JP2008524244A - Hydroxyl steroid dehydrogenase inhibitor - Google Patents

Hydroxyl steroid dehydrogenase inhibitor Download PDF

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JP2008524244A
JP2008524244A JP2007546949A JP2007546949A JP2008524244A JP 2008524244 A JP2008524244 A JP 2008524244A JP 2007546949 A JP2007546949 A JP 2007546949A JP 2007546949 A JP2007546949 A JP 2007546949A JP 2008524244 A JP2008524244 A JP 2008524244A
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alkyl
hetero
cycloalkyl
yl
bicycloaryl
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カルドール、スティーヴン、ダブリュ.
キリヤノフ、アンドレ、エー.
ジェニングス、アンドリュー、ジェイ.
スタフォード、ジェフリー、エー.
チャン、エドコン
ブレナン、ナンシー、ケイ.
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タケダ サン ディエゴ インコーポレイテッド
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Priority to PCT/US2005/045704 priority patent/WO2006066109A2/en
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D277/00Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20Heterocyclic 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
    • C07D277/32Heterocyclic 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
    • C07D277/38Nitrogen atoms
    • C07D277/50Nitrogen atoms bound to hetero atoms
    • C07D277/52Nitrogen atoms bound to hetero atoms to sulfur atoms, e.g. sulfonamides
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic 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
    • C07D417/02Heterocyclic 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
    • C07D417/06Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic 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
    • C07D417/02Heterocyclic 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
    • C07D417/12Heterocyclic 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

Abstract

Less than:

(Wherein the substituents are as defined herein)
Provided are compounds, pharmaceutical compositions, kits and methods for use against dehydrated oxidative steroid dehydrogenase comprising a compound selected from the group consisting of:
[Selection figure] None

Description

FIELD OF THE INVENTION This invention relates to compounds that can be used to inhibit hydroxyl steroid dehydrogenase and compositions and kits containing these compounds. The present invention also relates to methods and therapeutic methods for inhibiting hydroxyl steroid dehydrogenase using the compounds of the present invention. In particular, the present invention relates to 11β-hydroxysteroid dehydrogenase type 1 inhibitors, compositions and kits comprising these compounds and methods for inhibiting 11β-hydroxysteroid dehydrogenase type 1.

Description of Related Art The present invention relates to inhibitors of enzymes that catalyze the interconversion of active and inactive glucocorticoids, compositions comprising the inhibitors, kits and products comprising the inhibitors and compositions, and the inhibition The present invention relates to a method for producing an agent and a composition, and a method for using the inhibitor and the composition. Inhibitors and compositions containing them treat or modulate the effects of diseases involving enzymes that catalyze interconversion of glucocorticoids, symptoms of such diseases or other physiological phenomena mediated by those enzymes. Useful for. Accordingly, the present invention also provides a method for treating diseases involving one or more enzymes that catalyze interconversion of glucocorticoids.

  Short chain dehydrogenase / reductase is a reversible NAD (H) / NADP (H) -dependent oxidoreductase family that interconverts active and inactive glucocorticoids. For example, 11β-hydroxysteroid dehydrogenase type 1 (11b-HSD1) belongs to the enzyme family of short chain dehydrogenase / reductase. In particular, 11b-HSD1 converts active and inactive glucocorticoids in a number of neural tissues and organs including adipose tissue, liver, bone, pancreas, endothelium, eye tissue, muscle and parts of the central nervous system. Catalyze (Hosfield et al., J. Biol. Chem., Forthcoming).

  11b-HSD1 has been implicated in metabolic syndrome and type 2 diabetes in many studies. The non-specific 11b-HSD1 inhibitor carbenoxolone increases insulin sensitivity in healthy and slender people as well as those with symptoms of type 2 diabetes. Mice overexpressing 11b-HSD1 in adipocytes become hyperlipidemic, insulin resistant and visceral obesity. This phenotype has been shown to resemble the human metabolic syndrome (Andrews et al., J. Clin. Endocrinol. Metab., 88, 285 (2003)). Mice knocked out of 11b-HSD1 have been shown not only to exhibit decreased HDL-cholesterol and VLDL triglycerides, but are also resistant to becoming obesity- and stress-induced insulin resistance. These findings have stimulated interest in inhibitors of 11b-HSD1 as potential drugs in the treatment of diseases where a reduction in the amount of active intracellular glucocorticoid is desired.

  There is a continuing need to find new therapeutics to treat human diseases. Hydroxysteroid dehydrogenases (especially including but not limited to 11β-hydroxysteroid dehydrogenase type 1) are those in metabolic syndrome, Cushing's disease, hypertension, cognitive function, visual function and other diseases. Because of its important role, it is a particularly attractive subject for the discovery of new therapies.

SUMMARY OF THE INVENTION The present invention relates to a compound having activity of inhibiting hydroxyl steroid dehydrogenase. The present invention also provides compositions, products and kits comprising these compounds.

  In one embodiment, a pharmaceutical composition is provided that comprises a hydroxylated steroid dehydrogenase inhibitor of the present invention as an active ingredient. The pharmaceutical composition of the present invention may optionally contain 0.001% to 100% of one or more hydroxylated steroid dehydrogenase inhibitors of the present invention. These pharmaceutical compositions are, for example, oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, oral cavity, intranasal, liposome, trans-inhalation, vaginal, intraocular, It can be administered or co-administered by a wide variety of routes, including translocal delivery (eg, by catheter or stent), subcutaneous, intrafat, intra-articular, or intrathecal. The composition can also be administered or co-administered in a sustained release dosage form.

  The invention also relates to kits and other products for treating disease states associated with hydroxylated steroid dehydrogenase.

  In one embodiment, a kit is provided that comprises a composition comprising at least one hydroxylated steroid dehydrogenase inhibitor of the present invention along with instructions for use. The instructions may indicate the disease state for which the composition is to be administered, storage information, dosage information and / or instructions regarding how to administer the composition. The kit can also include packaging material. The packaging material may constitute a container for containing the composition. The kit can also optionally include additional elements such as a syringe for administration of the composition. The kit may contain the composition in single or multiple dosage forms.

  In another embodiment, an article of manufacture is provided that includes a composition comprising at least one hydroxylated steroid dehydrogenase inhibitor of the present invention along with packaging material. The packaging material may constitute a container for containing the composition. The container may optionally include a label indicating the disease state for which the composition is to be administered, storage information, dosage information, and / or instructions regarding how to administer the composition. The kit can also optionally include additional elements such as a syringe for administration of the composition. The kit may contain the composition in single or multiple dosage forms.

  Also provided are methods for preparing the compounds, compositions and kits of the invention. For example, several synthetic schemes for synthesizing the compounds of the present invention are provided herein.

  Also provided are methods for using the compounds, compositions, kits and products of the invention.

  In one embodiment, the compounds, compositions, kits and products are used to inhibit hydroxyl steroid dehydrogenase. In particular, the compounds, compositions, kits and products can be used to inhibit 11-beta hydroxyl steroid dehydrogenase type 1.

  In another embodiment, the compounds, compositions, kits and products are used to treat a disease state in which hydroxylated steroid dehydrogenase has an activity that contributes to the pathology and / or symptomology of the disease state. Is done.

  In another embodiment, the compound is administered to a subject whose hydroxyl steroid dehydrogenase activity is altered, preferably decreased, in the subject.

  In another embodiment, a prodrug of a compound that is converted to the compound in vivo (where the compound inhibits hydroxyl steroid dehydrogenase) is administered to the subject.

  In another embodiment, a method of inhibiting hydroxyl steroid dehydrogenase is provided, comprising contacting the hydroxyl steroid dehydrogenase with a compound of the invention.

  In another embodiment, a method of inhibiting hydroxyl steroid dehydrogenase is provided comprising the step of presenting a compound of the invention in a subject to inhibit hydroxyl steroid dehydrogenase in vivo. .

  In another embodiment, a method of inhibiting hydroxylated steroid dehydrogenase comprising administering to a subject a first compound that is converted to a second compound in vivo, said second compound Provides a method of inhibiting hydroxylated steroid dehydrogenase in vivo. It is noted that the compound of the present invention may be the first compound or the second compound.

  In another embodiment, a therapeutic method is provided that comprises administering a compound of the invention.

  In another embodiment, known to be mediated by hydroxylated steroid dehydrogenase or comprising hydroxylated steroid dehydrogenase inhibition comprising administering to a patient a therapeutically effective amount of a compound of the invention. A method of treating a condition in a patient known to be treated with an agent is provided.

  In another embodiment, a method for treating a disease state in which hydroxylated steroid dehydrogenase has an activity that contributes to the pathology and / or symptomology of the disease state, wherein the compound of the invention is treated with the disease state. A method comprising the step of presenting in a subject in a therapeutically effective amount.

  In another embodiment, a method for treating a disease state wherein hydroxylated steroid dehydrogenase has an activity that contributes to the pathology and / or symptomatology of the disease state, wherein the method is converted in vivo to a second compound. Administering a first compound to the subject, such that the second compound is present in the subject in a therapeutically effective amount for the disease state. It is noted that the compound of the present invention may be the first compound or the second compound.

  In another embodiment, a method for treating a disease state in which hydroxylated steroid dehydrogenase has an activity that contributes to the pathology and / or symptomatology of the disease state, wherein the compound of the invention is administered to a subject. Providing a method wherein the compound is present in the subject in a therapeutically effective amount for the disease state.

  In another embodiment, for use in the treatment of disease states known to be mediated by hydroxylated steroid dehydrogenase or known to be treated with a hydroxylated steroid dehydrogenase inhibitor. Methods are provided for using the compounds of the present invention for the manufacture of a medicament.

  For all of the above embodiments, it is well known in the art to administer an ionized or solvated form of the drug, so that all pharmaceutically acceptable ionized forms (eg, salts) and solvents of the compound. It is noted that solvates (eg, hydrates) are intended to be encompassed by the present invention, whether such ionized forms and solvates are specified. Where no specific stereochemistry is specified, a list of compounds includes all possible stereoisomers regardless of whether the compound exists as an individual isomer or a mixture of isomers (e.g., It is also noted that it is intended to include enantiomers or diastereomers depending on the number of chiral centers. Furthermore, unless otherwise specified, the listing of compounds is intended to encompass all possible resonance forms and tautomers. With respect to the claims, the wording “compound containing formula” means that the compound, and all pharmaceutically acceptable ionized forms and solvents, unless specifically stated otherwise in a particular claim. It is intended to encompass all possible stereoisomers, as well as all possible stereoisomers and tautomers.

  It is further noted that prodrugs that can be modified in vivo to become compounds of the invention can also be administered. Various methods of using the compounds of the invention are intended to include the administration of prodrugs that are converted in vivo to the compounds of the invention, regardless of whether prodrug delivery is specified. It is also noted that certain compounds of the present invention can be modified in vivo prior to inhibiting hydroxyl steroid dehydrogenase and thus can themselves be prodrugs of another compound. Such a prodrug of another compound may or may not have hydroxysteroid dehydrogenase inhibitory activity independently.

If listed defined differently as, the following terms used in the specification and claims, for the purposes of this application shall have the following meanings.

“Alicyclic” means a moiety containing a non-aromatic ring structure. The alicyclic moiety may be saturated or partially unsaturated with one, two or more double or triple bonds. The alicyclic moiety may also optionally contain heteroatoms such as nitrogen, oxygen and sulfur. The nitrogen atom can optionally be quaternized or oxidized, and the sulfur atom can optionally be oxidized. Examples of alicyclic moieties include moieties having a C 3-8 ring such as cyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene, cycloheptadiene, Examples include, but are not limited to, cyclooctane, cyclooctene, and cyclooctadiene.

  “Aliphatic” means a moiety characterized by a linear or branched arrangement of constituent carbon atoms and, even if saturated, a moiety having one, two or more double or triple bonds It may be unsaturated.

“Alkoxy” means an oxygen moiety having a further alkyl substituent. The alkoxy groups of the present invention can be optionally substituted.

“Alkyl” by itself means a straight or branched, saturated or unsaturated aliphatic group having a chain of carbon atoms, optionally oxygen (see “oxaalkyl”) or nitrogen atoms (“aminoalkyl” )) Between the carbon atoms. Typically, C X alkyl and C XY alkyl are used, where X and Y indicate the number of carbon atoms in the chain. For example, C 1-6 alkyl includes alkyl having a chain of 1 to 6 carbons (eg, 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 (as in arylalkyl, heteroarylalkyl) shown with another group means a straight or branched saturated or unsaturated aliphatic divalent group having the indicated number of atoms. Or when no atom is shown, it means a bond (eg (C 6-10 ) aryl (C 1-3 ) alkyl includes benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2 -Thienylmethyl, 2-pyridinylmethyl, etc.).

  “Alkenyl” means a straight or branched carbon atom chain having 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.

  “Alkynyl” means a straight or branched carbon atom chain having at least one carbon-carbon triple bond. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.

"Alkylene" means a straight or branched saturated or unsaturated aliphatic divalent group unless otherwise indicated. Typically, C X alkylene and C XY alkylene are used, where X and Y indicate the number of carbon atoms in the chain. For example, as C 1-6 alkylene, methylene (—CH 2 —), ethylene (—CH 2 CH 2 —), trimethylene (—CH 2 CH 2 CH 2 —), tetramethylene (—CH 2 CH 2 CH 2). CH 2 -) 2-butenylene (-CH 2 CH = CHCH 2 - ), 2- methyl-tetramethylene (-CH 2 CH (CH 3) CH 2 CH 2 -), pentamethylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -) and the like.

“Alkylidene” means a straight or branched saturated or unsaturated aliphatic group attached to the parent molecule by a double bond. Typically, C X alkylidene and C XY alkylidene are used, where X and Y indicate the number of carbon atoms in the chain. For example, as C 1-6 alkylidene, methylene (= CH 2 ), ethylidene (= CHCH 3 ), isopropylidene (= C (CH 3 ) 2 ), propylidene (= CHCH 2 CH 3 ), arylidene (= CH— CH = CH 2 ) and the like.

“Amino” means a nitrogen moiety having two additional substituents (eg, a hydrogen or carbon atom attached to the nitrogen). For example, representative amino groups include —NH 2 , —NHCH 3 , —N (CH 3 ) 2 , —NHC 1-10 -alkyl, —N (C 1-10 -alkyl) 2 , —NHaryl, -NH heteroaryl, -N (aryl) 2 , -N (heteroaryl) 2, etc. are mentioned. Optionally, two substituents that both have nitrogen can form a ring. Unless indicated differently, compounds of the invention containing an amino moiety may include protected derivatives thereof. Suitable protecting groups for the amino moiety include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.

“Aminoalkyl” means an alkyl as defined above except that one or more substituted or unsubstituted nitrogen atoms (—N—) are located between carbon atoms of the alkyl. For example, (C 2-6 ) aminoalkyl refers to a chain comprising 2 to 6 carbons and one or more nitrogen atoms disposed between carbon atoms.

  “Animals” include humans, non-human mammals (eg, dogs, cats, rabbits, cows, horses, sheep, goats, pigs, deer, etc.) and non-mammals (eg, birds, etc.).

“Aromatic” refers to a moiety in which the constituent atoms form an unsaturated ring system, all atoms in the ring system are sp 2 hybridized and the total number of π electrons is equal to 4n + 2. The aromatic ring may be one in which the ring atoms are only carbon atoms, or may include carbon atoms and non-carbon atoms (see heteroaryl).

“Aryl” refers to a monocyclic or polycyclic ring assembly that forms an aromatic ring assembly when each ring is aromatic or fused to one or more rings. means. When one or more ring atoms is not carbon (eg, N, S), aryl is heteroaryl. Typically, C X aryl and C XY aryl are 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 in which the rings are connected by a single bond or fused together and at least one of the members of the assembly is aromatic. Typically, C X bicycloaryl and C XY bicycloaryl are used, where X and Y indicate the number of carbon atoms directly attached to the ring in the bicyclic ring assembly.

  As used herein, a “bridged ring” is bonded to another ring to form a compound having a bicyclic structure in which the two ring atoms common to both rings are not directly bonded to each other. Refers to the ring to be. Non-limiting examples of common compounds having a bridged ring include borneol, norbornane, 7-oxabicyclo [2.2.1] heptane and the like. One or both rings of the bicyclic system can also contain heteroatoms.

“Carbamoyl” refers to the group —OC (O) NR a R b , where R a and R b are, independently of each other, two additional substituents in which a hydrogen or carbon atom is bonded to nitrogen. Means.

  “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 group can be further substituted with various 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 present invention that include a carboxy moiety may include protected derivatives thereof (ie, when oxygen is replaced with a protecting group). Suitable protecting groups for the carboxy moiety include benzyl, tert-butyl and the like.

  “Cyano” refers to the group —CN.

“Cycloalkyl” means a non-aromatic saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly. Typically, C X cycloalkyl and C XY cycloalkyl are used, where X and Y indicate the number of carbon atoms in the ring assembly. For example, C 3-10 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-1-yl, and the like.

“Cycloalkylene” means a divalent saturated or partially unsaturated monocyclic or polycyclic ring assembly. Typically, C X cycloalkylene and C XY cycloalkylene are used, where X and Y indicate the number of carbon atoms in the ring assembly.

  A “disease” specifically includes any unhealthy condition or part of an animal, and can be caused by or associated with medical or veterinary therapy applied to the animal. Includes conditions (ie, “side effects” of such therapies).

  As used herein, a “fused ring” refers to a ring that is bonded to another ring to form a compound having a bicyclic structure in which ring atoms common to both rings are directly bonded to each other. . Non-limiting examples of common fused rings include decalin, naphthalene, anthracene, phenanthrene, indole, furan, benzofuran, quinoline and the like. A compound having a fused ring system can be saturated, partially saturated, carbocyclic, heterocyclic, aromatic, heteroaromatic, and the like.

  “Halo” means fluoro, chloro, bromo or iodo.

“Halo-substituted alkyl” means “alkyl” substituted as an isolated group or as part of a larger group by one or more “halo” atoms, as that term is defined herein. . Examples of the halo-substituted alkyl include haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (for example, halo-substituted (C 1-3 ) alkyl includes chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2, 2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, etc.).

