C1.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
Ri5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-]2)bicycloalkyl, hetero(C3.12)bicycloalkyl, aryl(CM0)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(C1-10)alkyl, halo(Ci.i0)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
X is selected from the group consisting of unsubstituted and substituted Ci-6 alkylenes; and
Y is selected from the group consisting of (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-]2)bicycloalkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted.
17. The compound according to claim 1 comprising:
wherein: n is selected from the group consisting of 0, 1, 2,3, 4 and 5;
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NR ]5; R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-)2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C i -5)alkyl, (C3.12)cycloalkyl(C i . io)alkyl, halo(C ]-i0)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4.12)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3.12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-io)alkyl, heteroaryl(C1-5)alkyl, (C3-i2)cycloalkyl(C1-io)alkyl, halo(C1-1o)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Cι-3)alkyl, sulfinyl(Ci-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-] 2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-i2)cycloalkyl, hetero(C3_i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci.]o)alkyl, (C3-i2)cycloalkyl(Ci-io)alkyl, halo(C]-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci.3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-Io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, aryl(C].io)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci-io)alkyl, (C3-] 2)cycloalkyl(Ci.io)alkyl, halo(C].io)alkyl, carbonyl(C).3)alkyl, thiocarbonyl(C]-3)alkyl, sulfonyl(C].3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3.12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3.i2)bicycloalkyl, 3TyI(C1. io)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci_1o)alkyl, (C3-i2)cycloalkyl(CM0)alkyl, halo(Ci.io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or R7 and R8 are taken together to form a ring;
R13 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3_i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci-io)alkyl, (C3-12)cycloalkyl(C i_10)alkyl, halo(C j ., 0)alkyl, carbonyl(C i .3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-Io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or R13 and R7 are taken together to form a ring; each Ri4 is independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3.i2)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(C1-io)alkyl, (C302)cycloalkyl(Ci.io)alkyl, halo(Ci.io)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci.io)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, and hetero(C4_i2)bicycloaryl, each substituted or unsubstituted; and
Ri5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(C i -5)alkyl, (C3- 12)cycloalkyl(C i .10)alkyl, halo(C i .10)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted.
18. The compound according to claim 1 comprising:
wherein: n is selected from the group consisting of 0, 1, 2,3, 4 and 5;
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NRi5;
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C^^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C i -5)alkyl, (C3.12)cycloalkyl(C i . i o)alkyl, halo(C i . i o)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(Ci.3)alkyl, imino(C1-3)alk;yl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3.i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-)0)alkyl, heteroaryl(C]-5)alkyl, (C3.12)cycloalkyl(Ci-1o)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C!.3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1.3)alkyl, imino(Ci_3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci_io)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci-1o)alkyl, heteroaryl (C 1 -5)alkyl, perhalo(C 1.10)alkyl, (C3- 12)cycloalkyl(Ci .1 o)alkyl, halo(Ci-io)alkyl, carbonyl(Ci_3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci_3)alkyl, sulfinyl(C]-3)alkyl, amino (C1-1o)alkyl, imino^^alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (CMcOalkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C3-)2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3.12)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl (C i-5)alkyl, perhalo(C1-io)alkyl, (C3-I2)CyClOaIkVl(C1. iO)alkyl, halo(Ci-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-Io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3.12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(CM0)alkyl, heteroaryl(Ci-5)alkyl, perhalo(C1-io)alkyl, (C3-12)cycloalkyl(Ci.i0)alkyl, halo(C1-10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (C1-10)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R.9 and Ri0 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-Io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-12)cycloalkyl, (C9.12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci_1o)alkyl, (C3-12)cycloalkyl(Ci-1o)alkyl, halo(C1-1o)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-Io)alkyl, imino(C1.3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9 and R1O are taken together to form a ring;
R13 is selected from the group consisting of hydrogen, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1.1o)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-io)alkyl, heteroaryl(Ci.5)alkyl, perhalo(C1-io)alkyl, (C3-i2)cycloalkyl(Ci-10)alkyl, halo(C1-10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C1_3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-Io)alkyl, InUnO(C1 -3)alkyl, aryl, heteroaryl, (Cg.i^bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, or R13 and any one of R7 and R9 are taken together to form a ring; each R14 is independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.10)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-10)alkyl, (C3.i2)cycloalkyl(Ci-10)alkyl, halo(C1-10)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci.3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-10)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted; and
Ri5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3.i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(C1-5)alkyl, (C3.12)cycloalkyl(CM0)alkyl, halo(C1-io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(C!.3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C]-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted.