  “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 bound by that moiety is not carbon. Examples of heteroatom moieties include —N═, —NR c —, —N + (O ) ═, —O—, —S—, or —S (O) 2 —, where R c Is a further substituent.

“Heterobicycloalkyl” means bicycloalkyl as defined herein, provided that one or more atoms in the ring are heteroatoms. For example, as hetero (C 9-12 ) bicycloalkyl used in the present application, 3-aza-bicyclo [4.1.0] hept-3-yl, 2-aza-bicyclo [3.1.0] hexa 2-yl, 3-aza-bicyclo [3.1.0] hex-3-yl, and the like, but are not limited thereto.

  “Heterocycloalkylene” means cycloalkylene, as defined herein, provided that one or more ring member carbon atoms are replaced with a heteroatom.

  “Heteroaryl” means a cyclic aromatic group having 5 or 6 ring atoms, wherein at least one ring atom is a heteroatom and the remaining ring atoms are carbon. Nitrogen atoms can optionally be quaternized and sulfur atoms can optionally be oxidized. Examples of the heteroaryl group of the present invention include furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrroline, thiazole, 1, Examples derived from 3,4-thiadiazole, triazole, and tetrazole include, but are not limited to. “Heteroaryl” also includes, but is not limited to, bicyclic or tricyclic rings, where a heteroaryl ring includes an aryl ring, a cycloalkyl ring, a cycloalkenyl ring, and another single ring. Fused to one or two rings independently selected from the group consisting of cyclic heteroaryl or heterocycloalkyl rings. These bicyclic or tricyclic heteroaryls include 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 [1,2a] pyridine, quinoline, isoquinoline, phthalazine, quinoxaline, naphthyridine, quinolidine, indole, isoindole, indazole , Indoline, benzoxazole, benzopyrazole, benzothiazole, imidazo [1,5-a] pyridine, pyrazolo [1,5-a] pyridine, imidazo [1,2-a] pyrimidine, imidazo [1,2-c] Pyrimidine, imidazo [1,5-a] pyrimidine, imidazo [1,5-c] pi Midine, 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 [1,5-a] pyridine, pyrrolo [1,2-b] pyridazine, pyrrolo [1,2-c] Pyrimidine, pyrrolo [1,2-a] pyrimidine, pyrrolo [1,2-a] pyrazine, triazo [1,5-a] pyridine, pteridine, purine, carbazole, acridine, phenazine, phenothiazene, phenoxazine, Derived from 1,2-dihydropyrrolo [3,2,1-hi] indole, indolizine, pyrido [1,2-a] indole and 2 (1H) -pyridinone Those including but not limited to. The bicyclic or tricyclic heteroaryl ring 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 group of the present invention may be substituted or unsubstituted.

“Heterobicycloaryl” means bicycloaryl as defined herein, provided that one or more atoms in the ring are heteroatoms. For example, examples of hetero (C 4-12 ) bicycloaryl used in the present application include 2-amino-4-oxo-3,4-dihydropteridin-6-yl, tetrahydroisoquinolinyl, and the like. It is not limited to.

  “Heterocycloalkyl” means cycloalkyl as defined herein, provided that one or more of the atoms forming the ring is a heteroatom independently selected from N, O, or S ). Non-limiting examples of heterocycloalkyl include piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolidinyl, 1,4-diazaperhydroepinyl, 1, Examples include 3-dioxanyl and 1,4-dioxanyl.

  “Hydroxy” means the radical —OH.

  “Iminoketone derivative” means a derivative comprising the moiety —C (NR) —, wherein R comprises a hydrogen or carbon atom bonded to nitrogen.

“Isomers” means any compounds having the same molecular formula 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 non-superimposable 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 these two enantiomeric forms is called a “racemic mixture”. A compound having more than one chiral center has 2 n-1 enantiomeric pairs (where n is the number of chiral centers). Compounds with more than one chiral center can exist as ether individual diastereomers or as mixtures of diastereomers (referred to as “diastereomeric mixtures”). If there is one chiral center, a stereoisomer can be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the spatial configuration of substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and are described by the R- and S-rank rules of Cahn, Ingold and Prelog. Stereochemistry nomenclature, stereochemistry determination methods and stereoisomer separation conventions are well known in the art (eg, “Advanced Organic Chemistry”, 4th edition, March, Jerry, John Wiley & Sons, New York). , 1992).

“Nitro” refers to the group —NO 2 .

“Oxaalkyl” means alkyl as defined above, except where one or more oxygen atoms (—O—) are located between carbon atoms of the alkyl. For example, (C 2-6 ) oxaalkyl refers to a chain comprising 2 to 6 carbons and one or more oxygen atoms disposed between carbon atoms.

  “Oxoalkyl” means an alkyl further substituted with a carbonyl group. The carbonyl group can be an aldehyde, ketone, ester, amide, acid or acid chloride.

  “Pharmaceutically acceptable” means generally useful in preparing pharmaceutical compositions that are safe, non-toxic, and not biologically or otherwise undesirable. Including acceptable for veterinary use and human pharmaceutical use.

  "Pharmaceutically acceptable salt" means a salt of an inhibitor of the present invention that is pharmaceutically acceptable as defined above and has the desired pharmacological activity. Such salts include inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or organic acids (eg, acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycol Acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o- (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, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] Oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4′-methylenebi (3-hydroxy-2-ene-1-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). Examples of the acid addition salt formed include:

  Pharmaceutically acceptable salts also include base addition salts that can be formed when the acidic protons present can react with inorganic or organic bases. Acceptable inorganic salts include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Examples of acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, and N-methylglucamine.

  "Prodrug" means a compound that can be metabolically converted in vivo to an inhibitor of the present invention. The prodrug itself may or may not have hydroxylated steroid dehydrogenase inhibitory activity. For example, an inhibitor containing a hydroxy group can be administered as an ester that is converted to a hydroxy compound by in vivo hydrolysis. Suitable esters that can be converted to hydroxy compounds in vivo include acetate, citrate, lactate, tartaric acid, malonate, oxalate, salicylate, propionate, succinate, and fumarate. , Maleic acid ester, methylene-bis-b-hydroxynaphthoic acid ester, gentisic acid ester, isethionic acid ester, di-p-toluoyl tartaric acid ester, methanesulfonic acid ester, ethanesulfonic acid ester, benzenesulfonic acid ester, p-toluene Examples include sulfonic acid esters, cyclohexylsulfamic acid esters, quinic acid esters, and amino acid esters. Similarly, inhibitors containing amine groups can be administered as amides that are converted to amine compounds by in vivo hydrolysis.

  “Protected derivative” means a derivative of an inhibitor in which the reactive site or sites are blocked by protecting groups. Protected derivatives are useful in the preparation of inhibitors or may themselves be active as inhibitors. A comprehensive list of suitable protecting groups can be found in T.W. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. Can be found in 1999.

  “Ring” means a carbocyclic or heterocyclic ring system.

“Substituted or unsubstituted” is a use in which a given part can only consist of hydrogen substituents through available valences (unsubstituted) or is not specified differently depending on the name of the given part It means that one or more non-hydrogen substituents via possible valences may further be included (substitution). For example, isopropyl is an example of an ethylene moiety that is substituted by -CH 3. In general, a non-hydrogen substituent can be any substituent that can be attached to an atom of a given moiety that is identified as being substituted. Examples of substituents include aldehyde, cycloaliphatic, aliphatic, (C 1-10 ) 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 Examples include, but are not limited to, moieties, each of which may also be optionally substituted or unsubstituted.

  “Sulfinyl” means the radical —SO—. It is noted that the sulfinyl group can be further substituted with various 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 group can be further substituted with various substituents to form different sulfonyl groups including sulfonic acids, sulfonamides, sulfonate esters, and sulfones.

  “Therapeutically effective amount” means an amount that, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.

  “Thiocarbonyl” means the radical —CS—. It is noted that the thiocarbonyl group can be further substituted with various 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:
(1) to prevent the disease from occurring in an animal that appears to be susceptible to the disease but has not yet experienced or presented the pathology or symptomatology of the disease;
(2) suppressing the disease (ie, preventing further development of pathology and / or symptomatology) in an animal experiencing or presenting the pathology or symptomatology of the disease, or
(3) ameliorating the disease in an animal experiencing or presenting the pathology or symptomatology of the disease (ie, reversing the pathology and / or symptomology)
Is included.

For all of the definitions provided herein, the definition should be construed as open ended in the sense that additional substituents beyond those specified may be included. Is noted. Thus, C 1 alkyl indicates that there is one carbon atom but does not indicate what the substituents on that carbon atom are. Thus, C 1 alkyl includes methyl (ie, —CH 3 ), and —CR a R b R c , where R a , R b , and R c are each independently hydrogen or carbon Can be any other substituent wherein the atom attached to is a heteroatom or cyano). Thus, for example, CF 3 , CH 2 OH and CH 2 CN are all C 1 alkyl.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds, compositions that can be used to inhibit hydroxyl steroid dehydrogenase, particularly 11β-hydroxy steroid dehydrogenase type 1 (referred to herein as 11b-HSD1). Products, kits and products.

  11b-HSD1 belongs to the enzyme family of short chain dehydrogenase / reductase (SDR) (more than 60 types have been discovered in humans) (Opermann et al., Chem Biol Interact, 143-144, 247-253 ( 2003); Kallberg et al., Protein Sci, 11, 636-641 (2002)). SDR is a reversible NAD (H) / NADP (H) -dependent oxidoreductase, which has an α / a nucleotide binding Rossman fold that remains structurally constant. In the core structure, two conserved motifs are shared between all SDR enzymes. The dinucleotide-linked P-loop forms a turn between the β-strand and the α-helix and contacts the ribose sugar and pyrophosphate directly. The Tyr-X-X-X-Lys motif is often used in conjunction with a conserved Ser directed to the substrate, proton transfer to the reduced and oxidized reaction intermediates and their reactions. Catalyze proton transfer from intermediate products. The flexible region in the SDR enzyme often undergoes a conformational change as soon as the substrate binds, protecting the active surface from the bulk solvent and mediating enzyme specificity. Oligomerization and subcellular localization of SDR is often mediated by extensions at the N-terminus and C-terminus.

  11b-HSD1 is a NADPH-dependent enzyme that mainly functions as a reductase in vivo. In the cell, a single N-terminal transmembrane helix and associated linker anchors the C-terminal catalytic region in the lumen of the endoplasmic reticulum (ER).

  11b-HSD1 is important for regulating local concentrations of glucocorticoids in various tissue types such as adipose tissue, blood vessels, brain, testis, eyes and placenta. Dysregulation of 11b-HSD1 causes metabolic syndrome, Cushing's disease, hypertension, cognitive function and visual function in those areas.

  The compounds of the present invention may also have inhibitory activity against members of other short chain dehydrogenase families and thus may be used to address disease states associated with members of these other families. Is noted.

Crystal structure of 11β-hydroxysteroid dehydrogenase Syrrx, Inc. (San Diego, California) elucidated the crystal structure of 11β-hydroxysteroid dehydrogenase type 1 (11b-HSD1) (US Patent Application No. 10 / 800,024, filed March 12, 2004, and 10 / 800,427, filed March 12, 2004, each of which is hereby incorporated by reference in its entirety). This crystal structure knowledge was used to guide the design of the inhibitors provided herein.

  The overall Rossman fold form of 11b-HSD1 is similar to other SDR enzymes in that a central 6-strand, all parallel β-sheet is sandwiched on both sides by a 3α-helix (Hosfield et al. al., J. Biol. Chem, forthcoming). A conformationally unstable β6-α6 insert that forms one wall of the steroid binding pocket, an additional β-strand (β7) and two C-terminal α-helices (αE and αF), It is added to the core structure and completes the folding of 11b-HSD1. NADP + bound to 11b-HSD1 is similar to other SDR enzymes because there is a molecular bond in the extended conformation in which both ribose sugars take the C2 configuration. Both the adenine and nicotinamide rings are well aligned and are bound approximately perpendicular to the plane of the ribose sugar, with adenine in the anti configuration and nicotinamide in the syn configuration. The part of adenosine lies in the cleft formed by four loops (β1 / α1, β2 / α2, β3 / α3, and β4 / α4) and an α-helix (α4).

Hydroxysteroid Dehydrogenase Inhibitor In one embodiment, the hydroxysteroid dehydrogenase inhibitor of the present invention comprises:

(Where
J is selected from the group consisting of CR 6 and N (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
M is selected from the group consisting of S, O and NR 15 ;
R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
R 2 is

  Selected from the group consisting of:

R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any two of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 Together form a ring;
R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, or is selected from the group consisting of (C 9-12) bicycloaryl and hetero (C 4-12) bicycloaryl, or R 13 and R 7, Any one of R 9 and R 11 together forms a ring;
R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl;
X is selected from the group consisting of unsubstituted or substituted C 1-6 alkylene; and
Y is (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, each substituted or unsubstituted. , Aryl, heteroaryl, (C 9-12 ) bicycloaryl and hetero (C 4-12 ) bicycloaryl).

  In one embodiment, the hydroxylated steroid dehydrogenase inhibitors of the present invention include:

(Where
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 (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
M is selected from the group consisting of S, O and NR 15 ;
R 2 is

  Selected from the group consisting of:

R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any two of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 Together form a ring;
R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, or is selected from the group consisting of (C 9-12) bicycloaryl and hetero (C 4-12) bicycloaryl, or R 13 and R 7, Any one of R 9 and R 11 together forms a ring;
Each R 14 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, each substituted or unsubstituted Imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicyclo Alkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1 -10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfo Le (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl;
X is selected from the group consisting of unsubstituted or substituted C 1-6 alkylene; and
Y represents (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9- 12 ) selected from the group consisting of bicycloaryl and hetero ( C4-12 ) bicycloaryl).

  In one embodiment, the hydroxylated steroid dehydrogenase inhibitors of the present invention include:

(Where
J is selected from the group consisting of CR 6 and N (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
M is selected from the group consisting of S, O and NR 15 ;
R 2 is

  Selected from the group consisting of:

R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) each independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any one of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The two together form a ring;
R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, or is selected from the group consisting of (C 9-12) bicycloaryl and hetero (C 4-12) bicycloaryl, or R 13 and R 7, Any one of R 9 and R 11 together forms a ring;
R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl;
X is selected from the group consisting of unsubstituted or substituted C 1-6 alkylene; and
Y is (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, each substituted or unsubstituted. , Aryl, heteroaryl, (C 9-12 ) bicycloaryl and hetero (C 4-12 ) bicycloaryl).

  In one embodiment, the hydroxylated steroid dehydrogenase inhibitors of the present invention include:

(Where
R 2 is

Selected from the group consisting of:

R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) each independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any one of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The two together form a ring;
R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, or is selected from the group consisting of (C 9-12) bicycloaryl and hetero (C 4-12) bicycloaryl, or R 13 and R 7, Any one of R 9 and R 11 together forms a ring;
X is selected from the group consisting of unsubstituted or substituted C 1-6 alkylene; and
Y is (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, each substituted or unsubstituted. , Aryl, heteroaryl, (C 9-12 ) bicycloaryl and hetero (C 4-12 ) bicycloaryl).

  In one embodiment, the hydroxylated steroid dehydrogenase inhibitors of the present invention include:

(Where
R 2 is

Selected from the group consisting of:

R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl; and
R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) each independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any one of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The two together form a ring).

  In one embodiment, the hydroxylated steroid dehydrogenase inhibitors of the present invention include:

(Where
R 2 is

Selected from the group consisting of:

R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl; and
R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) each independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any one of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The two together form a ring).

  In one embodiment, the hydroxylated steroid dehydrogenase inhibitors of the present invention include:


(Where
R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
R 2 is

Selected from the group consisting of:

R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) each independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any one of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The two together form a ring;
R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, or is selected from the group consisting of (C 9-12) bicycloaryl and hetero (C 4-12) bicycloaryl, or R 13 and R 7, Any one of R 9 and R 11 together forms a ring;
X is selected from the group consisting of unsubstituted and substituted C 1-6 alkylene; and
Y is (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, each substituted or unsubstituted. , Aryl, heteroaryl, (C 9-12 ) bicycloaryl and hetero (C 4-12 ) bicycloaryl).

  In one embodiment, the hydroxylated steroid dehydrogenase inhibitors of the present invention include:

(Where
R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
R 2 is

Selected from the group consisting of:

R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl; and
R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) each independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any one of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The two together form a ring).

  In one embodiment, the hydroxylated steroid dehydrogenase inhibitors of the present invention include:

(Where
R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
R 2 is

Selected from the group consisting of:

R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl; and
R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) each independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any one of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The two together form a ring).

  In one embodiment, the hydroxylated steroid dehydrogenase inhibitors of the present invention include:


(Where
J is selected from the group consisting of CR 6 and N (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
M is selected from the group consisting of S, O and NR 15 ;
R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl, or R 7 and R 8 together form a ring;
R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) or is selected from the group consisting of bicycloaryl, or R 13 and R 7 Together form a ring; and
R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl).

  In one embodiment, the hydroxylated steroid dehydrogenase inhibitors of the present invention include:

(Where
J is selected from the group consisting of CR 6 and N (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
M is selected from the group consisting of S, O and NR 15 ;
R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl, or R 7 and R 8 together form a ring;
R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) or is selected from the group consisting of bicycloaryl, or R 13 and R 7 Together form a ring; and
R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl).

  In one embodiment, the hydroxylated steroid dehydrogenase inhibitors of the present invention include:

(Where
J is selected from the group consisting of CR 6 and N (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
M is selected from the group consisting of S, O and NR 15 ;
R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
R 9 and R 10 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, Ruhoniru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl, or any two of R 7 , R 8 , R 9 and R 10 together form a ring And
R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero (C 4-12) or is selected from the group consisting of bicycloaryl, or R 13 and R 7 and Together with any one of R 9 to form a ring; and
R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl).

  In one embodiment, the hydroxylated steroid dehydrogenase inhibitors of the present invention include:

Wherein J is selected from the group consisting of CR 6 and N (provided that J is CR 6 and R 6 is absent when J forms a double bond moiety);
K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
M is selected from the group consisting of S, O and NR 15 ;
R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
R 9 and R 10 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, Ruhoniru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl, or any two of R 7 , R 8 , R 9 and R 10 together form a ring And
R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero (C 4-12) or is selected from the group consisting of bicycloaryl, or R 13 and R 7 and Together with any one of R 9 to form a ring; and
R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl).

  In one embodiment, the hydroxylated steroid dehydrogenase inhibitors of the present invention include:

(Where
J is selected from the group consisting of CR 6 and N (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
M is selected from the group consisting of S, O and NR 15 ;
R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) each independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any one of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The two together form a ring;
R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, or is selected from the group consisting of (C 9-12) bicycloaryl and hetero (C 4-12) bicycloaryl, or R 13 and R 7, Any one of R 9 and R 11 together forms a ring; and
R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl).

  In one embodiment, the hydroxylated steroid dehydrogenase inhibitors of the present invention include:

(Where
J is selected from the group consisting of CR 6 and N (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
M is selected from the group consisting of S, O and NR 15 ;
R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) each independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any one of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The two together form a ring;
R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, or is selected from the group consisting of (C 9-12) bicycloaryl and hetero (C 4-12) bicycloaryl, or R 13 and R 7, Any one of R 9 and R 11 together forms a ring; and
R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl).

  In one embodiment, the hydroxylated steroid dehydrogenase inhibitors of the present invention include:


(Where
J is selected from the group consisting of CR 6 and N (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
M is selected from the group consisting of S, O and NR 15 ;
R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl;
X is selected from the group consisting of unsubstituted or substituted C 1-6 alkylene; and
Y is (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, each substituted or unsubstituted. , Aryl, heteroaryl, (C 9-12 ) bicycloaryl and hetero (C 4-12 ) bicycloaryl).

  In one embodiment, the hydroxylated steroid dehydrogenase inhibitors of the present invention include:

(Where
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 (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
M is selected from the group consisting of S, O and NR 15 ;
R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl, or R 7 and R 8 together form a ring;
R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, or is selected from the group consisting of (C 9-12) bicycloaryl and hetero (C 4-12) bicycloaryl, or R 13 and R 7 is Together form a ring;
Each R 14 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, each substituted or unsubstituted Imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicyclo Alkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1 -10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfo Le (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl; and
R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl).

  In one embodiment, the hydroxylated steroid dehydrogenase inhibitors of the present invention include:

(Where
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 (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
M is selected from the group consisting of S, O and NR 15 ;
R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
R 9 and R 10 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, Ruhoniru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl, or any two of R 7 , R 8 , R 9 and R 10 together form a ring And
R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero (C 4-12) or is selected from the group consisting of bicycloaryl, or R 13 and R 7 and Any one of R 9 together forms a ring;
Each R 14 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, each substituted or unsubstituted Imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicyclo Alkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1 -10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfo Le (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl; and
R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl).

  In one embodiment, the hydroxylated steroid dehydrogenase inhibitors of the present invention include:

(Where
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 (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
M is selected from the group consisting of S, O and NR 15 ;
R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) each independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any one of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The two together form a ring;
R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, or is selected from the group consisting of (C 9-12) bicycloaryl and hetero (C 4-12) bicycloaryl, or R 13 and R 7, Any one of R 9 and R 11 together forms a ring;
Each R 14 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, each substituted or unsubstituted Imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicyclo Alkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1 -10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfo Le (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl).

  In one embodiment, the hydroxylated steroid dehydrogenase inhibitors of the present invention include:

(Where
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 (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
M is selected from the group consisting of S, O and NR 15 ;
R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
Each R 14 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, each substituted or unsubstituted Imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicyclo Alkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1 -10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfo Le (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl;
X is selected from the group consisting of unsubstituted and substituted C 1-6 alkylene; and
Y is (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, each substituted or unsubstituted. , Aryl, heteroaryl, (C 9-12 ) bicycloaryl and hetero (C 4-12 ) bicycloaryl).

In one variation of each of the above embodiments, M is S. In another variation, M is O. In yet another variation, M is NR 15 and R 15 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 , each substituted or unsubstituted. ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, Heteroaryl (C 1-5 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1- 3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) A Kill, aryl, heteroaryl, selected from the group consisting of (C 9-12) bicycloaryl and hetero (C 4-12) bicycloaryl.

In one variation of each of the above embodiments and variations, J, K and L are CR 6.

In another variation of each of the above embodiments and variations, R 1 is a substituted or unsubstituted (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9- 12 ) selected from the group consisting of bicycloalkyl, hetero ( C3-12 ) bicycloalkyl, aryl, heteroaryl, ( C9-12 ) bicycloaryl, hetero ( C4-12 ) bicycloaryl. In yet another variation, R 1 is selected from the group consisting of (C 3-6 ) alkyl, aryl, (C 3-9 ) cycloalkyl, bicycloalkyl and adamantyl, each substituted or unsubstituted. . In yet another variation, R 1 is an alkylphenyl, halophenyl, alkylhalophenyl, alkoxyphenyl, alkylaminoalkoxyphenyl, heterocycloalkylalkoxyphenyl, alkylaminoalkylphenyl, each substituted or unsubstituted Heterocycloalkylalkylphenyl, cycloalkyl, bicycloalkyl and adamantyl are selected from the group. In a further variation, R 1 is cyano, carboxamide, aminoalkyl, aminoalkoxy, heterocycloalkyl, heterocycloalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aryloxy, hetero, each substituted or unsubstituted. Substituted with a substituent selected from the group consisting of aryloxy, bicycloaryl, heterobicycloaryl, bicycloaryloxy and heterobicycloaryloxy.

In another variation of each of the above embodiments and variations, R 3 is H.

In yet another variation of each of the above embodiments and variations, R 7 is H.

In yet another variation of each of the above embodiments and variations, R 7 and R 8 are independently from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, and heteroaryl, each substituted or unsubstituted. Selected. In a further variation, R 7 and R 8 are each substituted or unsubstituted 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 Each independently selected from the group consisting of ru, pyrazolyl and pyrimidinyl. In another variation, R 7 and R 8 are each substituted or unsubstituted (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, Together, a ring selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl and hetero (C 4-12 ) bicycloaryl is formed.

In yet another variation of each of the above embodiments and variations, R 13 is H.

In yet another variation of each of the above embodiments and variations, R 14 is a cyano, carboxamide, aminoalkyl, aminoalkoxy, heterocycloalkyl, heterocycloalkoxy, cycloalkyl, each substituted or unsubstituted. , Aryl, heteroaryl, heterocyclyl, aryloxy, heteroaryloxy, bicycloaryl, heterobicycloaryl, bicycloaryloxy and heterobicycloaryloxy.

  In a further variation of each of the above embodiments and variations, n is 0, 1 or 2.

  In another variation of each of the above embodiments and variations, X is methylene.

  In yet another variation of each of the above embodiments and variations, Y is selected from the group consisting of aryl and heteroaryl, each substituted or unsubstituted. In yet another variation, Y is selected from the group consisting of phenyl and pyridinyl, each substituted or unsubstituted. In a further variation, Y is selected from the group consisting of phenyl, halophenyl, dihalophenyl, methylphenyl, dimethylphenyl, cyanophenyl, aminocarboxyphenyl, haloalkylphenyl, alkoxyphenyl and oxopyridinyl.

Specific examples of hydroxyl steroid 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- (1-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;
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;
3-chloro-N- (4-((3-fluorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
3-chloro-N- (4-((3,4-difluorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
3-chloro-N- (4-((4-chloro-3-fluorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
3-chloro-N- (4-((3-chloro-5-fluorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
3-chloro-N- (4-((4-fluorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
3-chloro-N- (4- (hydroxy (phenyl) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
3-chloro-N- (4-((4-chlorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
3-chloro-N- (4-((3-chlorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
3-chloro-N- (4-((3-chloro-4-fluorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
3-chloro-N- (4-((3,5-difluorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
3-chloro-N- (4- (hydroxy (m-tolyl) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
3-chloro-N- (4-((2,3-dimethylphenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
3-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-methylbenzenesulfonamide;
3-chloro-N- (4- (1-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- (1-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- (1-hydroxy-2-pyrimidin-4-yl-ethyl) -thiazol-2-yl] -2-methyl-benzenesulfonamide;
1- [2- (3-chloro-2-methyl-benzenesulfonylmethyl) -thiazol-4-yl] -2-pyridazin-3-yl-ethanol;
3-chloro-N- {4- [1-hydroxy-2- (2H-pyrazol-3-yl) -ethyl] -thiazol-2-yl} -2-methyl-benzenesulfonamide; and 3-chloro-N -{4- [1-Hydroxy-2- (1H-pyrazol-4-yl) -ethyl] -thiazol-2-yl} -2-methyl-benzenesulfonamide.

Further specific examples of hydroxyl steroid 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-1-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-dimethylthiazol-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] dioxin-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] [1,2,5] thiadiazole-5-sulfonamide;
N- (4- (3-hydroxypentan-3-yl) thiazol-2-yl) -3,4-dihydro-2H-benzo [b] [1,4] dioxepin-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) -1,2,3,4-tetrahydroisoquinoline-7-sulfone An amide;
N- (4- (3-hydroxypentan-3-yl) thiazol-2-yl) -1,2,3,4-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] [1,3] dioxol-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.

Further specific examples of hydroxyl steroid 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-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-cyclopropyl-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-benzenesulfonamide;
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) -benzenesulfonamide;
3-chloro-N- [4- (2-hydroxy-butyl) -thiazol-2-yl] -4- (3-morpholin-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-morpholin-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.

Other specific examples of hydroxylated steroid 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-propylpentyl) 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-morpholin-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-morpholin-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-morpholinopropoxy) benzenesulfonamide;
N- (4- (2-ethyl-2-hydroxybutyl) thiazol-2-yl) -4- (3-morpholinopropoxy) 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- (1-hydroxy-cyclopentylmethyl) -thiazol-2-yl] -2-methyl-4- (3-morpholin-4-yl-propoxy) benzenesulfonamide;
N- [4- (1-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- (1-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-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-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] -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-morpholin-4-yl-propyl) -2-trifluoromethyl-benzenesulfonamide;
N- [4- (2-Ethyl-2-hydroxy-butyl) -thiazol-2-yl] -4- (4-morpholin-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- (1-hydroxy-cyclopentylmethyl) -thiazol-2-yl] -amide;
Ethanesulfonic acid [4- (1-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.

Further specific examples of hydroxylated steroid 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-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.

Yet another specific example of a hydroxylated steroid dehydrogenase inhibitor according to the present invention includes, but is 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-1 (2H) -yl) methyl) thiazol-2-yl) benzenesulfonamide; and N- (4- (3-methoxybenzyl ) Thiazol-2-yl) -3-chloro-2-methylbenzenesulfonamide.

  The compound of the present invention is a pharmaceutically acceptable salt, biohydrolyzed ester, biohydrolyzed amide, biohydrolyzed carbamate, solvate, hydrate, or prodrug thereof. It is noted that this is a form of For example, the compound optionally includes a substituent that can be substituted in vivo with another substituent, such as hydrogen.

  It is further noted that the compounds may exist in a mixture of stereoisomers or include a single stereoisomer.

  The present invention also provides a pharmaceutical composition containing any one of the above-described embodiments and variations as an active ingredient. 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 yet another particular variation, the composition is a liquid formulation adapted for parenteral administration.

  In another aspect, a pharmaceutical composition comprising a compound according to any one of the above embodiments and variations, wherein the composition is oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, From the group consisting of intramuscular, rectal, buccal, intranasal, liposome, inhalation, intravaginal, intraocular, translocal delivery (eg, by catheter or stent), subcutaneous, intrafacial, intraarticular and intrathecal Pharmaceutical compositions adapted for administration by the selected route are provided.

  In yet another aspect, a kit comprising the compound of any one of the above embodiments and variations: and one or more information (indicating a disease state to which the composition is to be administered, storage information for the composition, dosing Instructions are provided, including information and a selection from the group consisting of instructions on how to administer the composition. In one particular variation, the kit comprises the compound in a multiple dose form.

  In yet another aspect, a product comprising the compound of any one of the above embodiments and variations; and a packaging material are provided. In one variation, the packaging material constitutes a container for housing the compound. In one particular variation, the container comprises one or more elements of the group consisting of the disease state for which the compound is to be administered, storage information, dosage information, and / or instructions regarding how to administer the compound. Contains a label indicating. In another variation, the product comprises the compound in a multiple dose form.

  In a further aspect, there is provided a therapeutic method comprising the step of administering a compound of any one of the above embodiments and variations to a subject.

  In another aspect, there is provided a method for inhibiting HSD comprising contacting HSD with a compound of any one of the above embodiments and variations.

  In yet another aspect, there is provided a method of inhibiting HSD comprising the step of 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.

  In a further aspect, the method comprises administering to a subject a first compound that is converted in vivo to a second compound that inhibits HSD in vivo, wherein the second compound is any of the previous embodiments and variations. A method of inhibiting HSD, a compound, is provided.

  In another aspect, a method of treating a disease state in which HSD has an activity that causes pathology and / or symptomatology of the disease state, wherein the compound of any one of the above embodiments and variations is treated with the disease state. A method comprising the step of presenting in a subject in a therapeutically effective amount of

  In yet another aspect, a method of treating a disease state in which HSD has an activity that causes pathology and / or symptomatology of the disease state, wherein the method comprises a compound of any one of the above embodiments and variations. Providing a method wherein the compound is present in the subject in a therapeutically effective amount of the disease state comprising administering to the subject.

  In a further aspect, there is provided a method of treating a disease state in which HSD has an activity that causes pathology and / or symptomatology of the disease state, the method in vivo to a second compound that inhibits HSD in vivo. The method includes a step of administering a first compound to be converted to a subject, and the second compound is any one of the above embodiments and variations.

  In one variation of each of the methods, the disease state is selected from the group consisting of metabolic syndrome, Cushing's disease, hypertension, cognitive function, and visual function.

  In another variation of each of the methods, the HSD is 11b-HSD1.

Salts, hydrates, and prodrugs of hydroxylated steroid dehydrogenase inhibitors

It is to be understood that the compounds of the present invention may exist in the form of salts, hydrates and prodrugs that are converted in vivo to the compounds of the present invention and can optionally be administered. For example, it is within the scope of the present invention to convert and use the compounds of the present invention into their pharmaceutically acceptable salt forms derived from various organic and inorganic acids and bases according to procedures well known in the art. Is within.

  When the compound of the present invention has a free base form, the compound converts the free base form of the compound to a pharmaceutically acceptable inorganic or organic acid (for example, a hydrohalide such as hydrochloride, hydrobromide, hydroiodide, etc.). Other mineral acids and their corresponding salts (sulfates, nitrates, phosphates, etc.); and alkyl sulfonates and monoaryl sulfonic acids (ethane sulfonates, toluene sulfonates, benzene sulfonates, etc.) And by reacting with other organic acids and their corresponding salts (such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate); It can be prepared as a pharmaceutically acceptable acid addition salt.Additional acid addition salts of the present invention include adipate, alginate Alginate, aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, cyclopentanepropionate, digluconic acid Salt, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, fumarate, galactate (derived from mucic acid), galacturonic acid, glucoheptaoate, gluconate, glutamate, glyceroline Acid salt, hemisuccinic acid, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionic acid Salt, isobutyrate, lactate, lactobionate, malic acid , Malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogen phosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, Examples include but are not limited to pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate and phthalate. The free base forms will differ somewhat from their respective salt forms in physical properties (eg, solubility) in polar solvents, but for other purposes for the purposes of the present invention the salts are It should be understood that they are equivalent to their respective free base forms.

  When the compound of the present invention has 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 (eg potassium hydroxide, sodium hydroxide and lithium hydroxide); alkaline earth metal hydroxides (eg barium hydroxide and calcium hydroxide); alkali metals Alkoxides (eg, potassium ethanolate and sodium propanolate); and various organic bases (eg, ammonium hydroxide, piperidine, diethanolamine, and N-methylglutamine). Also included are aluminum salts of the compounds of the present invention. Additional 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 primary amines, secondary amines and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins (eg, 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 (Hydrabamine), isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theo Romin, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris - (hydroxymethyl) - but include salts of methylamine (tromethamine)), but are not limited to. Typically, the free acid form will differ somewhat from the respective salt form in physical properties (eg, solubility) in polar solvents, but for other purposes for the present invention, the salt Should be understood to be equivalent to its respective free acid form.

Compounds of the present invention containing basic nitrogen-containing groups are (C 1-4 ) alkyl halides (eg, methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide); di (C 1- 4 ) alkyl sulfates (eg, dimethyl, diethyl and diamyl sulfates); (C 10-18 ) alkyl halides (eg, decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides). And quaternized with agents such as aryl (C 1-4 ) alkyl halides (eg, benzyl chloride and phenethyl bromide). Such salts allow the preparation of the compounds of the invention that are both water-soluble and oil-soluble.

  N-oxides of the compounds of the present invention can be prepared by methods known to those skilled in the art. For example, N-oxide can be used to form an unoxidized form of the compound in an appropriate inert organic solvent (eg, a halogenated hydrocarbon such as dichloromethane) at approximately 0 ° C. with an oxidizing agent (eg, trifluoroperacetic acid). , Permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, etc.). Alternatively, the N-oxide of the compound can be prepared from the appropriate starting N-oxide.

  Prodrug derivatives of the compounds of the invention can be prepared by modifying substituents of a compound of the invention that are subsequently converted in vivo to a different substituent. It is noted that in many cases the prodrug itself is also included within the scope of the compounds of the invention. For example, prodrugs can be prepared by reacting a compound with a carbamylating agent (eg, 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, etc.) or an acylating agent. Additional examples of methods for making prodrugs can be found in Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985.

  Protected derivatives of the compounds of the invention can also be made. Examples of techniques applicable to the production of protecting groups and their removal are described in T.W. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. Can be found in 1999.

  The compounds of the invention can also be conveniently prepared or formed as solvates (eg, hydrates) during the process of the invention. Hydrates of compounds of the present invention can be conveniently prepared by recrystallization from an aqueous / organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran and methanol.