19. The compound according to claim 1 comprising:
wherein: n is selected from the group consisting of 0, 1, 2,3, 4 and 5;
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond;
K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NRi5; R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(C]-io)alkyl, halo(C1-io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9.12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(C1-5)alkyl, (C3-12)cycloalkyl(Ci.io)alkyl, halo(C1-10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (XLV12)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-1o)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-10)alkyl, heteroaryl(Ci-5)alkyl, perhalo(C1-1o)alkyl, (C3-12)cycloalkyl(C1.io)alkyl, halo(C1-1o)alkyl, carbonyl(C1.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci-10)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9_12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3.|2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci-10)alkyl, heteroaryl(C i -5)alkyl, perhalo(C i . i o)alkyl, (C3-] 2)cycloalkyl(C j . i o)alkyl, halo(Ci-io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R7 and R8 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3.]2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci.5)alkyl, perhalo(Ci-10)alkyl, (C3-i2)cycloalkyl(CMO)alkyl, halo(Ci.io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci_3)alkyl, sulfinyl(Ci-3)alkyl, amino (d.io)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
R9, Rio, Rn and R12 are each independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-io)alkyl, (C3-12)cycloalkyl(Ci-10)alkyl, halo(C1-io)alkyl, carbonyl(Ci.3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (Ci-io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or any two of R7, R8, R9, R1O, Rn and R12 are taken together to form a ring;
Ri3 is selected from the group consisting of hydrogen, carbonyl, amino, (Ci_10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3.12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-io)alkyl, (C3-12)cycloalkyl(Ci.10)alkyl, halo(Ci.io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, amino (d.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, or R13 and any one of R7, R9 and Rn are taken together to form a ring; each R14 is independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C1-io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C].iO)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci-iO)alkyl, heteroaryl(Ci-5)alkyl, perhalo(Ci-10)alkyl, (C3.i2)cycloalkyl(C1-10)alkyl, halo(Ci-,o)alkyl, carbonyl(C,-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted; and
R\5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C1-5)alkyl, (C3_12)cycloalkyl(Ci-10)alkyl, halo(Ci_10)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted.
20. The compound according to claim 1 comprising:
wherein: n is selected from the group consisting of 0, 1, 2,3, 4 and 5;
J is selected from the group consisting of CR6 and N, with the proviso that J is CR6 and R6 is absent when J forms part of a double bond; K is selected from the group consisting of CR6 and N, with the proviso that K is CR6 and R6 is absent when K forms part of a double bond;
L is selected from the group consisting of CR6 and N, with the proviso that L is CR6 and R6 is absent when L forms part of a double bond;
M is selected from the group consisting of S, O and NRi5;
R3 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3.i2)cycloalkyl, hetero(C3_i2)cycloalkyl, (C9_i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(Ci-10)alkyl, halo(C1-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted;
R4 is selected from the group consisting of hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-Io)alkyl, (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(d.io)alkyl, heteroaryl(Ci-5)alkyl, (C3-i2)cycloalkyl(CM0)alkyl, halo(Ci.io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci.3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(C1-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted, with the proviso that R4 is absent when the N to which it is bound forms part of a double bond;
R5 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci-Io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci.io)alkyl, (C3.i2)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero(C3.12)bicycloalkyl, aryl(Ci-io)alkyl, heteroaryl (C i -5)alkyl, perhalo(C u 10)alkyl, (C3- 12)cycloalkyl(C i . i o)alkyl, halo(Ci.i0)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci_3)alkyl, sulfonyl(Ci_3)alkyl, sulfinyl(Ci_3)alkyl, amino (Ci.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted; R6 is selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-io)alkyl, (C3.i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(C1-10)alkyl, heteroaryl(C1-5)alkyl, perhalo(Ci-10)alkyl, (C3-i2)cycloalkyl(Ci.i0)alkyl, halo(Ci.io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1_3)alkyl, sulfinyl(C1-3)alkyl, amino (C|.io)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C9_i2)bicycloaryl, and hetero(C4-12)bicycloaryl, each substituted or unsubstituted; each R]4 is independently selected from the group consisting of hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (Ci.io)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C].1o)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(Ci-5)alkyl, perhalo(C1-1o)alkyl, (C3-i2)cycloalkyl(CMO)alkyl, halo(C1-io)alkyl, carbonyl(C1-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C].3)alkyl, sulfinyl(C1-3)alkyl, amino (C1-1o)alkyl, imino(C)-3)alkyl, aryl, heteroaryl, (C9-12)bicycloaryl, and hetero(C4.i2)bicycloaryl, each substituted or unsubstituted;
R1S is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-io)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, aryl(C1-1o)alkyl, heteroaryl(Ci-5)alkyl, (C3.12)cycloalkyl(Ci_io)alkyl, halo(C1-i0)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci.3)alkyl, aryl, heteroaryl, (C9.i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted;
X is selected from the group consisting of unsubstituted and substituted C1-6 alkylenes; and
Y is selected from the group consisting of (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cg.i^bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl, heteroaryl, (C9-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted.
21. The compound according to any one of claims 1-3 and 10-20, wherein M is S.
22. The compound according to any one of claims 1-3 and 10-20, wherein M is O.
23. The compound according to any one of claims 1-3 and 10-20, wherein M is NR 15 and Rj5 is selected from the group consisting of hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-Io)alkyl, (C3-i2)cycloalkyl, hetero(C3.i2)cycloalkyl, (C9.i2)bicycloalkyl, hetero(C3-i2)bicycloalkyl, aryl(Ci.io)alkyl, heteroaryl(C1-5)alkyl, (C3.12)cycloalkyl(CM0)alkyl, halo(C1-io)alkyl, carbonyl(Ci-3)alkyl, thiocarbonyl(Ci-3)alkyl, sulfonyl(Ci-3)alkyl, sulfinyl(Ci-3)alkyl, imino(Ci-3)alkyl, aryl, heteroaryl, (C^i^bicycloaryl, and hetero(C4.12)bicycloaryl, each substituted or unsubstituted.