  As used herein, “pharmaceutically acceptable salt” is intended to encompass any compound of the invention utilized in the form of a salt thereof (in particular, the salt is When giving the compound improved pharmacokinetic properties compared to the free form compound or a different salt form compound). Pharmaceutically acceptable salt forms can also initially give the compound the desired pharmacokinetic properties that it had not previously had, and with respect to its therapeutic activity in the body, the pharmacodynamics of the compound It can even have a positive impact. Examples of pharmacokinetic properties that can be favorably influenced are in a manner that allows the compound to be transported across the cell membrane and then directly and positively affect the absorption, distribution, biotransformation and excretion of the compound. is there. The route of administration of the pharmaceutical composition is important, and various anatomical, physiological and pathological factors can greatly affect bioavailability, but the solubility of the compound is usually utilized by it. Depends on the specific properties of its salt form. One skilled in the art will know that an aqueous solution of the compound will provide the fastest absorption of the compound into the body of the subject being treated, while lipid solutions and suspensions and solid dosage forms You will understand that it will result in slower absorption.

Preparation of Hydroxysteroid Dehydrogenase Inhibitors Various methods can be developed to synthesize the compounds of the present invention. Representative methods for synthesizing these compounds are provided in the examples. However, it is noted that the compounds of the present invention may also be synthesized by other synthetic routes that others may devise.

  It will be readily appreciated that certain compounds of the present invention have atoms with bonds to other atoms that confer particular stereochemistry (eg, chiral centers) to the compound. It is understood that the synthesis of the compounds of the invention can result in the generation of a mixture of different stereoisomers (enantiomers, diastereomers). Unless a specific stereochemistry is specified, the list of compounds is intended to encompass all possible different stereoisomers.

  Various methods for separating mixtures of different stereoisomers are known in the art. For example, a racemic mixture of compounds can be reacted with an optically active resolving agent to form a pair of diastereoisomeric compounds. The diastereomers can then be separated to recover the optically pure enantiomer. The separable complex can also be used to resolve enantiomers (eg, crystalline diastereoisomeric salts). Diastereomers typically have sufficiently different physical properties (eg, melting point, boiling point, solubility, reactivity, etc.) and can be easily separated by taking advantage of these dissimilarities. . For example, diastereomers can be separated typically by chromatographic or separation / resolution techniques based on differences in solubility. A more detailed description of techniques that can be used to resolve the stereoisomers of compounds from their racemic mixture is given by Jean Jacques Andre Collet, Samuel H., et al. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

Compositions Containing Hydroxysteroid Dehydrogenase Inhibitors A wide variety of compositions and administration methods can be used with the hydroxysteroid dehydrogenase inhibitors of the present invention. Such compositions may include, in addition to the hydroxylated steroid dehydrogenase inhibitors of the present invention, conventional pharmaceutical excipients and other conventional pharmaceutically inert agents. In addition, the composition may include an active agent in addition to the hydroxylated steroid dehydrogenase inhibitor of the present invention. These additional active agents can include additional compounds of the present invention and / or one or more other pharmaceutically active agents.

  The composition may be in the form of a gas, liquid, semi-liquid or solid formulated in a manner suitable for the route of administration used. For oral administration, capsules and tablets are typically used. For parenteral administration, reconstitution of lyophilized powder, typically prepared as described herein, is used.

  The composition comprising the hydroxylated steroid dehydrogenase inhibitor of the present invention is an oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, oral cavity, intranasal, liposome, It can be administered or co-administered by intra-inhalation, vaginal, intraocular, trans-local delivery (eg, by catheter or stent), subcutaneous, intrafat, intra-articular, or intrathecal. The compounds and / or compositions of the invention can also be administered or coadministered in sustained release dosage forms.

  Hydroxysteroid dehydrogenase inhibitors and compositions comprising them can be administered or co-administered in any conventional dosage form. Co-administration in the context of the present invention involves more than one therapeutic agent (of which one comprises a hydroxylated steroid dehydrogenase inhibitor) in the course of a coordinated treatment to achieve improved clinical outcome. ) Is intended to mean administration. Such co-administration can also be coextensive in time, i.e., occur between overlapping periods.

  Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may optionally contain one or more of the following components: sterile diluent (eg, water for injection, saline solution, Non-volatile oils, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents); antibacterial agents (eg, benzyl alcohol and methyl paraben); antioxidants (eg, ascorbic acid and sodium bisulfite); chelating agents (eg, ethylenediamine) Tetraacetic acid (EDTA)); buffers (eg, acetate, citrate and phosphate); tonicity modifiers (eg, sodium chloride or dextrose), and acidity or alkalinity modifiers of the composition ( For example, alkali or acidifying agents, or buffers such as organic acids (carbonates, bicarbonates, phosphates, hydrochloric acid and acetic acid) Fine citric acid)). The parenteral preparation can optionally be enclosed in ampoules, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material.

  If the hydroxylated steroid dehydrogenase inhibitor of the present invention exhibits insufficient solubility, methods for solubilizing the compound can be used. Such methods are known to those skilled in the art and include using a co-solvent (eg, dimethyl sulfoxide (DMSO)), using a surfactant (eg, TWEEN), or And dissolution in an aqueous sodium hydrogen carbonate solution, but is not limited thereto. Derivatives of the compounds (eg, prodrugs of the compounds) can also be used to formulate effective pharmaceutical compositions.

  When the hydroxylated steroid dehydrogenase inhibitor of the present invention is mixed or added to the composition, solutions, suspensions, emulsions and the like can be formed. The resulting composition form depends on 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 required to ameliorate the disease being treated can be determined empirically.

  The compositions of the present invention are optionally unit-dosage forms (eg, tablets, capsules, pills, powders, dry powders for inhalers, granules) for administration to humans and animals. A sterile parenteral solution or suspension, and an oral solution or suspension, and an appropriate amount of the compound, in particular an pharmaceutically acceptable salt thereof, preferably an oil-water emulsion containing its sodium salt) Provided. Pharmaceutically therapeutically active compounds and derivatives thereof are typically formulated and administered in unit-dosage forms or multiple-dosage forms. As used herein, unit-dosage forms are suitable for human and animal subjects and are physically packaged individually as known in the art. A separate unit. Each unit dose contains a predetermined quantity of therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit dosage forms include ampoules and syringes, individually packaged tablets or capsules. A unit dosage form can be administered in that fraction or in multiple fractions. A multiple-dose form is a plurality of identical unit dosage forms packaged in a single container to be administered in separate unit dosage forms. Examples of multiple dose forms include vials, tablet or capsule bottles, or pint or gallon bottles. Thus, a multiple dose form is a plurality of unit doses that are not separated in a package.

  In addition to one or more hydroxylated steroid dehydrogenase inhibitors of the present invention, the composition comprises a diluent (eg, lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose); a lubricant (eg, stearin). Magnesium, calcium stearate and talc); and binders (eg starch, natural gums (eg gum acacia latin), glucose, molasses, polyvinylpyrrolidine, cellulose and its derivatives, povidone, cloth A liquid pharmaceutically administrable composition may contain, for example, the active compound as defined above and any pharmaceutically adjuvant, as well as povidone and other such binders known to those skilled in the art. , Carrier (eg For example, water, saline, aqueous dextrose, glycerol, glycol, ethanol, etc.) may be dissolved, dispersed, or otherwise mixed to form a solution or suspension. If present, the administered pharmaceutical composition may also contain small amounts of auxiliary substances (eg, wetting agents, emulsifiers, or solubilizers, pH buffering agents, etc. (eg, acetates, sodium citrate, cyclodextrin 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 the art (eg, Remington's Pharmaceutical Sciences, Mac k Publishing Company, Easton, Pa., 15th Edition, 1975.) The administered composition or formulation will in any event reduce hydroxylated steroid dehydrogenase activity in vivo and thereby be tested. A sufficient amount of a hydroxylated steroid dehydrogenase inhibitor of the present invention to treat a bodily disease state will be included.

  The dosage form or composition is optionally in the range of 0.005% to 100% (weight / weight), balanced by the inclusion of additional materials such as those described herein, One or more hydroxylated steroid dehydrogenase inhibitors of the present invention may be included. For oral administration, the pharmaceutically acceptable composition optionally comprises one or more excipients (commonly used, eg, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, Croscarmellose sodium, glucose, sucrose, magnesium carbonate, sodium saccharin, talcum, etc.). Such compositions include solutions, suspensions, tablets, capsules, powders, dry powders and sustained release formulations for inhalers (eg, implants and microencapsulated delivery systems), and biodegradable, biocompatible Examples thereof include, but are not limited to, collagen polymers, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid, and the like. Methods for preparing these formulations are known to those skilled in the art. The composition optionally comprises 0.01% to 100% (w / w), optionally 0.1 to 95%, and optionally 1 to 95% of one or more hydroxylated steroid dehydrogenase inhibitors. May be included.

  Salts of hydroxylated steroid dehydrogenase inhibitors (preferably sodium salts) can be prepared using carriers that protect the compound against rapid elimination from the body, such as sustained release formulations or coatings. The formulation may further comprise other active compounds to obtain the desired combination of properties.

Formulation for oral administration
Oral pharmaceutical dosage forms can exist as solids, gels or liquids. 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, which can be enteric-coated, sugar-coated or film-coated. Examples of capsules include hard gelatin capsules or soft gelatin capsules. Granules and powders can be provided in a non-foaming or foaming form. Each can be combined with other ingredients known to those skilled in the art.

  In certain embodiments, the hydroxylated steroid dehydrogenase inhibitors of the present invention are provided as solid dosage forms, preferably capsules or tablets. Tablets, pills, capsules, troches and the like may optionally contain one or more of the following ingredients or compounds of similar nature: binders; diluents; disintegrants; lubricants; glidants; Agents; and fragrances.

  Examples of binders that can be used include, but are not limited to, microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste.

  Examples of lubricants that can be used include, but are not limited to, talc, starch, magnesium or calcium stearate, stone mushroom and stearic acid.

  Examples of diluents that can be used include, but are not limited to, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.

  Examples of glidants that can be used include, but are not limited to, colloidal silicon dioxide.

  Examples of disintegrants that may be used include, but are not limited to, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose.

  Examples of colorants that may be used include any of the approved and proven water-soluble FD & C dyes, mixtures thereof; and water-insoluble FD & C dyes suspended in alumina hydroxide. It is not limited.

  Examples of sweeteners that can be used include, but are not limited to, sucrose, lactose, mannitol and artificial sweeteners (eg, sodium cyclamate and saccharin) and any number of spray-dried flavors.

  Examples of fragrances that can be used include, but are not limited to, natural fragrances extracted from plants such as fruits and synthetic mixtures of compounds that produce a preferred sensation (eg, but not limited to peppermint and methyl salicylate). Not.

  Examples of wetting agents that can be used include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.

  Examples of antiemetic coatings that can be used include, but are not limited to, fatty acids, lipids, waxes, shellac, ammoniated shellac and cellulose acetate phthalate.

  Examples of film coatings that can be used include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.

  Where oral administration is desired, the salt of the compound can 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 remains intact in the stomach and releases the active compound in the intestine. The composition can also be formulated in combination with an antacid or other such ingredient.

  Where the dosage unit form is a capsule, it can optionally further comprise a liquid carrier (eg, a fatty oil). In addition, the dosage unit form may optionally further comprise a variety of other materials that modify the physical form of the dosage unit, such as coatings of sugar and other enteric agents.

  The compounds of the present invention may also be administered as a component of an elixir, suspension, syrup, cachet, sprinkle, chewing gum or the like. A syrup may optionally contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

  The hydroxylated steroid dehydrogenase inhibitor of the present invention also contains other active substances that do not impair the desired action, or substances that supplement the desired action (for example, antacids, H2 blockers, and diuretics). Can be mixed. For example, if the compound is used to treat asthma or hypertension, the compound can be used with other bronchodilators and antihypertensive agents, respectively.

  Examples of pharmaceutically acceptable carriers that can be included in tablets containing the hydroxylated steroid dehydrogenase inhibitor of the present invention include binders, lubricants, diluents, disintegrants, colorants, fragrances, and wetting agents. However, it is not limited to these. Tablets with an enteric coating are resistant to the action of gastric acid due to the enteric coating and dissolve or disintegrate in the neutral or alkaline intestine. Sugar-coated tablets can be compressed into tablets, which are coated with various layers of pharmaceutically acceptable substances. A tablet with a film coating may be a compressed tablet coated with a polymer or other suitable coating. Multiple compressed tablets can be compressed tablets made by more than one compression cycle utilizing the pharmaceutically acceptable substances described above. Coloring agents can also be used in the tablets. Fragrances and sweeteners can be used in tablets and are particularly useful in the formation of chewable tablets and lozenges.

  Examples of liquid oral dosage forms that may be used include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-foamable granules, and foam reconstituted from foamable granules. Non-limiting preparations.

  Examples of aqueous solutions that can be used include, but are not limited to, elixirs and syrups. As used herein, an elixir refers to a clear and sweet hydroalcoholic preparation. Examples of pharmaceutically acceptable carriers that can be used in elixirs include, but are not limited to solvents. Particular examples of solvents that can be used include glycerin, sorbitol, ethyl alcohol and syrup. As used herein, syrup refers to a concentrated aqueous solution of sugar (eg, sucrose). The syrup may optionally further comprise a preservative.

  An emulsion refers to a two-phase system in which one liquid is dispersed in the form of small particles throughout another liquid. The emulsion can optionally be an oil-in-water or water-in-oil emulsion. Examples of pharmaceutically acceptable carriers that can be used in emulsions include, but are not limited to, non-aqueous liquids, emulsifiers and preservatives.

  Examples of pharmaceutically acceptable substances that can be used in non-foamable granules reconstituted into a liquid oral dosage form include diluents, sweeteners and wetting agents.

  Examples of pharmaceutically acceptable substances that can be used in effervescent granules to be reconstituted into liquid oral dosage forms include sources of organic acids and carbon dioxide.

  Coloring and flavoring agents may optionally be used in all of the above dosage forms.

  Particular examples of preservatives that can be used include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.

  Particular examples of non-aqueous liquids that can be used in emulsions include mineral oil and cottonseed oil.

  Specific examples of emulsifiers that can be used include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate.

  Particular examples of suspending agents that can be used include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluents include lactose and sucrose. Sweetening agents include sucrose, syrup, glycerin and artificial sweeteners (eg, sodium cyclamate and saccharin).

  Specific examples of wetting agents that may be used include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.

  Particular examples of organic acids that can be used include citric acid and tartaric acid.

  Sources of carbon dioxide that can be used in the foamable composition include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved and proven water soluble FD & C dyes and mixtures thereof.

  Particular examples of fragrances that can be used include natural fragrances extracted from plants such as fruits and synthetic mixtures of compounds that produce a favorable taste.

  In the case of solid dosage forms, for example, solutions or suspensions in propylene carbonate, vegetable oils or triglycerides are preferably enclosed in gelatin capsules. Such solutions, and their preparation and encapsulation, are disclosed in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. ing. In the case of liquid dosage forms, the solution (eg, in polyethylene glycol) is diluted with an amount of a pharmaceutically acceptable liquid carrier (eg, water) sufficient to be easily measured for administration. obtain.

  Alternatively, liquid or semisolid oral formulations can be prepared by dissolving or dispersing the active compound or salt in vegetable oil, glycol, triglyceride, propylene glycol ester (eg, propylene carbonate) and other such carriers, It can be prepared by encapsulating the suspension in a hard or soft gelatin capsule shell. Other useful formulations include those described in US Reissue Patent No. 28,819 and US Pat. No. 4,358,603.

Injectables, Solutions and Emulsions The present invention is also for administering the hydroxylated steroid dehydrogenase inhibitors of the present invention by parenteral administration (typically characterized by injection (either subcutaneously, intramuscularly or intravenously)). Relates to a composition designed in Injectables may be prepared in any conventional form, for example as liquid solutions or suspensions, solid forms suitable for solutions or suspensions in liquid prior to injection, or as emulsions.

  Examples of excipients that can be used with the injections of the present invention include, but are not limited to, water, saline, dextrose, glycerol or ethanol. Injectable compositions also optionally contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents such as Sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrin). Sustained-release or sustained-release system implantation (see, eg, US Pat. No. 3,710,795) such that a constant level of dosage is maintained is also described herein. Conceived in. The proportion 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 need of the compound in the subject.

  Parenteral administration of the formulation includes intravenous, subcutaneous and intramuscular administration. Formulations for parenteral administration include sterile solutions prepared for injection, sterile dry soluble products prepared for combination with a solvent immediately before use (eg, freezing as described herein, including subcutaneous tablets) Dry powders), sterile suspensions prepared for injection, sterile dry insoluble products and emulsions prepared to be combined with a vehicle just prior to use. The solution may be aqueous or non-aqueous.

  When administered intravenously, examples of suitable carriers include saline or phosphate buffered saline (PBS), and thickeners and solubilizers (eg, glucose, polyethylene glycol, and polypropylene glycol and A solution containing these mixtures), but is not limited thereto.

  Examples of pharmaceutically acceptable carriers that can optionally be used in parenteral formulations include aqueous vehicles, non-aqueous vehicles, antibacterial agents, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending agents and Dispersants, emulsifiers, sequestering or chelating agents, and other pharmaceutically acceptable substances include, but are not limited to.

  Examples of aqueous vehicles that can optionally be used include sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection.

  Examples of non-aqueous parenteral vehicles that may optionally be used include non-volatile oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil.

  Antibacterial agents in bacteriostatic or fungistatic concentrates can be used parenterally, especially when the formulation is designed to be packaged in multi-dose containers and thus stored and multiple aliquots removed. Can be added to the formulation. Examples of antibacterial agents that can be used include phenol or cresol, mercury, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride and benzethonium chloride.

  Examples of isotonic agents that can be used include sodium chloride and dextrose. Examples of buffering agents that can be used include phosphate and citrate. An example of an antioxidant that may be used is sodium hydrogen sulfate. An example of a local anesthetic that can be used is procaine hydrochloride. Examples of suspending and dispersing agents that can be used include sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. An example of an emulsifier that may be used is polysorbate 80 (TWEEN 80). Examples of the sequestering or chelating agent for metal ions include EDTA.

  Pharmaceutical carriers can also optionally include ethyl alcohol, polyethylene glycol and propylene glycol in the case of water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid in the case of pH adjustment.

  The concentration of the hydroxysteroid dehydrogenase inhibitor in the parenteral formulation can be adjusted such that a pharmaceutically effective amount sufficient to produce the desired pharmacological effect is administered by injection. The exact concentration of the 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. Let's go.

  Unit dose parenteral formulations can be packaged in ampoules, vials or syringes with needles. All formulations for parenteral administration should be sterile, as is known and practiced in the art.

  Injectables may be designed for local or systemic administration. Typically, a therapeutically effective dosage is at least about 0.1% w / w to about 90% w / w or more, preferably 1%, for the tissue or tissues being treated. Formulated to contain greater than w / w hydroxylated steroid dehydrogenase inhibitor. The hydroxylated steroid dehydrogenase inhibitor may be administered at once, or may be administered multiple times at time intervals divided into small doses. The exact dosage and duration of treatment can be determined empirically using known test protocols, the site at which the composition is administered parenterally, and by estimation from in vivo or in vitro test data. It is understood that it will be a function of variables. It should be noted that concentration and dosage values may also vary with the age of the individual being treated. For any particular subject, there may be a need to adjust the specific dosage regimen over time according to the individual needs and the professional judgment of the person or person who supervises the administration of the formulation. Should be further understood. Accordingly, the concentration ranges set forth herein are intended to be exemplary and are not intended to limit the scope or practice of the claimed formulation.

  Hydroxyl steroid dehydrogenase inhibitors can optionally be suspended in micronized or other suitable form, or to produce a more soluble active product or to produce a prodrug To be derivatized. The form of the resulting mixture will depend on 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 to ameliorate the symptoms of the disease state and can be determined empirically.

Lyophilized powder The hydroxylated steroid dehydrogenase inhibitors of the present invention can also be prepared as a lyophilized powder that can be reconstituted for administration as a solution, emulsion, and other mixtures. The lyophilized powder can also be formulated as a solid or gel.

  Sterile lyophilized powder can be prepared by dissolving the compound in a sodium phosphate buffer solution containing dextrose or other suitable excipient. The solution is then sterile filtered, followed by lyophilization under standard conditions known to those skilled in the art to produce the desired formulation. Briefly, the lyophilized powder optionally comprises dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agent, about 1-20%, preferably about 5-15. %, In a suitable buffer (eg citrate, sodium phosphate or potassium phosphate or other such buffers known to those skilled in the art (typically around neutral pH) The hydroxylated steroid dehydrogenase inhibitor is then added to the resulting mixture, preferably above room temperature, more preferably at about 30-35 ° C. and stirred until it dissolves. The resulting mixture is diluted by adding additional buffer to the desired concentration, and the resulting mixture is sterile filtered or to remove particulates and Treated to ensure fungal and aliquot into vials for lyophilization. Each vial may contain a single dosage or multiple dosages of hydroxide dehydrogenase inhibitors.

Topical Administration The hydroxylated steroid dehydrogenase inhibitors of the present invention can also be administered as a topical mixture. Topical mixtures can be used for local and systemic administration. The resulting mixture can be a solution, suspension, emulsion, etc., cream, gel, ointment, emulsion, solution, elixir, lotion, suspension, tincture, pasta, foam, Formulated as an aerosol, irrigation, spray, suppository, bandage, skin patch or any other formulation suitable for topical administration.

  Hydroxylsteroid dehydrogenase inhibitors can be formulated as aerosols for topical application (eg, by inhalation) (US Pat. Nos. 4,044,126, 4,414,209, And No. 4,364,923, which describe aerosols for the delivery of steroids useful for the treatment of inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract can be in the form of a nebulizer aerosol or solution, or as a fine powder for inhalation alone or in combination with an inert carrier such as lactose. In such cases, the particles of the formulation typically have a diameter of less than 50 microns, preferably less than 10 microns.

  Hydroxyl steroid dehydrogenase inhibitors are also in the form of gels, creams, and lotions for topical application, eg, topical application to the skin and mucous membranes (eg ocular mucosa). And can be formulated for ocular or intracisternal or intrathecal application. For transdermal delivery, topical administration is also contemplated for ocular or mucosal administration or for inhalation therapy. Nasal solutions of hydroxylated steroid dehydrogenase inhibitors alone or in combination with other pharmaceutically acceptable excipients may also be administered.

Formulations for other routes of administration Depending on the disease state being treated, other routes of administration (eg, 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 action. Rectal suppository is used herein to mean a solid material for insertion into the rectum that melts or softens 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 for increasing the melting point. Examples of bases include cocoa butter (cocoa butter), glycerin-gelatin, carbowax, (polyoxyethylene glycol), and suitable mixtures of mono-, di- and triglycerides of fatty acids. Various base combinations may be used. Agents for increasing the melting point of suppositories include whale wax and wax. Rectal suppositories can be prepared either by the compressed method or by molding. The typical weight of a rectal suppository is about 2-3 gm. Tablets and capsules for rectal administration can be manufactured by the same method using the same pharmaceutically acceptable substances as in the preparation for oral administration.

Formulation Examples The following are specific examples of oral, intravenous and tablet formulations that can optionally be used with the compounds of the present invention. It is noted that these formulations may vary depending on the particular compound used and the indication for which the formulation is to be used.

Oral formulation 10-100 mg of the compound of the present invention
Citric acid monohydrate 105mg
Sodium hydroxide 18mg
A proper amount of perfume water to 100 mL

Intravenous preparations Compounds of the invention 0.1-10 mg
Dextrose monohydrate 1.05mg citric acid monohydrate isotonic with appropriate amount
Sodium hydroxide 0.18mg
Water for injection

Tablet formulation Compound of the present invention 1%
Microcrystalline cellulose 73%
Stearic acid 25%
Colloidal silica 1%

The present invention also relates to kits and other products for treating diseases associated with hydroxyl steroid dehydrogenase. It is noted that the disease is intended to encompass all conditions in which the hydroxyl steroid dehydrogenase has activity that contributes to the pathology and / or symptomatology of the condition.

  In one embodiment, a kit is provided that comprises a composition comprising at least one hydroxylated steroid dehydrogenase inhibitor of the present invention along with instructions for use. The instructions may indicate the disease state for which the composition is to be administered, storage information, dosage information and / or instructions regarding how to administer the composition. The kit can also include packaging material. The packaging material may constitute a container for containing the composition. The kit can also optionally include additional elements such as a syringe for administration of the composition. The kit may include the composition in single or multiple dose forms.

  In another embodiment, an article of manufacture is provided that includes a composition comprising at least one hydroxylated steroid dehydrogenase inhibitor of the present invention along with packaging material. The packaging material may constitute a container for containing the composition. The container may optionally include a label indicating the disease state for which the composition is to be administered, storage information, dosage information, and / or instructions regarding how to administer the composition. The kit can also optionally include additional elements such as a syringe for administration of the composition. The kit may contain the composition in single or multiple dosage forms.

  It is noted that the packaging material used in the kits and products of the present invention may form a plurality of separated containers (eg, separated bottles or separated foil pockets). The container may be any conventional shape or form known in the art made of pharmaceutically acceptable materials (eg, paper or cardboard boxes, glass or plastic bottles or jars, resealable bags ( For example, to hold “refills” of tablets for placement in different containers) or blister packs with individual doses to be pushed out of the pack according to the treatment schedule. The container used depends exactly on the dosage form involved (eg, conventional cardboard boxes are not normally used to hold liquid suspensions). It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, a tablet can be contained in a bottle and then it can be contained in a box. Typically, the kit includes instructions for administering the separate components. The kit form may be administered at different dosage intervals if the separate components are preferably administered in different dosage forms (eg, oral, topical, transdermal and parenteral), or the individual components of the combination Titration is particularly advantageous when desired by the prescribing physician.

  A specific example of the kit of the present invention is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively hard material, preferably covered with a foil of transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recess may have the size and shape of individual tablets or capsules to be packed, or may be sized and shaped to fit a plurality of tablets and / or capsules to be packed. The tablets or capsules are then placed in the recesses accordingly, and the sheet of relatively hard material is sealed against the plastic foil on the face of the foil opposite to 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 tablet or capsule can be removed from the blister pack by manually applying pressure to the recess, thereby forming an opening in the sheet at the location of the recess. is there. The tablet or capsule can then be removed through the opening.

  Another specific embodiment of the kit is a dispenser designed to dispense daily doses one by one in the order of their intended use. Preferably, the dispenser is equipped with a memory aid to further promote compliance with the regimen. An example of such a memory aid is a mechanical counter that indicates the number of daily doses dispensed. Another example of such a memory aid is a battery-powered microchip memory combined with a liquid crystal readout, or, for example, retrieving the date of the last daily dose taken and / or taking the next dose An audible reminder signal reminding you of the date to be.

Examples Preparation of Hydroxysteroid Dehydrogenase Inhibitors Various methods can be developed to synthesize the compounds of the present invention. The respective methods for synthesizing these compounds are provided in the examples. However, it is noted that the compounds of the present invention may also be synthesized by other synthetic routes that others may devise.

  It will be readily appreciated that certain compounds of the present invention have atoms with linkages to other atoms that confer particular stereochemistry to the compound (eg, chiral centers). It is understood that the synthesis of the compounds of the invention can result in the generation of a mixture of different stereoisomers (enantiomers, diastereomers). Unless a specific stereochemistry is specified, the list of compounds is intended to encompass all possible different stereoisomers.

  Various methods for separating mixtures of different stereoisomers are known in the art. For example, a racemic mixture of compounds can be reacted with an optically active resolving agent to form a pair of diastereoisomeric compounds. The diastereomers can then be separated to recover the optically pure enantiomer. The separable complex can also be used to resolve enantiomers (eg, crystalline diastereoisomeric salts). Diastereomers typically have sufficiently different physical properties (eg, melting point, boiling point, solubility, reactivity, etc.) that they can be easily separated by taking advantage of these dissimilarities. . For example, diastereomers can be separated typically by chromatographic or separation / resolution techniques based on differences in solubility. A more detailed description of the techniques that can be used to resolve the stereoisomers of a compound from its racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. et al. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

  The compounds of the present invention can also be prepared as pharmaceutically acceptable acid addition salts by reacting the free base forms of the compounds with pharmaceutically acceptable inorganic or organic acids. 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 pharmaceutically acceptable salts of the compounds are described in the definitions section of this application. Alternatively, salt forms of the compounds may be prepared using starting materials or intermediate salts.

  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, an acid addition salt form of a compound can be converted to the corresponding free base form by treatment with a suitable base (eg, ammonium hydroxide solution, sodium hydroxide, etc.). A compound in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (eg, hydrochloric acid, etc.).

  N-oxides of the compounds of the present invention can be prepared by methods known to those skilled in the art. For example, an N-oxide can be used to form an unoxidized form of a compound in an appropriate inert organic solvent (eg, a halogenated hydrocarbon (eg, dichloromethane, etc.) at about 0 ° C. Peracetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid and the like). Alternatively, the N-oxide of the compound can be prepared from the appropriate starting N-oxide.

  The non-oxidized form of the compound is reduced to a reducing agent (eg, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride) at 0-80 ° C. in a suitable inert organic solvent (eg, acetonitrile, ethanol, aqueous dioxane, etc.). , Sodium borohydride, phosphorus trichloride, tribromide, etc.) can be prepared from the N-oxide of the compound.

  Prodrug derivatives of said compounds can be prepared by methods known to those skilled in the art (see, for example, Saunier et al. (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985 for further details). thing). For example, suitable prodrugs are prepared by reacting a non-derivatized compound with a suitable carbamylating agent (eg, 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, etc.). obtain.

Protected derivatives of the compounds can be prepared by methods known to those skilled in the art. A detailed description of techniques applicable to the creation and removal of protecting groups can be found in T.W. W. Greene, Protecting Groups in Organic Chemstry, 3 rd edition, John Wiley & Sons, Inc. Can be found in 1999.

  The compounds of the invention can be conveniently prepared as solvates (eg, hydrates) or can be formed during the process of the invention. Hydrates of compounds of the present invention can be conveniently prepared by recrystallization from an aqueous / organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.

  The compounds of the invention also react a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereoisomeric compounds, separate the diastereomers, and convert the optically pure enantiomers. By recovery, it can be prepared as its individual stereoisomer. While resolution of enantiomers can be performed using covalent diastereomeric derivatives of the compounds, separable complexes (eg, crystalline diastereoisomeric salts) are preferred. Diastereomers have different physical properties (eg, melting point, boiling point, solubility, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities. Diastereomers can be separated by chromatography or, preferably, by separation / resolution techniques based on differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that will not result in racemization. A more detailed description of techniques applicable to the resolution of stereoisomers of compounds from their racemic mixtures can be found in Jean Jacques Andre Collet, Samuel H. et al. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

As used herein, the symbols and conventions used in these processes, schemes, and examples are used in modern scientific literature (e.g., the Journal of the American Chemical Society or the Journal of Biological Chemistry). Match what you have. Standard one-letter or three-letter abbreviations are commonly used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise stated. 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 (liter); mL (milliliter);
μL (microliter); psi (pounds per square inch);
M (molar concentration); mM (molar concentration);
i. v. (Intravenous); Hz (hertz);
MHz (megahertz); mol (mol);
mmol (mmol); 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 (dimethyl sulfoxide); 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);
Et 2 O (diethyl ether);
EDCI (ethylcarbodiimide hydrochloride);
BOC (tert-butyloxycarbonyl);
FMOC (9-fluorenylmethoxycarbonyl);
DCC (dicyclohexylcarbodiimide);
CBZ (benzyloxycarbonyl);
Ac (acetyl); atm (atmospheric pressure);
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.

All references to ether or Et 2 O are to diethyl ether and brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in ° C. (degrees Centigrade). Unless otherwise stated, all reactions were conducted under an inert atmosphere at RT.

1 H NMR spectra were recorded on a Bruker Avance 400. Chemical shifts are expressed in parts per million (ppm). The coupling constant is in units of hertz (Hz). The split pattern describes the apparent multiplicity and is specified as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).

  Low resolution mass spectra (MS) and compound purity data were obtained from a Waters ZQ LC / MS single quadrature equipped with an electrospray ionization (ESI) source, UV detector (220 and 254 nm), and evaporative light scattering detector (ELSD). Obtained with a bipolar system. Thin layer chromatography is 0.25 mm E.I. Performed on 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).

  Starting materials and reagents used to prepare these compounds are available from commercial suppliers such as Aldrich Chemical Company (Milwaukee, WI), Bachem (Torrance, CA), Sigma (St. Louis, MO). Or 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; : Advanced Organic Chemistry, 4th ed. , John Wiley and Sons, New York, NY; and Larock: Comprehensive Organic Transformations, VCH Publishers, New York, 1989, according to procedures well known to those skilled in the art and prepared by methods known in the art. Can be done.

  The entire disclosures of all documents cited throughout this application are hereby incorporated by reference.

Synthesis Scheme of Hydroxylsteroid Dehydrogenase Inhibitor of the Present Invention The hydroxylated steroid dehydrogenase inhibitor of the present invention can be synthesized according to the reaction scheme shown below. Other reaction schemes can be readily devised by those skilled in the art. It should be understood that a variety of different solvents, temperatures and other reaction conditions can be varied to optimize the yield of the reaction.

  In the reactions described below, reactive functional groups (e.g., hydroxy, amino, imino, thio or carboxy groups) (wherein these are in the final product to avoid their unnecessary involvement in the reaction) It may be necessary to protect). Conventional protecting groups may be used in accordance with standard conventions (see, eg, TW Greene and PGM Wuts “Protecting Groups in Organic Chemistry” John Wiley and Sons, 1991).

To obtain secondary α-alcohols as in Scheme 1, key esters can be prepared by coupling a carboxy-substituted aminothiazole and various sulfonyl chlorides with DMAP in pyridine. This key ester can then be reduced to an alcohol with LAH and oxidized to the corresponding aldehyde using MnO 2 . The resulting aldehyde can then be treated with various nucleophiles (eg, Grignard reagents) to give the desired product.

  The tertiary α-alcohol of Scheme 2 can be prepared by reacting the key ester (see Scheme 1) with various Grignard reagents.

  Cyclic alcohols such as Scheme 3 can be synthesized by addition of a bis-organomagnesium species, or by Kulinkovich cyclopropanation.

  To obtain a tertiary β-alcohol as in Scheme 4, the key ester can be prepared by coupling a carboxymethyl substituted aminothiazole and various sulfonyl chlorides with DMAP in pyridine. This key ester can then be treated with various Grignard reagents to give the desired product.

  Alternatively, a tertiary β-alcohol as in Scheme 5 is a chloromethyl substituted N-sulfonylamino that can be obtained from sulfonylating a cyclic ketone with the known chloromethyl substituted aminothiazole HCl salt with various sulfonyl chlorides. It can be prepared from a samarium (II) mediated Barbier reaction with thiazole.

  To obtain a secondary β-alcohol as in Scheme 6, the key ester can be reduced to the corresponding aldehyde with DIBAL-H at low temperature. The desired product can then be obtained by the addition of various nucleophiles (eg, Grignard reagents).

Alternatively, to obtain a secondary β-alcohol as in Scheme 7, the key ester is reacted with various nucleophiles such as Grignard reagents, followed by the resulting ketone with LAH or NaBH 4 . It may be reduced.

  For separation of racemic mixtures of β-alcohols as in Scheme 8, the alcohol can be derivatized with the R or S enantiomer of O-methoxyphenylacetic acid. Separation of the resulting diastereomeric products can be accomplished by chromatography or by other means. The separated diastereomer can then be reduced to the corresponding alcohol.

Secondary γ-alcohols such as Scheme 9 can be used for aldol condensation of key aldehydes with methyl ketone, the resulting hydrogenation using double-bonded PtO 2 as a catalyst, and (+) or (−)-DIPCl It can be obtained via asymmetric reduction of the ketone functional group at either. Alternatively, other methods of asymmetric reduction known to those skilled in the art can be used.

  To obtain benzyl compounds as in Scheme 10, aryl secondary α-alcohols are prepared according to Carey, F. et al. A. Tremper, H .; S; Am. Chem. Soc. 1968, 90, 2578-2583, and may be reacted by ionic hydrogenation.