24. The compound according to any one of claims 1-3 and 10-23, wherein J, K and L are CR6.
25. The compound according to any one of claims 1 and 7-24, wherein R1 is selected from the group consisting of (C3-12)cycloalkyl, hetero(C3.12)cycloalkyl, (Ccι-12)bicycloalkyl, hetero(C3.]2)bicycloalkyl, aryl, heteroaryl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, each substituted or unsubstituted.
26. The compound according to any one of claims 1 and 7-24, wherein R1 is selected from the group consisting of (C3_6)alkyl, aryl, (C3_9)cycloalkyl, bicycloalkyl and adamantanyl, each unsubstituted or substituted.
27. The compound according to any one of claims 1 and 7-24, wherein Ri is selected from the group consisting of alkylphenyl, halophenyl, alkylhalophenyl, alkoxyphenyl, alkylaminoalkoxyphenyl, heterocycloalkylalkoxyphenyl, alkylaminoalkylphenyl, heterocycloalkylalkylphenyl, cycloalkyl, bicycloalkyl and adamantanyl, each unsubstituted or substituted.
28. The compound according to any one of claims 1 and 7-24, wherein R1 is substituted with a substituent selected from the group consisting of cyano, carboxamido, aminoalkyl, aminoalkoxy, heterocycloalkyl, heterocycloalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aryloxy, heteroaryloxy, bicycloaryl, heterobicycloaryl, bicycloaryloxy, and heterobicycloaryloxy, each unbsubstituted or substituted.
29. The compound according to any one of claims 1-4, 7 and 10-28, wherein R3 is H.
30. The compound according to any one of claims 1-15, 17-19 and 21-29, wherein R7 is H.
31. The compound according to any one of claims 1-15, 17-19 and 21-29, wherein R7 and R8 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heteroaryl, each unsubstituted or substituted.
32. The compound according to any one of claims 1-15, 17-19 and 21-29, wherein R7 and R8 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, alkylaminoalkyl, dialkylaminoalkyl, benzyl, halobenzyl, dihalobenzyl, phenylethyl, pyrimidinylalkyl, pyrazolylalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methylphenyl, dimethylphenyl, ethylphenyl, halophenyl, dihalophenyl, methoxyphenyl, cyanophenyl, haloalkylphenyl, pyridinyl, halopyridinyl, alkoxypyridinyl, tetrahydropyranyl, pyrazolyl and pyrimidinyl, each unsubstituted or substituted.
33. The compound according to any one of claims 1-15, 17-19 and 21-29, wherein R7 and R8 are taken together to form a ring selected from the group consisting of a (C3-i2)cycloalkyl, hetero(C3-i2)cycloalkyl, (Cc,-12)bicycloalkyl, hetero(C3-ι2)bicycloalkyl, aryl, heteroaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted.
34. The compound according to any one of claims 1-4, 7, 10-1517-19 and 21-33, wherein Ri3 is H.
35. The compound according to any one of claims 2, 17-20 and 21-34, wherein Ri4 is selected from the group consisting of cyano, carboxamido, aminoalkyl, aminoalkoxy, heterocycloalkyl, heterocycloalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aryloxy, heteroaryloxy, bicycloaryl, heterobicycloaryl, bicycloaryloxy, and heterobicycloaryloxy, each unsubstituted or substituted.
36. The compound according to any one of claims 2, 17-20 and 21-35, wherein n is 0, l or 2.
37. The compound according to any one of claims 1-4, 7, 16, 20 and 21-36, wherein X is methylene.
38. The compound according to any one of claims 1-4, 7, 16, 20 and 21-37, wherein Y is selected from the group consisting of aryl and heteroaryl, each unsubstituted or substituted.
39. The compound according to any one of claims 1-4, 7, 16, 20 and 21-37, wherein Y is selected from the group consisting of phenyl and pyridinyl, each unsubstituted or substituted.
40. The compound according to any one of claims 1-4, 7, 16, 20 and 21-37, wherein Y is selected from the group consisting of phenyl, halophenyl, dihalophenyl, methylphenyl, dimethylphenyl, cyanophenyl, aminocarboxyphenyl, haloalkylphenyl, alkoxyphenyl and oxopyridinyl.