  To obtain secondary α-alcohols as in Scheme 11, Corey, E .; J. et al. , Chaykovsky, M .; J .; Am. Chem. Soc. 1965, 87, 1353-1364, intermediate epoxides can be prepared from trimethylsulfonium iodide and key aldehydes. This epoxide can be exposed to commercially available amines in the presence of activated alumina, Posner, G. et al. H. Rogers, D .; Z. J .; Am. Chem. Soc, 1977, 99, 8214-8218 may provide the desired product in a regioselective manner as described in.

  To obtain a tertiary β-alcohol as in Scheme 12, the key ester can be prepared by coupling a carboxy-substituted aminothiazole and various fluorine-substituted arylsulfonyl chlorides with DMAP in pyridine. This key ester may then be reacted with a Grignard reagent to provide the desired intermediate alcohol. Aromatic nucleophilic substitution with various nucleophiles provides the desired product.

  Tertiary β-alcohols such as Scheme 13 are also Boc protected 4- (chloromethyl) thiazole-2 via a samarium (II) mediated Barbier reaction with various cyclic or acyclic ketones. -Can be obtained from amines. The resulting acid degradation of the intermediate Boc protecting group followed by the sulfonylation of various sulfonyl chlorides provides the desired β-alcohol.

  Tertiary α-alcohols such as Scheme 14 can also be prepared from ethyl 2-aminothiazole-4-carboxylate. For example, ethyl 2-aminothiazole-4-carboxylate may be reacted with ethyl magnesium chloride to provide the corresponding diethyl hydroxy derivative. The amine function was then coupled with various sulfonyl chlorides to yield the desired sulfonamide.

  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, a chiral analytical SFC / MS analysis is performed using a Berger SFC dual pump fluid conditioning module with a Berger FCM 1100/1200 supercritical fluid pump and an FCM 1200 modifier fluid pump, a Berger TCM 2000 oven, And a Berger analytical SFC system (AutoChem, Newark, DE) consisting of an Alcott 718 autosampler. The integrated system can be controlled by BI-SFC Chemstation software version 3.4. Detection can be achieved by a Waters ZQ 2000 detector with an ESI interface, a scan range of 200-800 Da, a scan every 0.5 seconds and operating in positive mode. Chromatographic separations include ChiralPak AD-H, ChiralPak AS-H, ChiralCel OD-H, or ChiralCel OJ-, which contains 10-40% methanol as a regulator and may or may not contain ammonium acetate (10 mM). It may be performed on an H column (5μ, 4.6 × 250 mm; Chiral Technologies, Inc. West Chester, PA). Any of a variety of flow rates may be used, for example, 1.5 or 3.5 mL / min and an inlet pressure set to 100 bar. Further, various sample injection conditions may be used, for example, injecting sample of either 5 μL or 10 μL of methanol at a concentration of 0.1 mg / mL.

  In another variation, preparative chiral separation is performed using a Berger MultiGram II SFC purification system. For example, the sample can be loaded onto a ChiralPak AD column (21 × 250 mm, 10 μ). In a particular variation, the separation flow rate may be 70 mL / min, the injection volume may be up to 2 mL, and the inlet pressure may be set to 130 bar. Stacked injections can be applied to increase efficiency.

  For example, the above reaction scheme, and variations thereof, can be used to prepare:

  In each of the above reaction procedures or schemes, the various substituents can be selected from a variety of substituents different from those taught herein.

  A description of the synthesis of certain compounds of the present invention based on the above reaction scheme is set forth herein.

Examples of Hydroxysteroid Dehydrogenase Inhibitors The present invention is further illustrated, but the invention is not limited by the following examples describing the synthesis of specific compounds of the invention.

Example 1-1: 3-chloro-N- (4- (1-hydroxyethyl) thiazol-2-yl) -2-methylbenzenesulfonamide

Step A: Ethyl 2- (3-chloro-2-methylphenylsulfonamido) thiazole-4-carboxylate

According to Scheme 1, DMAP (150 mg, 1.23 mmol) was added to 3-chloro-2-methylbenzene-1-sulfonyl chloride (4.54 g, 20.2 mmol) and 2-aminothiazole-4-in pyridine (30 mL). To a stirred solution of ethyl carboxylate (2.89 g, 16.8 mmol). The reaction mixture was stirred at 20 ° C. for 19 hours and an additional portion of sulfonyl chloride was added (1.58 g, 7.02 mmol). After a total of 3 days, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (150 mL), washed with phosphoric acid (1N, 2 × 50 mL), brine (50 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The title product is suspended in beige solid by suspending the crude product in ether (150 mL), stirring vigorously until a fine suspension is obtained, cooling to 10 ° C., filtering and drying under reduced pressure. Obtained as a product (3.70 g, 61%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 1.37 (t, J = 7.20 Hz, 3 H), 2.73 (s, 3 H), 4.37 (q, J = 7. 24 Hz, 2 H), 7.24 (t, J = 7.9 Hz, 1 H), 7.27 (s, 1 H), 7.54 (d, J = 8.08 Hz, 1 H) , 8.00 (d, J = 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

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 (1M in THF, 15 mL, 15 mmol) was added dropwise over 5 minutes. The reaction mixture was stirred at 0 ° C. for 30 minutes, carefully quenched with tartaric acid (10% aqueous solution, 10 mL), and the reaction mixture was allowed to warm to room temperature. This was extracted with ethyl acetate (3 × 50 mL) and the combined organic extracts were dried (MgSO 4 ), filtered and concentrated under reduced pressure. The residue is suspended in ether (150 mL) and stirred vigorously until a fine suspension is obtained, filtered and dried under reduced pressure to give the title compound as an off-white solid. Obtained (1.32 g, quantitative). 1 H NMR (400 MHz, CDCl 3 ) δ, ppm: 2.62 (s, 3 H), 4.25 (d, J = 5.31 Hz, 2 H), 5.39 (t, J = 5 .68 Hz, 1 H), 6.58 (s, 1 H), 7.37 (t, J = 7.96 Hz, 1 H), 7.65 (d, J = 7.07 Hz, 1 H) ), 7.88 (d, J = 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

3-Chloro-N- (4- (hydroxymethyl) thiazol-2-yl) -2-methylbenzenesulfonamide (1.10 g, 3.45 mmol) was suspended in methanol (25 mL) and MnO 2 (85%, Treated with activated powder, 6.00 g). The reaction mixture was stirred vigorously for 3 hours and filtered through a plug consisting of silica (bottom, 6 mL) and celite (top, 15 mL). The stopper was washed thoroughly with methanol (100 mL, Celite stirring was required to achieve filtration) and the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (1. 07 g, 98%). This material was pure enough to be used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ, ppm: 2.63 (s, 3 H), 7.23 (t, J = 7.83 Hz, 1 H), 7.48 (d, J = 7 .83 Hz, 1 H), 7.65 (s, 1 H), 7.84 (d, J = 7.33 Hz, 1 H), 9.47 (s, 1 H); ESI-MS: m / Z 317.1 (M + H) <+> .

Step D: 3-Chloro-N- (4- (1-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 methylmagnesium chloride solution (3.0 M in THF, 0.33 mL, 1.0 mmol). The reaction mixture was stirred for 15 minutes, quenched with NH 4 Cl (sat. Aq.)-Ice mixture (1: 1, 5 mL), stirred vigorously for 5 minutes and extracted with ethyl acetate (5 mL). The extract was dried (MgSO 4 ), filtered and concentrated. The residue was purified by HPLC (45-60% acetonitrile in water, buffered with TFA) to give the title compound as a white solid (52.5 mg, 72%). 1 H NMR (400 MHz, DMSO-D6) δ, ppm: 1.54 (d, J = 6.57 Hz, 3 H), 2.63 (s, 3 H), 4.86 (q, J = 6.32 Hz, 1 H), 6.30 (s, 1 H), 7.23 (t, J = 8.08 Hz, 1 H), 7.57 (d, J = 8.08 Hz, 1 H), 8.00 (d, J = 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- (1-hydroxypropyl) thiazol-2-yl) -2-methylbenzenesulfonamide

The title compound was prepared as described in Example 1-1 except that ethylmagnesium bromide (1.0 M in THF, 1.00 mL, 1.00 mmol) was used. HPLC (35-55% acetonitrile in water, buffered with TFA) gave the title compound as a white solid (39.5 mg, 56%). 1 H NMR (400 MHz, CDCl 3 ) δ, ppm: 1.04 (t, J = 7.33 Hz, 3 H), 1.85 (quint, J = 7.26 Hz, 2 H), 2.62 (s, 3 H), 4.55 ( t, J = 6.82 Hz, 1 H), 6.30 (s, 1 H), 7.24 (t, J = 8.08 Hz, 1 H), 7.57 (d, J = 8.08 Hz, 1 H), 8.00 (d, J = 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- (1-hydroxybutyl) thiazol-2-yl) -2-methylbenzenesulfonamide

The title compound was prepared as described in Example 1-1 except that n-propylmagnesium chloride (2.0 M in THF, 0.50 mL, 1.00 mmol) was used. HPLC (45-60% acetonitrile in water, buffered with TFA) gave the title compound as a white solid (46.5 mg, 64%). 1 H NMR (400 MHz, CDCl 3 ) δ, ppm: 0.96 (t, J = 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, J = 8.46, 5.18 Hz, 1 H), 6.28 (s, 1 H), 7.24 (t, J = 8.08 Hz, 1 H) , 7.57 (d, J = 7.83 Hz, 1 H), 8.00 (d, J = 8.08 Hz, 1 H), 11.60 (br s, 1H); ESI-MS: m / z 361.2 (M + H) + .

Example 1-4: 3-chloro-N- (4- (cyclopropyl (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide

The title compound was prepared as described in Example 1-1 except that cyclopropylmagnesium bromide (0.5M in THF, 2.00 mL, 1.00 mmol) was used. HPLC (45-60% acetonitrile in water, buffered with TFA) gave the title compound as a white solid (52.5 mg, 72%). 1 H NMR (400 MHz, CDCl 3 ) 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, J = 7.83 Hz, 1 H), 6.46 (s, 1 H), 7.23-7.25 (t, J = 8.08 Hz, 1 H), 7.56 ( d, J = 8.08 Hz, 1 H), 8.00 (d, J = 8.08 Hz, 1 H), 11.51 (br s, 1H); 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

The title compound was prepared as described in Example 1-1 except that i-propylmagnesium chloride (2.0 M in ethyl ether, 0.50 mL, 1.00 mmol) was used. HPLC (45-60% acetonitrile in water, buffered with TFA) gave the title compound as a white solid (13.2 mg, 18%). 1 H NMR (400 MHz, CDCl 3 ) δ, ppm: 0.93 (d, J = 6.57 Hz, 3 H), 1.05 (d, J = 6.57 Hz, 3 H), 2.01-2.10 (sept, J = 6.76 Hz , 1 H), 2.61 (s, 3 H), 3.84 (br s, 1 H), 4.33 (d, J = 6.57 Hz, 1 H), 6.26 (s, 1 H), 7.23 (t, J = 7.96 Hz, 1 H), 7.56 (d, J = 8.08 Hz, 1 H), 8.00 (d, J = 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

The title compound was prepared as described in Example 1-1 except that cyclopentylmagnesium bromide (2.0 M in ethyl ether, 0.50 mL, 1.00 mmol) was used. HPLC (45-60% acetonitrile in water, buffered with TFA) gave the title compound as a white solid (7.8 mg, 10%). 1 H NMR (400 MHz, CDCl 3 ) 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, J = 8.59 Hz, 1 H), 6.27 (s, 1 H), 7.24 (t, J = 7.96 Hz, 1 H), 7.56 (d, J = 7.83 Hz, 1 H), 8.00 (d, J = 7.83 Hz, 1 H), 11.42 (br s, 1H). ESI-MS: m / z 387.1 (M + H) + .

Example 1-7: 3-chloro-N- (4- (cyclohexyl (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide

The title compound was prepared as described in Example 1-1 except that cyclohexylmagnesium bromide (2.0 M in ethyl ether, 0.50 mL, 1.00 mmol) was used. HPLC (45-60% acetonitrile in water, buffered with TFA) gave the title compound as a white solid (33.1 mg, 41%). 1 H NMR (400 MHz, CDCl 3 ) 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, J = 7.58 Hz, 1 H), 6.25 (s, 1 H), 7.23 (t, J = 7.96 Hz, 1 H), 7.56 (d, J = 8.08 Hz, 1 H), 8.00 (d, J = 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- (1-hydroxy-2-phenylethyl) thiazol-2-yl) -2-methylbenzenesulfonamide

The title compound was prepared as described in Example 1-1 except that benzylmagnesium chloride was used (1.0 M in THF, 1.00 mL, 1.00 mmol). HPLC (45-60% acetonitrile in water, buffered with TFA) gave the title compound as a white solid (23.2 mg, 28%). 1 H NMR (400 MHz, CDCl 3 ) δ, ppm: 2.64 (s, 3 H), 3.05-3.15 (m, 2 H), 4.91 (dd, J = 7.83, 6.06 Hz, 1 H), 6.25 (s , 1 H), 7.20-7.35 (m, 6 H), 7.56 (d, J = 7.83 Hz, 1 H), 8.00 (d, J = 8.08 Hz, 1 H), 11.44 (br s, 1H). ESI -MS: m / z 409.2 (M + H) + .

Example 1-9: 3-chloro-N- (4- (1-hydroxy-3-phenylpropyl) thiazol-2-yl) -2-methylbenzenesulfonamide

The title compound was prepared as described in Example 1-1 except that the following amounts were used; aldehyde (3-chloro-N- (4-formylthiazol-2-yl) -2-methyl Benzenesulfonamide) (250 mg, 0.789 mmol), THF (2 mL), phenethylmagnesium chloride (1M in THF, 3.00 mL, 3.00 mmol). HPLC (45-60% acetonitrile in water, buffered with TFA) gave the title compound as a white solid (15 mg, 4.5%). 1 H 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, J = 8.08 Hz, 1 H ), 7.97 (d, J = 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

The title compound was prepared as described in Example 1-1. 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, J = 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, J = 8.08 Hz, 1 H), 8.00 (d, J = 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

The title compound was prepared as described in Example 1-1. 1 H NMR (400 MHz, DMSO-D6) δ, ppm 1.07 (t, J = 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, J = 8.08 Hz, 1 H), 7.88 (d, J = 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

The title compound was prepared as described in Example 1-1. 1 H 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 , J = 8.21, 2.02 Hz, 1 H), 7.15-7.21 (m, 2 H), 7.23-7.28 (m, 1 H), 7.36 (td, J = 7.96, 5.81 Hz, 1 H), 7.59 (d , J = 8.08 Hz, 1 H), 7.99 (d, J = 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

The title compound was prepared as described in Example 1-1. 1 H NMR (400 MHz, CHLOROFORM-D) δ, ppm 2.68 (s, 3 H), 4.87 (br d, J = 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, J = 8.08 Hz, 1 H), 7.99 (d, J = 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

The title compound was prepared as described in Example 1-1. 1 H 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, J = 8.34 Hz, 1 H), 7.27 (t, J = 7.45 Hz, 1 H), 7.36 (d, J = 10.11 Hz, 1 H), 7.46-7.57 (m, 2 H), 7.84 (d, J = 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

The title compound was prepared as described in Example 1-1. 1 H 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, J = 8.08 Hz, 1 H), 7.98 (d, J = 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

Commercially available 4-fluorophenyl magnesium bromide (0.950 mL, 1.0 M in THF, 0.950 mmol) was added to 3-chloro-N- (4-formylthiazol-2-yl) -2 in tetrahydrofuran (3 mL). -Methylbenzenesulfonamide It was dripped at the stirring solution of Example 1-1-C (0.100g, 0.32mmol), and it stirred for 1 hour. The reaction mixture was quenched by adding a cold solution of saturated ammonium chloride (3 mL). The resulting solution was extracted with ethyl acetate (2 × 3 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by SiO 2 column chromatography eluting with hexane / ethyl acetate (1: 1) to yield 0.096 g (74%) of the title compound as a white foam. 1 H NMR (400 MHz, DMSO-d6) δ, ppm: 2.62 (s, 3 H), 5.54 (d, J = 4.29 Hz, 1 H,) 6.19 (d, J = 4.55 Hz, 1 H), 6.44 (S, 1 H), 7.16 (t, J = 8.84 Hz, 2 H), 7.36 (t, J = 7.96 Hz, 1 H), 7.42 (dd, J = 8.72, 5.68 Hz, 2 H), 7.64 ( d, J = 7.83 Hz, 1 H), 7.87 (d, J = 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

The title compound was obtained from commercially available phenylmagnesium bromide (3.0 M in diethyl ether) and 3-chloro-N- (4-formylthiazol-2-yl) -2-methylbenzenesulfonamide from Example 1-1-C. Prepared according to the procedures described in Examples 1-16. 1 H NMR (400 MHz, DMSO-d6) δ, ppm: 2.61 (s, 3 H), 5.52 (d, J = 4.29 Hz, 1 H), 6.19 (d, J = 4.80 Hz, 1 H), 6.43 (S, 1 H), 7.28 (t, J = 7.20 Hz, 1 H), 7.32-7.39 (m, 5 H), 7.65 (d, J = 9.35 Hz, 1 H), 7.87 (d, J = 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

The title compound was prepared from commercially available 4-chlorophenylmagnesium bromide (1.0 M in Et 2 O) and 3-chloro-N- (4-formylthiazol-2-yl) -2-methylbenzenesulfonamide Example 1-1 Prepared from C according to the procedure described in Example 1-16. 1 H NMR (400 MHz, DMSO-d6) δ, ppm: 2.61 (s, 3 H), 5.54 (d, J = 4.55 Hz, 1 H), 6.28 (d, J = 4.55 Hz, 1 H), 6.45 (S, 1 H), 7.34-7.43 (m, 5 H), 7.65 (d, J = 7.83 Hz, 1 H), 7.87 (d, J = 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

The title compound was obtained from commercially available 3-chlorophenylmagnesium bromide (0.5M in THF) and 3-chloro-N- (4-formylthiazol-2-yl) -2-methylbenzenesulfonamide from Example 1-1-C. Prepared according to the procedures described in Examples 1-16. 1 H NMR (400 MHz, DMSO-d6) δ, ppm: 2.62 (s, 9 H), 2.66 (s, 1 H), 5.56 (d, J = 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, J = 8.08 Hz, 4 H), 7.87 (d, J = 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

The title compound was obtained 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 Prepared from -1-C according to the procedure described in Example 1-16. 1 H NMR (400 MHz, DMSO-d6) δ, ppm: 2.61 (s, 3 H), 5.57 (d, J = 4.55 Hz, 1 H), 6.37 (d, J = 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, J = 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

The title compound was obtained 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 Prepared from -C according to the procedure described in Example 1-16. 1 H NMR (400 MHz, DMSO-d6) δ, ppm: 2.62 (s, 3 H), 5.59 (d, J = 4.55 Hz, 1 H), 6.44 (d, J = 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, J = 8.34 Hz, 1 H), 7.87 (d, J = 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

The title compound was obtained from commercially available m-tolyl magnesium bromide (1.0 M in THF) and 3-chloro-N- (4-formylthiazol-2-yl) -2-methylbenzenesulfonamide from Example 1-1-C. Prepared according to the procedures described in Examples 1-16. 1 H NMR (400 MHz, DMSO-d6) δ, ppm: 2.28 (s, 2 H), 2.61 (s, 2 H), 5.47 (d, J = 4.80 Hz, 1 H), 6.14 (d, J = 3.54 Hz, 1 H), 6.43 (s, 1 H), 7.09 (d, J = 7.58 Hz, 1 H), 7.14-7.26 (m, 3 H), 7.36 (t, J = 7.96 Hz, 1 H) , 7.65 (d, J = 8.08 Hz, 1 H), 7.87 (d, J = 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

The title compound was obtained 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 Prepared from -C according to the procedure described in Example 1-16. 1 H 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, J = 4.80 Hz, 1 H ), 6.03 (d, J = 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, J = 7.96 Hz, 1 H), 7.66 (d, J = 8.08 Hz, 1 H), 7.88 (d, J = 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

The title compound was obtained 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 From and according to the procedure described in Example 1-16. 1 H NMR (400 MHz, DMSO-d6) δ, ppm: 2.63 (s, 2 H), 3.73 (s, 2 H), 5.76 (d, J = 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, J = 8.34 Hz, 1 H), 7.36 (t, J = 8.08 Hz, 1 H), 7.43 ( d, J = 7.58 Hz, 1 H), 7.65 (d, J = 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

Commercially available isopropyl magnesium chloride (1.42 mL, 2.0 M in dimethyl ether, 2.84 mmol) was added to a stirred solution of 4-iodobenzenenitrile (0.651 g, 2.84 mmol) in THF at −10 ° C. The reaction was warmed to room temperature and stirred for 1 h, which was then treated with 3-chloro-N- (4-formylthiazol-2-yl) -2-methylbenzenesulfonamide in THF Example 1-1-C (0 150 g, 0.474 mmol) in 3 mL of stirred solution at room temperature. The reaction was stirred at ambient temperature for 1 hour and quenched with saturated ammonium chloride solution (5 mL). The resulting solution was extracted with ethyl acetate (2 × 3 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by SiO 2 column chromatography eluting with hexane / ethyl acetate (2: 1) to give 0.115 g (58%) of the title compound as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ, ppm: 2.60 (s, 3 H), 5.64 (t, J = 4.55 Hz, 1 H), 6.38-6.45 (m, 1 H), 6.50 (s, 1 H), 7.35 (t, J = 8.08 Hz, 1 H), 7.58 (d, J = 8.08 Hz, 2 H), 7.64 (d, J = 7.58 Hz, 1 H), 7.81 (d, J = 8.59 Hz, 2 H), 7.86 (d, J = 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

The title compound was obtained from commercially available 1-iodo-3- (trifluoromethyl) benzene and 3-chloro-N- (4-formylthiazol-2-yl) -2-methylbenzenesulfonamide from Example 1-1-C. Prepared according to the procedures described in Examples 1-25. 1 H NMR (400 MHz, DMSO-d6) δ, ppm: 2.61 (s, 3 H), 5.67 (d, J = 4.55 Hz, 1 H), 6.42 (d, J = 4.80 Hz, 1 H), 6.53 (S, 1 H), 7.36 (t, J = 7.71 Hz, 1 H), 7.58 (t, J = 7.58 Hz, 1 H), 7.63-7.69 (m, 3 H), 7.79 (s, 1 H) , 7.87 (d, J = 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

The title compound was prepared from commercially available 2-pyridylmagnesium bromide (7.6 mL, 0.25 M in dimethyl ether) and 3-chloro-N- (4-formylthiazol-2-yl) -2-methylbenzenesulfonamide. Prepared from 1-C according to the procedure described in Example 1-16. 1 H 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 = 11.12, 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

The title compound was obtained from commercially available 2-chloro-3-iodopyridine and 3-chloro-N- (4-formylthiazol-2-yl) -2-methylbenzenesulfonamide Example 1-1-C to Example 1- Purified according to the procedure described in 25. 1 H NMR (400 MHz, DMSO-d6) δ, ppm: 2.62 (s, 3 H), 5.71 (d, J = 5.05 Hz, 1 H), 6.38 (s, 1 H), 6.45 (s, 1 H ), 7.35 (t, J = 8.08 Hz, 1 H), 7.45-7.53 (m, 1 H), 7.63 (d, J = 7.83 Hz, 1 H), 7.87 (d, J = 7.83 Hz, 1 H) , 8.01 (d, J = 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

Sodium hydride (0.080 g, 95% dry, 3.2 mmol) was added to a stirred solution of trimethylsulfonium iodide (0.644 g, 3.2 mmol) in dimethyl sulfoxide (1 mL). The resulting reaction was stirred at ambient temperature for 0.5 hour until gas evolution ceased. 3-Chloro-N- (4-formylthiazol-2-yl) -2-methylbenzenesulfonamide in dimethyl sulfoxide (1 mL) Syringe a solution of Example 1-1-C (0.100 g, 0.32 mmol) And the resulting reaction was stirred for 1 hour at ambient temperature and then quenched with pH 7 phosphate buffer (2 mL). The resulting solution was extracted with ethyl acetate (2 × 2 mL). The combined organic fractions were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The yellow oily residue was dissolved in THF (1 mL) and THF (1 mL) N, N-diethylamine (0.136 mL, 1.31 mmol) and Brockman neutral aluminum oxide (2.4 g, 23.5 mmol). After 1 hour, the reaction was filtered, rinsed with methanol (4 mL) and concentrated. The resulting yellow residue was purified by preparative HPLC-MS (5-95% CH 3 CN in water) to give 0.003 g of the title compound as a white foam. 1 H NMR (400 MHz, Methanol-d4) δ, ppm: 1.24 (t, J = 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, J = 12.51, 4.67 Hz, 1 H), 3.99 (dd, J = 12.38, 7.58 Hz, 1 H), 4.31 (dd, J = 7.71, 4.67 Hz, 1 H) , 6.74 (s, 1 H), 7.22 (t, J = 8.21 Hz, 1 H), 7.49 (d, J = 8.84 Hz, 1 H), 7.97 (d, J = 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

According to the procedure described in Example 2-20, the title compound was prepared from 4-methylpyrimidine and 3-chloro-N- (4-formylthiazol-2-yl) -2-methylbenzenesulfonamide from Example 1-1-C. Prepared. 1 H 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 = 5.30 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

3-Iodobenzenenitrile (0.33 g, 1.4 mmol) was dissolved in THF (10 ml) and cooled to −10 ° C. Isopropylmagnesium chloride (0.71 ml, 1.4 mmol) was added dropwise, and the mixture was stirred at −10 ° C. for 1.5 hours. 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 ° C. Added at. After stirring at −10 ° C. for 3 hours, the reaction mixture was quenched with saturated NH 4 Cl at 0 ° C. The mixture was further diluted with brine and extracted 3 times with EtOAc. The combined organic layers were dried over MgSO 4 , filtered and concentrated. The crude product was purified by SiO 2 column chromatography eluting with EtOAc / hexane (3: 1) to give 0.11 g (55%) of the title compound. 1 H 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, J = 8.0 Hz, 1 H), 7.23 (t, J = 8.1 Hz, 1 H), 7.48 (t, J = 7.7 Hz, 1 H), 7.56 (d, J = 7.8 Hz, 1 H), 7.61 (d , J = 7.6 Hz, 1 H), 7.66 (d, J = 7.8 Hz, 1 H), 7.73 (s, 1 H), 7.94 (d, J = 7.8 Hz, 1 H); 13C NMR (100 MHz, CHLOROFORM-D) δ, 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

The title compound was prepared from commercially available 2-iodobenzenenitrile 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 SiO 2 column chromatography eluting with EtOAc / hexane (3: 1) to give 0.10 g (50%) of the title compound. 1 H 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, J = 8.0 Hz, 1 H), 7.52 (t, J = 7.6 Hz, 1 H), 7.63 (d, J = 7.8 Hz, 1 H), 7.66 (d, J = 7.8 Hz, 1 H), 7.73 (t, J = 7.6 Hz, 1 H), 7.83 (d, J = 7.6 Hz, 1 H), 7.87 (d, J = 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

The title compound was obtained from commercially available 3-methoxyphenylmagnesium bromide (1.0 M in THF) and 3-chloro-N- (4-formylthiazol-2-yl) -2-methylbenzenesulfonamide from Example 1-25. Prepared according to the procedure described in. The crude product was purified by SiO 2 column chromatography eluting with EtOAc / hexane (3: 2) to give 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-hydroxypropyl) thiazol-2-yl) -2-methylbenzenesulfonamide

The title compound was prepared as described in Example 1-2 except that it was asymmetrically reduced (82% enantiomeric excess) with (+) DIPCl. The configuration was specified based on the example of DIPCI reduction. 1 H NMR (400 MHz, CDCl 3 ) δ, ppm: 1.04 (t, J = 7.33 Hz, 3 H), 1.85 (quint, J = 7.26 Hz, 2 H), 2.62 (s, 3 H), 4.55 ( t, J = 6.82 Hz, 1 H), 6.30 (s, 1 H), 7.24 (t, J = 8.08 Hz, 1 H), 7.57 (d, J = 8.08 Hz, 1 H), 8.00 (d, J = 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- (1-hydroxypropyl) thiazol-2-yl) -2-methylbenzenesulfonamide

The title compound was obtained from 3-chloro-2-methyl-N- (4-propionylthiazol-2-yl) benzenesulfonamide as described in Example 1-2 with 81% enantiomer using (−) DIPCl. Purification by excess asymmetric reduction. The configuration was specified based on the example of DIPCI reduction. 1 H NMR (400 MHz, CDCl 3 ) δ, ppm: 1.04 (t, J = 7.33 Hz, 3 H), 1.85 (quint, J = 7.26 Hz, 2 H), 2.62 (s, 3 H), 4.55 ( t, J = 6.82 Hz, 1 H), 6.30 (s, 1 H), 7.24 (t, J = 8.08 Hz, 1 H), 7.57 (d, J = 8.08 Hz, 1 H), 8.00 (d, J = 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

The title compound was prepared by the preparative SFC separation method of Examples 1-11 above (> 98% enantiomeric excess). 1 H NMR (400 MHz, DMSO-D6) δ, ppm 1.07 (t, J = 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, J = 8.08 Hz, 1 H), 7.88 (d, J = 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

The title compound was prepared by the preparative SFC separation method of Examples 1-11 above (> 98% enantiomeric excess). 1 H NMR (400 MHz, DMSO-D6) δ, ppm 1.07 (t, J = 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, J = 8.08 Hz, 1 H), 7.88 (d, J = 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: 2- (2- (3-Chloro-2-methylphenylsulfonamido) thiazol-4-yl) ethyl acetate

DMAP (50 mg, 0.41 mmol) was added 2- (2-aminothiazol-4-yl) in 3-chloro-2-methylbenzene-1-sulfonyl chloride (3.92 g, 17.4 mmol) and pyridine (20 mL). ) To a stirred solution of ethyl acetate (3.21 g, 17.2 mmol). The reaction mixture was stirred at 20 ° C. for 16 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), washed with HCl (6N, 3 × 50 mL), water (50 mL), brine (50 mL), dried (MgSO 4 ) and concentrated under reduced pressure. Suspend the crude product in ether (150 mL) and stir vigorously until a fine suspension is obtained, cool to 10 ° C., filter and dry under reduced pressure to give the title compound as a pink solid Obtained as a product (5.39 g, 83%). 1 H NMR (400 MHz, CDCl 3 ) δ, ppm: 1.25 (t, J = 7.20 Hz, 3 H), 2.63 (s, 3 H), 3.75 (s, 2 H), 4.18 (q, J = 7.07 Hz, 2 H), 6.33 (s, 1 H), 7.21 (t, J = 8.34 Hz, 1 H), 7.53 (d, J = 8.08 Hz, 1 H), 8.00 (d, J = 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

Cold 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) 78 ° C.) DIBAL-H (1M in hexane, 1.10 mL, 1.10 mmol) was added over 5 minutes. The reaction mixture was stirred at −78 ° C. for 40 minutes. Acetone (0.4 mL) was added and subsequently stirred for 10 minutes. The reaction was then treated with tartaric acid (10% aqueous solution, 10 mL) and the mixture was allowed to warm to room temperature, stirred overnight, and extracted with ethyl acetate (4 × 3 mL). The combined organic layers were washed with brine (5 mL), dried (MgSO 4 ), filtered and concentrated under reduced pressure. Silica gel flash column chromatography (40 mL SiO 2, hexane - ethyl acetate 1: 4,300mL) was passed through to give the title compound as a brownish solid (0.107g, 64%). 1 H 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, J = 7.83 Hz, 1 H) 7.53 (d , J = 8.08 Hz, 1 H) 7.96 (d, J = 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

3-Chloro-2-methyl-N- (4- (2-oxoethyl) thiazol-2-yl) benzenesulfonamide (0.190 g, 0.534 mmol) was dissolved in THF and −10 ° C. under nitrogen atmosphere. Cooled down to 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 minutes. It was quenched with a cooled NH 4 Cl (saturated aqueous solution, 5 mL) -water (5 mL) mixture and stirred vigorously for 5 min. The resulting mixture was extracted with ethyl acetate (3 × 7 mL). The combined organic extracts were dried (MgSO 4 ), filtered and concentrated under reduced pressure. The crude product was purified by TLC (ethyl acetate) to give the title compound as a white solid (37.2 mg, 19%). 1 H NMR (400 MHz, CHLOROFORM-D) δ, ppm: 0.93 (t, J = 7.07 Hz, 3 H), 1.29-1.54 (m, 4 H), 2.44 (br s, 1 H), 2.62 (dd , J = 15.3, 7.96 Hz, 1 H), 2.70 (s, 3 H), 2.78 (dd, J = 15.2, 3.30 Hz, 1 H), 3.83-3.90 (m, 1 H), 6.09 (s, 1 H), 7.21 (t, J = 7.96 Hz, 1 H), 7.52 (d, J = 7.58 Hz, 1 H), 8.02 (d, J = 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

The title compound was prepared as described in Example 2-1. 1 H NMR (400 MHz, CHLOROFORM-D) δ, ppm 0.94 (d, J = 6.82 Hz, 3 H), 0.97 (d, J = 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 , J = 7.45 Hz, 1 H), 7.51 (d, J = 7.58 Hz, 1 H), 8.02 (d, J = 7.33 Hz, 1 H), 10.17 (br s, 1H). ESI-MS: m / z 375.1 (M + H) + .

Example 2-3: 3-chloro-N- (4- (2-cyclopentyl-2-hydroxyethyl) thiazol-2-yl) -2-methylbenzenesulfonamide

The title compound was prepared as described in Example 2-1. 1 H NMR (400 MHz, CHLOROFORM-D) δ, ppm 1.09-0.92 (m, 9 H), 2.59 (dd, J = 15.4, 8.08 Hz, 1 H), 2.73 (s, 3 H), 2.77 (dd , J = 15.4, 2.56 Hz, 1 H), 3.61-3.67 (m, 1 H), 6.05 (s, 1 H), 7.21 (t, J = 7.45 Hz, 1 H), 7.51 (d, J = 7.58 Hz, 1 H), 8.02 (d, J = 7.33 Hz, 1 H), 10.18 (br s, 1H). ESI-MS: m / z 401.1 (M + H) + .