41. The compound according to claim 1 selected from the group consisting of:
3-Chloro-N-(4-( 1 -hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-(l-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-( 1 -hydroxybutyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-(cyclopropyl(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-( 1 -hydroxy-2-methylpropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-(cyclopentyl(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-(cyclohexyl(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-( 1 -hydroxy-2-phenylethyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-( 1 -hydroxy-3-phenylpropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; -chloro-N-(4-(hydroxy(o-tolyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; -chloro-N-(4-(hydroxy(o-ethylphenyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; -chloro-N-(4-((3-fluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; -chloro-N-(4-((3,4-difluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; -chloro-N-(4-((4-chloro-3-fluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; -chloro-N-(4-((3-chloro-5-fluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide ; -chloro-N-(4-((4-fluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulf onamide ; -chloro-N-(4-(hydroxy(phenyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; -chloro-N-(4-((4-chlorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulf onamide ; -chloro-N-(4-((3-chlorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; -chloro-N-(4-((3-chloro-4-fluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; -chloro-N-(4-((3,5-difluorophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulf onamide ; -chloro-N-(4-(hydroxy(m-tolyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; -chloro-N-(4-((2,3-dimethylphenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; -chloro-N-(4-(hydroxy(2-methoxyphenyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-((4-cyanophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(hydroxy(3-(trifluoromethyl)phenyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide ; 3-chloro-N-(4-(hydroxy(pyridin-2-yl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-((2-chloropyridin-3-yl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(2-(diethylamino)- 1 -hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulf onamide ; 3-chloro-N-(4-(l-hydroxy-2-(pyrimidin-4-yl)ethyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-((3-cyanophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulf onamide ; 3-chloro-N-(4-((2-cyanophenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(hydroxy(3-methoxyphenyl)methyl)thiazol-2-yl)-2- methylbenzenesulf onamide ; (R)-3-chloro-N-(4-(l-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; (S)-3-chloro-N-(4-(l-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; (R)-3-chloro-N-(4-((2-ethylphenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; (S)-3-chloro-N-(4-((2-ethylphenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-{4-[hydroxy-(2-methoxy-pyridin-3-yl)-methyl]-thiazol-2-yl}-
2-methyl-benzenesulfonamide; 3-Chloro-N-{4-[(2-chloro-pyridin-3-yl)-hydroxy-methyl]-thiazol-2-yl}-2- methyl-benzenesulfonamide; 3-Chloro-N-[4-(l-hydroxy-2-pyrimidin-4-yl-ethyl)-thiazol-2-yl]-2-methyl- benzenesulfonamide; l-[2-(3-Chloro-2-methyl-benzenesulfonylmethyl)-thiazol-4-yl]-2- pyridazin-3-yl-ethanol; 3-Chloro-N- { 4- [ 1 -hydroxy-2-(2H-ρyrazol-3-yl)-ethyl] -thiazol-2-yl } -2- methyl-benzenesulfonamide; and 3-Chloro-N- {4-[ 1 -hydroxy-2-( lH-pyrazol-4-yl)-ethyl] -thiazol-2-yl } -2- methyl-benzenesulfonamide.
42. The compound according to claim 1 selected from the group consisting of:
3-chloro-N-(4-(2-hydroxypropan-2-yl)thiazol-2-yl)-2- methylbenzenesulf onamide ; 3-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(4-hydroxyheptan-4-yl)thiazol-2-yl)-2- methylbenzenesulf onamide ; 3-chloro-N-(4-( 1 -hydroxycyclopropyl)thiazol-2-yl)-2- methylbenzenesulf onamide ; 3-chloro-N-(4-( 1 -hydroxycyclopentyl)thiazol-2-yl)-2- methylbenzenesulf onamide ;
N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4-phenoxybenzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-6-phenoxypyridine-3- sulfonamide;
N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)naphthalene-2-sulfonamide; 2,3-dichloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzofuran-2-sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzo[d]thiazole-6-sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzo[b]thiophene-2- sulfonamide;
N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)naphthalene-l-sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-5-methylbenzo[b]thiophene-2- sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2,3-dihydrobenzofuran-5- sulfonamide;
N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)(p-tolyl)methanesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2-oxo-2H-chromene-6- sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2,4-dimethylthiazole-5- sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-5-(oxazol-5-yl)thiophene-2- sulfonamide; 5-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)naphthalene-2- sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzo[b]thiophene-3- sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2,3- dihydrobenzo[b] [ 1 ,4]dioxine-6-sulfonamide; 2-Chloro-4,5-difluoro-N-(4-(3-hydroxypentan-3-yl)thiazol-2- yl)benzenesulfonamide; N-(4-(3-Hydroxypentan-3-yl)thiazol-2-yl)-4-methyl-3,4-dihydro-2H- benzo[b] [ 1 ,4]oxazine-6-sulfonamide; 5-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3- methylbenzo[b]thiophene-2-sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2,5- dimethylbenzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3,4- dimethylbenzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3,4- dimethoxybenzenesulfonamide; N-(4-(N-(4-(3-hydroxypentan-3-yl)thiazol-2- yl)sulfamoyl)phenyl)acetamide; 4-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3- nitrobenzenesulfonamide ; 2-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-5-(trifluoromethyl) benzenesulfonamide; 4,5-dichloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)thiophene-2- sulfonamide;
4-ethyl-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide; 4-propyl-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzo[c][l,2,5]thiadiazole-5- sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3,4-dihydro-2H-benzo[b] [ 1 ,4] dioxepine-7-sulfonamide;
3-bromo-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2-(2,2,2-trifluoroacetyl)-l,2,3,4- tetrahydroisoquinoline-7-sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-l,2,3,4-tetrahydroisoquinoline-7- sulfonamide; 2-fluoro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-5- methylbenzenesulfonamide;
3-cyano-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide; 4-bromo-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2- methylbenzenesulfonamide; 4-bromo-2-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2- yl)benzenesulfonamide; 4-bromo-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2-(trifluoromethyl) benzenesulfonamide; 4-bromo-5-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)thiophene-2- sulfonamide;
4-cyano-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3-nitrobenzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4-nitrobenzenesulfonamide; 2-chloro-4-cyano-N-(4-(3-hydroxypentan-3-yl)thiazol-2- yl)benzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4-(methylsulfonyl) benzenesulfonamide;
N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4-methoxybenzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4-isopropylbenzenesulfonamide; 4-(difluoromethoxy)-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl) benzenesulfonamide; 3-(difluoromethoxy)-N-(4-(3-hydroxypentan-3-yl)thiazol-2- yl)benzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4- isopropoxybenzenesulfonamide; 2-chloro-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4-(trifluoromethyl) benzenesulfonamide;
N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3-methoxybenzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzo[d][l,3]dioxole-5- sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3-oxo-3,4-dihydro-2H- benzo [b] [ 1 ,4] oxazine-6-sulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-4-methyl-3- nitrobenzenesulfonamide;
4-acetyl-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-2-methyl-5- nitrobenzenesulfonamide ;
3-acetyl-N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)benzenesulfonamide; N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)-3-(methylsulfonyl) benzenesulfonamide; and N-(2-chloro-4-(N-(4-(3-hydroxypentan-3-yl)thiazol-2-yl)sulfamoyl) phenyl)acetamide.
43. The compound according to claim 1 selected from the group consisting of:
3-Chloro-N-(4-(2-hydroxypentyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-(2-hydroxy-3-methylbutyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-(2-cyclopentyl-2-hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-(2-hydroxy-2-phenylethyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(2-hydroxy-3,3-dimethylbutyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(2-(3-fluorophenyl)-2-hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(3-(2,5-difluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(3-(4-fluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(3-(2-fluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; (S)-3-chloro-N-(4-(3-(2-fluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; (R)-3-chloro-N-(4-(3-(2-fluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(2-hydroxy-3-phenylpropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; (S)-3-Chloro-N-(4-(2-hydroxy-3-phenylpropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(3-(2,4-difluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(3-(2,6-difluorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(3-(3-chlorophenyl)-2-hydroxypropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(2-cyclopropyl-2-hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulfonamide; (R)-3-Chloro-N-(4-(2-cyclopropyl-2-hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulfonamide; (S)-3-Chloro-N-(4-(2-cycloρropyl-2-hydroxyethyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-(2-hydroxy-3-(pyriirndin-4-yl)propyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 4-Fluoro-N- [4-(2-hydroxy-butyl)-thiazol-2-yl] -2-methyl- benzenesulfonamide;
3-chloro-4-fluoro-iV-(4-(2-hydroxybutyl)thiazol-2-yl)benzenesulfonamide; 3-fluoro-N-(4-(2-hydroxybutyl)thiazol-2-yl)benzenesulfonamide; (R)-3-Chloro-N-(4-(2-hydroxy-3-phenylpropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; N-[4-(2-Hydroxy-butyl)-thiazol-2-yl]-2-methyl-4-(2-morpholin-4-yl- ethoxy)-benzenesulfonamide; N-[4-(2-Hydroxy-butyl)-thiazol-2-yl]-2-niethyl-4-(3-morpholin-4-yl- propoxy)-benzenesulfonamide; 3-Chloro-N-[4-(2-hydroxy-butyl)-thiazol-2-yl]-4-(2-morpholin-4-yl- ethoxy)-benzenesulfonamide; 3-Chloro-N-[4-(2-hydroxy-butyl)-thiazol-2-yl]-4-(3-moφholin-4-yl- propoxy)-benzenesulfonamide; 3-Chloro-N-[4-(2-hydroxy-butyl)-thiazol-2-yl]-5-(2-moq)holin-4-yl- ethoxy) -benzenesulf onamide ; 3-Chloro-N-[4-(2-hydroxy-butyl)-thiazol-2-yl]-5-(3-moφholin-4-yl- propoxy)-benzenesulfonamide; 3-Chloro-N-[4-(2-hydroxy-3-pyridazin-3-yl-propyl)-thiazol-2-yl]-2- methyl-benzenesulfonamide; and 3-Chloro-N-{4-[2-hydroxy-3-(2H-pyrazol-3-yl)-propyl]-thiazol-2-yl}-2- methyl-benzenesulfonamide.
44. The compound according to claim 1 selected from the group consisting of: 3-chloro-N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-Chloro-N-(4-(2-hydroxy-2-propylpentyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 3-chloro-N-(4-((l-hydroxycyclobutyl)methyl)thiazol-2-yl)-2- methylbenzenesulf onamide ; 3-chloro-N-(4-(( 1 -hydroxycyclopentyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; N-[4-(2-Ethyl-2-hydroxy-butyl)-thiazol-2-yl]-4-fluoro-2-methyl- benzenesulfonamide; 4-(2-Dimethylamino-ethoxy)-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-
2-methyl-benzenesulf onamide ; N-[4-(2-Ethyl-2-hydroxy-butyl)-thiazol-2-yl]-2-methyl-4-(2-moφholin-4- yl-ethoxy)-benzenesulfonamide; 4-(3-Dimethylamino-propoxy)-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2- yl]-2-methyl-benzenesulfonamide; 3-chloro-N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-4- fluorobenzenesulf onamide ; 3-Chloro-4-(2-dimethylamino-ethoxy)-N-[4-(2-ethyl-2-hydroxy-butyl)- thiazol-2-yl] -benzenesulf onamide ; 3-Chloro-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-5-(2-moφholin-4- yl-ethoxy)-benzenesulfonamide; 3-Chloro-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-4-(3-morpholin-4- yl-propoxy)-benzenesulfonamide; 3-Chloro-4-(3-dimethylamino-propoxy)-N-[4-(2-ethyl-2-hydroxy-butyl)- thiazol-2-yl]-benzenesulfonamide; N-[4-(2-Ethyl-2-hydroxy-butyl)-thiazol-2-yl]-2-methyl-4-(3-morpholin-4- yl-propoxy)-benzenesulfonamide;
N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-4-fluorobenzenesulfonamide; N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-3-fluorobenzenesulfonamide; N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-3-(3-moφholinopropoxy) benzenesulfonamide; N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl)-4-(3-moφholinopropoxy) benzenesulfonamide ; 4-(3-(dimethylamino)propoxy)-N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl) benzenesulfonamide ; 3-(3-(dimethylamino)propoxy)-N-(4-(2-ethyl-2-hydroxybutyl)thiazol-2-yl) benzenesulfonamide ; 3-chloro-N-(4-((4-hydroxy-tetrahydro-2H-pyran-4-yl)methyl)thiazol-2-yl)-
2-methylbenzenesulfonamide; 4-bromo-N-(4-(( 1 -hydroxycyclobutyl)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide; N-[4-(l-Hydroxy-cyclopentylmethyl)-thiazol-2-yl]-2-methyl-4-(3- morpholin-4-yl-propoxy) -benzenesulfonamide ; N-[4-(l-Hydroxy-cyclohexylmethyl)-thiazol-2-yl]-2-methyl-4-(3- moφholin-4-yl-propoxy)-benzenesulfonamide; 3-Chloro-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-4-(2-morpholin-4- yl-ethoxy)-benzenesulfonamide; 3-Chloro-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-5-(3-morpholin-4- yl-propoxy)-benzenesulfonamide; 3-Chloro-4-(2-dimethylamino-ethoxy)-N-[4-( 1 -hydroxy- cyclopentylmethyl)-thiazol-2-yl]-benzenesulfonamide; 3-Chloro-4-(2-dimethylamino-ethoxy)-N-[4-(l-hydroxy- cyclohexylmethyl)-thiazol-2-yl]-benzenesulfonamide; 3-Chloro-5-(2-dimethylamino-ethoxy)-N-[4-(2-ethyl-2-hydroxy-butyl)- thiazol-2-yl] -benzenesulfonamide; 3-Chloro-5-(3-dimethylamino-propoxy)-N-[4-(2-ethyl-2-hydroxy-butyl)- thiazol-2-yl]-benzenesulfonamide; 3-Chloro-2-methyl-N-[4-(4-methyl-tetrahydro-pyran-4-ylmethyl)-thiazol-2- yl] -benzenesulf onamide ; N-[4-(2-Ethyl-2-hydroxy-butyl)-thiazol-2-yl]-2-methyl-4-(3-morpholin-4- yl-propyl)-benzenesulfonamide; N-[4-(2-Ethyl-2-hydroxy-butyl)-thiazol-2-yl]-2-methyl-4-(4-morpholin-4- yl-butyl)-benzenesulfonamide; 4-(3-Dimethylamino-propyl)-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-
2-methyl-benzenesulfonaniide; 4-(4-Dimethylamino-butyl)-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-
2-methyl-benzenesulf onamide ; 2-Chloro-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-4-(3-morpholin-4- yl-propyl)-benzenesulfonamide; 2-Chloro-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-4-(4-morpholin-4- yl-butyl)-benzenesulfonamide; 2-Chloro-4-(3-dimethylamino-propyl)-N-[4-(2-ethyl-2-hydroxy-butyl)- thiazol-2-yl]-benzenesulfonamide; 2-Chloro-4-(4-dimethylamino-butyl)-N-[4-(2-ethyl-2-hydroxy-butyl)- thiazol-2-yl]-benzenesulfonamide; N-[4-(2-Ethyl-2-hydroxy-butyl)-thiazol-2-yl]-4-(3-moφholin-4-yl-propyl)-
2-trifluoromethyl-benzenesulfonamide; N-[4-(2-Ethyl-2-hydroxy-butyl)-thiazol-2-yl]-4-(4-moφholin-4-yl-butyl)-
2-trifluoromethyl-benzenesulfonamide; 4-(3-Dimethylamino-propyl)-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-
2-trifluoromethyl-benzenesulfonamide; 4-(4-Dimethylamino-butyl)-N-[4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-
2-trifluoromethyl-benzenesulfonamide; Cyclopropanesulfonic acid [4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]- amide; Cyclopentanesulfonic acid [4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl] - amide; Cyclohexanesulfonic acid [4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl] - amide; Cycloheptanesulfonic acid [4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl] - amide; Cyclopropanesulfonic acid [4-( 1 -hydroxy-cyclopentylmethyl)-thiazol-2- yl]-amide; Cyclopropanesulfonic acid [4-( 1 -hydroxy-cyclohexylmethyl)-thiazol-2-yl] - amide; Adamantane- 1 -sulfonic acid [4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]- amide; Adamantane- 1 -sulfonic acid [4-( 1 -hydroxy-cyclopentylmethyl)-thiazol-2- yl]-amide; Adamantane- 1 -sulfonic acid [4-( 1 -hydroxy-cyclohexylmethyl)-thiazol-2- yl]-amide; Bicyclo[2.2.2]octane-1 -sulfonic acid [4-(2-ethyl-2-hydroxy-butyl)-thiazol-
2-yl]-amide;
Ethanesulfonic acid [4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl]-amide; Ethanesulfonic acid [4-( l-hydroxy-cyclopentylmethyl)-thiazol-2-yl]-amide; Ethanesulfonic acid [4-(l-hydroxy-cyclohexylmethyl)-thiazol-2-yl]-amide; Propane- 1 -sulfonic acid [4-(2-ethyl-2-hydroxy-butyl)-thiazol-2-yl] -amide; and 2-Methyl-propane-2-sulfonic acid [4-(2-ethyl-2-hydroxy-butyl)-thiazol-2- yl]-amide.
45. The compound according to claim 1 selected from the group consisting of:
(S)-3-chloro-N-(4-(3-hydroxy-3-phenylpropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; (R)-3-chloro-N-(4-(3-hydroxy-3-phenylpropyl)thiazol-2-yl)-2- methylbenzenesulfonamide; 4-Fluoro-N-[4-(3-hydroxy-pentyl)-thiazol-2-yl]-2-methyl- benzenesulfonamide; N-[4-(3-Ethyl-3-hydroxy-pentyl)-thiazol-2-yl]-4-fluoro-2-methyl- benzenesulfonamide; 4-(2-Dimethylamino-ethoxy)-N-[4-(3-ethyl-3-hydroxy-pentyl)-thiazol-2- yl]-2-methyl-benzenesulfonamide; N-[4-(3-Ethyl-3-hydroxy-pentyl)-thiazol-2-yl]-2-methyl-4-(2-morpholin-4- yl-ethoxy)-benzenesulfonamide; and N- { 4-[2-( 1 -Hydroxy-cyclohexyl)-ethyl]-thiazol-2-yl } -2-methyl-4-(3- morpholin-4-yl-propoxy)-benzenesulfonamide.
46. The compound according to claim 1 selected from the group consisting of:
N-(4-(4-fluorobenzyl)thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide;
N-(4-benzylthiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide;
N-(4-(4-chlorobenzyl)thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide;
N-(4-(3-chlorobenzyl)thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide;
N-(4-(3-chloro-4-fluorobenzyl)thiazol-2-yl)-3-chloro-2- methylbenzenesulfonamide; N-(4-(3,5-difluorobenzyl)thiazol-2-yl)-3-chloro-2- methylbenzenesulfonamide;
3-chloro-N-(((m-tolyl)methyl)thiazol-2-yl)-2-methylbenzenesulfonamide; 3-chloro-N-(4-((2,5-dimethylphenyl)(hydroxy)methyl)thiazol-2-yl)-2- methylbenzenesulfonamide;
3-chloro-N-(((o-tolyl)methyl)thiazol-2-yl)-2-methylbenzenesulfonamide; N-(4-(4-cyanobenzyl)thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide; 4-((2-(3-chloro-2-methylphenylsulfonamido)thiazol-4- yl)methyl)benzamide;
N-(4-(3-cyanobenzyl)thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide; 3-((2-(3-chloro-2-methylphenylsulfonamido)thiazol-4- yl)methyl)benzamide; N-(4-(3-(trifluoromethyl)benzyl)thiazol-2-yl)-3-chloro-2- methylbenzenesulfonamide; 3-chloro-2-methyl-N-(4-((2-oxopyridin-l(2H)-yl)methyl)thiazol-2- yl)benzenesulfonamide; and N-(4-(3 -methoxybenzyl)thiazol-2-yl)-3 -chloro-2- methylbenzenesulfonamide.
47. The compound according to any one of claims 1-46, wherein the compound is in the form of a pharmaceutically acceptable salt.
48. The compound according to any one of claims 1-47, wherein the compound is present in a mixture of stereoisomers.
49. The compound according to any one of claims 1-47, wherein the compound comprises a single stereoisomer.
50. A pharmaceutical composition comprising as an active ingredient a compound according to any one of claims 1-49.
51. The pharmaceutical composition according to claim 50, wherein the composition is a solid formulation adapted for oral administration.
52. The pharmaceutical composition according to claim 50, wherein the composition is a liquid formulation adapted for oral administration.
53. The pharmaceutical composition according to claim 50, wherein the composition is a tablet.
54. The pharmaceutical composition according to claim 50, wherein the composition is a liquid formulation adapted for parenteral administration.
55. A pharmaceutical composition comprising a compound according to any one of claims 1-49, wherein the composition is adapted for administration by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, and intrathecally.
56. A kit comprising: a compound of any one of claims 1-49; and instructions which comprise one or more forms of information selected from the group consisting of indicating a disease state for which the composition is to be administered, storage information for the composition, dosing information and instructions regarding how to administer the composition.
57. The kit of claim 56, wherein the kit comprises the compound in a multiple dose form.
58. An article of manufacture comprising: a compound of any one of claims 1-49; and packaging materials.
59. The article of manufacture of claim 58, wherein the packaging material comprises a container for housing the compound.
60. The article of manufacture of claim 59, wherein the container comprises a label indicating one or more members of the group consisting of a disease state for which the compound is to be administered, storage information, dosing information and/or instructions regarding how to administer the compound.
61. The article of manufacture of claim 58, wherein the article of manufacture comprises the compound in a multiple dose form.
62. A therapeutic method comprising administering a compound of any one of claims 1-49 to a subject.
63. A method of inhibiting HSD comprising contacting HSD with a compound of any one of claims 1-49.
64. A method of inhibiting HSD comprising causing a compound of any one of claims 1-49 to be present in a subject in order to inhibit HSD in vivo.
65. A method of inhibiting HSD comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits HSD in vivo, the second compound being a compound according to any one of claims 1-49.
66. A method of treating a disease state for which HSD possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising causing a compound of any one of claims 1-49 to be present in a subject in a therapeutically effective amount for the disease state.
67. A method of treating a disease state for which HSD possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising administering a compound of any one of claims 1-49 to a subject, wherein the compound is present in the subject in a therapeutically effective amount for the disease state.
68. A method of treating a disease state for which HSD possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits HSD in vivo, the second compound being a compound according to any one of claims 1-49.
69. The method according to any one of claims 66-68, wherein the disease state is selected from the group consisting of the metabolic syndrome, Cushing's disease, hypertension, cognitive function, and ocular function.
70. The method according to any one of claims 63-69, wherein the HSD is an 1 Ib- HSDl.
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Families Citing this family (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8415354B2 (en) 2004-04-29 2013-04-09 Abbott Laboratories Methods of use of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US20100222316A1 (en) 2004-04-29 2010-09-02 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US7880001B2 (en) 2004-04-29 2011-02-01 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
US8198331B2 (en) 2005-01-05 2012-06-12 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
KR101496206B1 (en) 2005-01-05 2015-02-27 애브비 인코포레이티드 Adamantyl derivatives as inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
US7217838B2 (en) 2005-01-05 2007-05-15 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US20090192198A1 (en) 2005-01-05 2009-07-30 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
CA2607670A1 (en) 2005-05-10 2006-11-16 Vertex Pharmaceuticals Incorporated Bicyclic derivatives as modulators of ion channels
PE20080251A1 (en) 2006-05-04 2008-04-25 Boehringer Ingelheim Int USES OF DPP IV INHIBITORS
RU2009108280A (en) 2006-08-08 2010-09-20 Санофи-Авентис (Fr) Arylamino-arylalkyl-substituted imidazolidine-2,4-dione, methods for their preparation containing these compounds and their use
WO2009001817A1 (en) 2007-06-27 2008-12-31 Taisho Pharmaceutical Co., Ltd. COMPOUND HAVING 11β-HSD1 INHIBITORY ACTIVITY
EP2025674A1 (en) 2007-08-15 2009-02-18 sanofi-aventis Substituted tetra hydro naphthalines, method for their manufacture and their use as drugs
JP5736098B2 (en) 2007-08-21 2015-06-17 アッヴィ・インコーポレイテッド Pharmaceutical composition for treating central nervous system disorders
WO2010003624A2 (en) 2008-07-09 2010-01-14 Sanofi-Aventis Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof
WO2010068601A1 (en) 2008-12-08 2010-06-17 Sanofi-Aventis A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof
WO2011023754A1 (en) 2009-08-26 2011-03-03 Sanofi-Aventis Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use
WO2011107494A1 (en) 2010-03-03 2011-09-09 Sanofi Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof
JP5960683B2 (en) 2010-04-28 2016-08-02 バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングＢａｙｅｒ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ ＧｍｂＨ Ketoheteroarylpiperidine and -piperazine derivatives as fungicides
WO2011157827A1 (en) 2010-06-18 2011-12-22 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
US8530413B2 (en) 2010-06-21 2013-09-10 Sanofi Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments
TW201215387A (en) 2010-07-05 2012-04-16 Sanofi Aventis Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament
TW201215388A (en) 2010-07-05 2012-04-16 Sanofi Sa (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments
TW201221505A (en) 2010-07-05 2012-06-01 Sanofi Sa Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
EP2683701B1 (en) 2011-03-08 2014-12-24 Sanofi Oxathiazine derivatives substituted with benzyl or heteromethylene groups, method for their preparation, their usage as medicament, medicament containing same and its use
EP2683698B1 (en) 2011-03-08 2017-10-04 Sanofi Benzyl-oxathiazine derivates substituted with adamantane or noradamantane, medicaments containing said compounds and use thereof
US8828995B2 (en) 2011-03-08 2014-09-09 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
EP2683700B1 (en) 2011-03-08 2015-02-18 Sanofi Tetra-substituted oxathiazine derivatives, method for their preparation, their usage as medicament and medicament containing same and its use
WO2012120057A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
US8809324B2 (en) 2011-03-08 2014-08-19 Sanofi Substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
EP2760862B1 (en) 2011-09-27 2015-10-21 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
TW201512171A (en) 2013-04-19 2015-04-01 Pfizer Ltd Chemical compounds
TN2018000385A1 (en) 2016-05-20 2020-06-15 Xenon Pharmaceuticals Inc Benzenesulfonamide compounds and their use as therapeutic agents
TN2019000175A1 (en) * 2016-12-09 2020-10-05 Xenon Pharmaceuticals Inc Benzenesulfonamide compounds and their use as therapeutic agents
MX2020013317A (en) 2018-06-13 2021-04-13 Xenon Pharmaceuticals Inc Benzenesulfonamide compounds and their use as therapeutic agents.
WO2020047312A1 (en) 2018-08-31 2020-03-05 Xenon Pharmaceuticals Inc. Heteroaryl-substituted sulfonamide compounds and their use as sodium channel inhibitors
US10981905B2 (en) 2018-08-31 2021-04-20 Xenon Pharmaceuticals Inc. Heteroaryl-substituted sulfonamide compounds and their use as therapeutic agents

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE0001899D0 (en) * 2000-05-22 2000-05-22 Pharmacia & Upjohn Ab New compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006066109A2 *

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