Example 2-4: 3-chloro-N- (4- (2-hydroxy-2-phenylethyl) thiazol-2-yl) -2-methylbenzenesulfonamide

The title compound was prepared as described in Example 2-1. 1 H NMR (400 MHz, CHLOROFORM-D) δ, ppm 2.60 (br s, 1 H), 2.73 (s, 3 H), 2.94 (d, J = 5.81 Hz, 2 H), 4.97 (t, J = 5.68 Hz, 1 H), 6.01 (s, 1 H), 7.22 (t, J = 7.96 Hz, 1 H), 7.33 (m, 5 H), 7.53 (d, J = 7.33 Hz, 1 H), 8.03 (D, J = 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

The title compound was prepared as described in Example 2-1. 1 H NMR (400 MHz, CHLOROFORM-D) δ, ppm 0.95 (s, 9 H), 1.70 (br s, 1H), 2.52 (ddd, J = 15.22, 10.55, 1.26 Hz, 1 H), 2.69-2.75 (M, 4 H), 3.46 (dd, J = 10.74, 1.64 Hz, 1 H), 6.08 (s, 1 H), 7.21 (t, J = 7.96 Hz, 1 H), 7.52 (d, J = 7.83 Hz, 1 H), 8.02 (d, J = 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

The title compound was prepared as described in Example 2-1. 1 H 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, J = 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, J = 7.96 Hz, 1 H), 7.31 (m, 1 H), 7.54 (d, J = 8.08 Hz, 1 H), 8.02 (d, J = 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

Mg powder (0.729 g, 30.0 mmol) was placed in a flame-dried flask and ethyl ether (2 mL) was added under nitrogen. Once 1,2-dibromoethane (0.1 mL) was added and gas evolution almost ceased, 2- (bromomethyl) -1,4-difluorobenzene (2.07 g, 10.7 g) in ethyl ether (8 mL). 0 mmol) was added at a rate that maintained a gentle reflux (20 minutes). The reaction mixture was then heated to reflux for 10 minutes and cooled to room temperature. Half of the resulting solution was a solution of 2- (2- (3-chloro-2-methylphenylsulfonamido) thiazol-4-yl) ethyl acetate (0.325 g, 0.865 mmol) in THF (2 mL). At room temperature over 1 hour and the resulting mixture was stirred for 30 minutes. It was then quenched with a cooled (0 ° C.) NH 4 Cl (saturated aqueous solution, 5 mL) -water (5 mL) mixture and stirred vigorously for 5 minutes. The resulting mixture was extracted with ethyl acetate (3 × 3 mL). The combined organic extracts were dried (MgSO 4 ), filtered and concentrated under reduced pressure. The resulting residue was dissolved in THF (2 mL) and treated with the same method as above with half of the remaining Grignard solution. The resulting crude product was purified by HPLC (45-60% acetonitrile in water, buffered with TFA) to give the title compound as a white solid (0.160 g, 41%). 1 H 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, J = 7.96 Hz, 1 H) 7.56 (d, J = 8.08 Hz, 1 H) 8.00 (d, J = 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

3-Chloro-N- (4- (3- (2,5-difluorophenyl) -2-oxopropyl) thiazol-2-yl) -2-methyl-benzenesulfonamide (60 mg, 0.131 mmol) was added to THF ( 1.5 mL) and cooled to −10 ° C. under nitrogen. LiAlH 4 (1.0 M in THF, 1.00 mL, 1.00 mmol) was added over 1 minute and the reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. It was then quenched with tartaric acid (10% aqueous solution, 3 mL) and extracted with ethyl acetate (3 × 3 mL). The combined organic extracts were dried (MgSO 4 ), filtered and concentrated under reduced pressure. HPLC (45-60% acetonitrile in water, buffered with TFA) gave the title compound as a white solid (34.3 mg, 57%). 1 H 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, J = 7.83 Hz, 1 H) 7.54 (d, J = 8.59 Hz, 1 H) 8.01 (d, J = 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

The title compound was prepared as described in Example 2-7. 1 H 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, J = 8.46 Hz, 2 H) 7.16 (t, J = 6.32 Hz, 2 H) 7.22 (t, J = 7.83 Hz, 1 H) 7.54 (d, J = 8.08 Hz, 1 H) 8.01 (d, J = 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

The title compound was prepared as described in Example 2-7. 1 H 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, J = 8.08 Hz, 1 H) 8.01 (d, J = 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) -1- (2- (3-chloro-2-methylphenylsulfonamido) thiazol-4-yl) -3- (2-fluorophenyl) propan-2-yl) 2-methoxy-2-phenylacetic acid

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) in dichloromethane (5 mL) and EDCI (77.0 mg, 0.402 mmol) was added followed by DMAP (10 mg, 0.082 mmol) was added. The reaction mixture was stirred for 15 h, diluted with ethyl acetate (10 mL), washed with water (5 mL), sodium bicarbonate (saturated aqueous solution, 10 mL), dried (MgSO 4 ) and concentrated under reduced pressure. HPLC (60-99% acetonitrile in water, buffered with TFA) afforded a 1: 1 diastereomeric mixture of esters as a white solid (0.151 mg, 78%). Diastereomers were separated using preparative silica gel TLC (dichloromethane-ethyl acetate 40: 1, 4 x 20 x 20 cm plates, 1 mm thickness). The bottom band contained the title compound (78.8 mg, 41%, 95% enantiomeric excess). 1 H 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, J = 7.96 Hz, 1 H) 7.30-7.36 (m, 5 H 7.54 (d, J = 8.08 Hz, 1 H) 8.02 (d, J = 7.33 Hz, 1 H) 10.70 (br s, 1H). ESI-MS: m / z 589.2 (M + H) + .

The top band contained another diastereomer (63.1 mg, 32%,> 99: 1 diastereo ratio). 1 H 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, J = 7.83 Hz, 1 H) 8.02 (d, J = 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

(R)-((S) -1- (2- (3-Chloro-2-methylphenylsulfonamido) thiazol-4-yl) -3- (2-fluorophenyl) propan-2-yl) 2-methoxy 2-Phenylacetic acid (78.0 mg, 0.132 mmol) was dissolved in dichloromethane, cooled to −78 ° C. under nitrogen and treated with DIBAL-H (1.0 M in hexane, 1.20 mL, 1.20 mmol). did. The reaction mixture was warmed to room temperature over 30 minutes and stirred for 5 minutes. Then it was cooled to −78 ° C., methanol (1 mL) was added and stirred for 5 minutes. The mixture was then treated with Rochelle salt solution (20% aqueous solution, 8 mL), diluted with ethyl ether (8 mL) and stirred vigorously overnight. The bottom aqueous layer was discarded and the organic layer was dried (MgSO 4 ), filtered and concentrated under reduced pressure. HPLC (60-99% acetonitrile in water, buffered with TFA) gave the title compound as a white solid (45.7 mg, 79%). The configuration was determined based on the NMR analysis of diastereomers of the methoxyphenylacetic acid derivatives of Examples 2-9 and 2-13 in a known configuration.

Example 2-11: (R) -3-Chloro-N- (4- (3- (2-fluorophenyl) -2-hydroxypropyl) thiazol-2-yl) -2-methylbenzenesulfonamide

  Example 2-10-A Starting from the other diastereomers separated by preparative TLC, the title compound was prepared as described in Example 2-10-B except that the following amounts were used. Obtained. : (R)-((R) -1- (2- (3-chloro-2-methylphenylsulfonamido) thiazol-4-yl) -3- (2-fluorophenyl) propan-2-yl) 2- Methoxy-2-phenylacetic acid (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%). The configuration was determined based on the NMR analysis of diastereomers of the methoxyphenylacetic acid derivatives of Examples 2-9 and 2-13 in a known configuration.

Example 2-12: 3-chloro-N- (4- (2-hydroxy-3-phenylpropyl) thiazol-2-yl) -2-methylbenzenesulfonamide

The title compound was prepared as described in Example 2-7 except that commercially available benzylmagnesium chloride (1M in ethyl ether) was used. 1 H 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, J = 7.83 Hz, 1 H) 8.02 (d, J = 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-phenylpropyl) thiazol-2-yl) -2-methylbenzenesulfonamide

The title compound was prepared by the method of preparative SFC separation of Example 2-12 as described above (> 98% enantiomeric excess). The configuration was determined based on the X-ray crystal structure. 1 H 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, J = 7.83 Hz, 1 H) 8.02 (d, J = 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

The title compound was prepared as described in Example 2-7. 1 H 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, J = 8.08 Hz, 1 H) 8.01 (d, J = 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

The title compound was prepared as described in Example 2-7. 1 H 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, J = 7.83 Hz, 1 H) 8.01 (d, J = 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

The title compound was prepared as described in Example 2-7. 1 H NMR (400 MHz, CHLOROFORM-D) δ, ppm 2.55 (d, J = 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, J = 7.83 Hz, 1 H) 8.02 (d, J = 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

The title compound was prepared as described in Example 2-7. 1 H 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, J = 15.2, 7.82 Hz, 1 H) 2.89-2.95 (dd, J = 15.2, 3.04 Hz, 1 H) 3.10 (t , J = 7.45 Hz, 1 H) 6.13 (s, 1 H) 7.21 (t, J = 7.96 Hz, 1 H) 7.52 (d, J = 8.08 Hz, 1 H) 8.02 (d, J = 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

The title compound was prepared as described in Example 2-10 except that dichloromethane-ethyl ether (7: 1) was used for preparative TLC separation. The configuration was determined based on NMR analysis of the diastereomers of the methoxyphenylacetic acid derivatives of Examples 2-17 and 2-13 in known configurations. 1 H 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, J = 15.2, 7.82 Hz, 1 H) 2.89-2.95 (dd, J = 15.2, 3.04 Hz, 1 H) 3.10 (t , J = 7.45 Hz, 1 H) 6.13 (s, 1 H) 7.21 (t, J = 7.96 Hz, 1 H) 7.52 (d, J = 8.08 Hz, 1 H) 8.02 (d, J = 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

The title compound was prepared as described in Example 2-11 except that dichloromethane-ethyl ether (7: 1) was used for preparative TLC separation. The configuration was determined based on NMR analysis of the diastereomers of the methoxyphenylacetic acid derivatives of Examples 2-17 and 2-13 in known configurations. 1 H 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, J = 15.2, 7.82 Hz, 1 H) 2.89-2.95 (dd, J = 15.2, 3.04 Hz, 1 H) 3.10 (t, J = 7.45 Hz, 1 H) 6.13 (s, 1 H) 7.21 (t, J = 7.96 Hz, 1 H) 7.52 (d, J = 8.08 Hz, 1 H) 8.02 (d, J = 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

Lithium diisopropylamide (9 mL in THF, 0.44 M solution) was added to a stirred solution of 4-methylpyrimidine in THF (7 mL) at −78 ° C. After stirring for 0.5 hour, the resulting solution was added via cannula to 3-chloro-2-methyl-N- (4- (2-oxoethyl) thiazol-2-yl) benzenesulfonamide in THF. To the stirred solution (2 mL) of Example 2-1-B at -78 ° C. The resulting reaction was stirred at −78 ° C. for 0.5 h and then warmed to ambient temperature. After 2 hours, the reaction was quenched with saturated ammonium chloride solution (10 mL). The resulting solution was extracted with ethyl acetate (2 × 20 mL). The combined organic fractions were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting brown oil was purified by preparative HPLC-MS (30-45% CH 3 CN in H 2 O) to give 0.003 g of the title compound as a yellow oil. 1 H 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 = 1.01 Hz, 1 H), 8.63 ( d, J = 5.05 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: 2- (2- (4-Fluoro-2-methylphenylsulfonamido) thiazol-4-yl) ethyl acetate

The title compound was prepared as described in Example 2-1-A. 1 H 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

The title compound was prepared as described in Example 2-1. 1 H 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-N- (4- (2-hydroxybutyl) thiazol-2-yl) benzenesulfonamide

The title compound was prepared as described in Example 2-1. 1 H 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

The title compound was prepared as described in Example 2-1. 1 H 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) benzenesulfonamide

The title compound was prepared as described in Example 2-1. 1 H 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

The title compound was purified by the preparative SFC separation method of Example 2-12 above (> 98% enantiomeric excess). The configuration was determined based on the X-ray crystal structure. 1 H 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, J = 7.83 Hz, 1 H) 8.02 (d, J = 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

3-Chloro-N- (4-formylthiazol-2-yl) -2-methylbenzenesulfonamide Example 1-1-C (0.859 g, 2.71 mmol) was dissolved in EtOH (20 mL) and acetophenone ( 0.350 mL, 3.00 mmol) was added. This mixture was treated with NaOH (5M in water, 5 mL) and the resulting red clear mixture was stirred for 5 minutes. The reaction mixture was diluted with NH 4 Cl to pH 7 (about 50 mL) and extracted with ethyl acetate (50 mL). The organic extract was dried (MgSO 4 ), filtered and concentrated under reduced pressure. The crude product (1.25 g) was suspended in ethyl acetate (150 mL) and PtO 2 (100 mg, 0.440 mmol) was added. The reaction mixture was hydrogenated at room temperature with a hydrogen pressure of 40 psi for 20 hours. This was diluted with MeOH (100 mL) and filtered through a plug consisting of celite (top, 10 mL) and silica gel (bottom, 3 mL). The stopper was washed thoroughly with MeOH and the filtrate was concentrated under reduced pressure. The resulting crude product was recrystallized from ethyl acetate-ethyl ether (1: 2, 50 mL) to give the title compound as an off-white solid (0.313 g, 27%). 1 H NMR (400 MHz, DMSO-D6) δ, ppm 2.64 (s, 3 H) 2.77 (t, J = 7.33 Hz, 2 H) 3.38 (t, J = 7.20 Hz, 2 H) 6.50 (s, 1 H) 7.37 (t, J = 7.96 Hz, 1 H) 7.51 (t, J = 7.58 Hz, 2 H) 7.60-7.69 (m, 2 H) 7.89 (d, J = 7.83 Hz, 1 H) 7.97 (d , J = 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

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 THF (30 mL) was dissolved. ) And cooled to −10 ° C. under nitrogen. (-) DIPCl (150 mg, 0.468 mmol) was quickly added dropwise and the reaction mixture was allowed to warm to room temperature over 3 hours and stirred overnight. This was then treated with EtOH (0.8 mL), NaOH (3M in water, 0.15 mL) and H 2 O 2 (35% in water, 0.15 mL) and stirred at 60 ° C. for 1.5 hours. The mixture was cooled, diluted with water (3 mL) and extracted with ethyl acetate (3 mL). The combined organic extracts were dried (MgSO 4 ), filtered and concentrated under reduced pressure. 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 mL) to give the title compound. Obtained as a white solid (46 mg, 51%, 98% enantiomeric excess). The configuration was determined based on the X-ray crystal structure. 1 H 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, J = 8.08 Hz, 1 H) 7.65 (d, J = 8.84 Hz, 1 H) 7.88 (d, J = 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-phenylpropyl) thiazol-2-yl) -2-methylbenzenesulfonamide

Asymmetric reduction of (+) DIPCl from 3-chloro-2-methyl-N- (4- (3-oxo-3-phenylpropyl) thiazol-2-yl) benzenesulfonamide (98% optical purity) ) And was prepared as described in Example 3-1B. The configuration was determined based on the X-ray crystal structure. 1 H 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, J = 8.08 Hz, 1 H) 7.65 (d, J = 8.84 Hz, 1 H) 7.88 (d, J = 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

Ethyl 2- (3-chloro-2-methylphenylsulfonamido) thiazole-4-carboxylate (0.109 g, 0.302 mmol) was dissolved in THF (2 mL) and methylmagnesium chloride (3.0 M in ethyl ether, 0.5 mL, 1.5 mmol) for 1 hour. The reaction mixture was stirred for 0.5 h, quenched with a cooled (0 ° C.) NH 4 Cl (saturated aqueous solution, 2.5 mL) -water (2.5 mL) mixture and extracted with ethyl acetate (5 mL). The organic extract was dried (MgSO 4 ), filtered and concentrated under reduced pressure. The resulting crude product was purified by HPLC (20-60% acetonitrile in water, buffered with TFA) to give the title compound as a white solid (53.4 mg, 51%). 1 H 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, J = 7.96 Hz , 1 H) 7.66 (d, J = 8.08 Hz, 1 H) 7.89 (d, J = 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

The title compound was obtained as described in Example 4-1. 1 H NMR (400 MHz, DMSO-D6) δ, ppm 0.66 (t, J = 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, J = 1.52 Hz, 1 H) 7.38 (t, J = 7.96 Hz, 1 H) 7.66 (d, J = 8.08 Hz, 1 H) 7.89 (d, J = 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

The title compound was obtained as described in Example 4-1. 1 H NMR (400 MHz, CHLOROFORM-D) δ, ppm 0.90 (t, J = 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, J = 8.08 Hz, 1 H) 7.53 (d, J = 8.08 Hz, 1 H) 8.01 (d, J = 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

Ethyl 2- (3-chloro-2-methylphenylsulfonamido) thiazole-4-carboxylate (180.4 mg, 0.500 mmol) was dissolved in THF (3 mL) and cooled to 0 ° C. under nitrogen. Then Ti (OiPr) 4 (0.15 mL, 0.49 mmol) was added dropwise over 30 minutes. The resulting dark mixture was quenched with a cooled (0 ° C.) NH 4 Cl (saturated aqueous solution, 2.5 mL) -water (2.5 mL) mixture and stirred vigorously for 5 minutes. 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 stopper was thoroughly washed with ethyl acetate and filtered under reduced pressure. The resulting crude product was purified by HPLC (40-50% acetonitrile in water, buffered with TFA) to give the title compound as a white solid (34.6 mg, 20%). 1 H NMR (400 MHz, DMSO-D6) δ, ppm 0.96 (app d, J = 9.09 Hz, 4 H) 2.63 (s, 3 H) 6.25 (s, 1 H) 6.50 (s, 1 H) 7.37 ( t, J = 8.46 Hz, 1 H) 7.66 (d, J = 7.83 Hz, 1 H) 7.89 (d, J = 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- (1-hydroxycyclopentyl) thiazol-2-yl) -2-methylbenzenesulfonamide

Magnesium powder (3.90 g, 0.160 mol) in THF (5 mL) was treated with 1,2-dibromoethane (0.1 mL) under nitrogen. When gas evolution ceased, a solution of 1,4-dibromoethane (3.1 mL, 26.2 mmol) in THF (10 mL) was added at a rate to maintain reflux (about 20 minutes). After the addition was complete, the reaction mixture was heated to reflux for 10 minutes and cooled to room temperature. 4 mL of the resulting solution (about 5 mmol Grignard reagent) was added to 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, quenched very carefully with a cooled (0 ° C.) NH 4 Cl (saturated aqueous solution, 2.5 mL) -water (2.5 mL) mixture, stirred vigorously for 5 min and acetic acid. Extracted with ethyl (10 mL). The combined organic extracts were dried (MgSO 4 ), filtered and concentrated under reduced pressure. HPLC (45-60% acetonitrile in water, buffered with TFA) gave the title compound as a white solid (0.181 g, 49%). 1 H 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, J = 7.96 Hz, 1 H) 7.66 (d, J = 8.59 Hz, 1 H) 7.89 (d, J = 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

The title compound was obtained from ethyl 2- (4-phenoxyphenylsulfonamido) thiazole-4-carboxylate and ethylmagnesium bromide as described in Example 4-1. 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.66 (t, J = 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, J = 8.84 Hz, 2 H) 7.11 (d, J = 8.59 Hz, 2 H) 7.23 (t, J = 7.45 Hz, 1 H) 7.44 (t, J = 7.45 Hz, 2 H) 7.78 (d , J = 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

The title compound was obtained from ethyl 2- (2-phenoxypyridine-5-sulfonamido) thiazole-4-carboxylate and ethylmagnesium bromide as described in Example 4-1. 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.66 (t, J = 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, J = 9.09 Hz, 1 H) 7.18 (d, J = 8.34 Hz, 2 H) 7.26 (t, J = 7.45 Hz, 1 H) 7.43 (t, J = 7.58 Hz, 2 H) 8.15 (ddd , J = 8.59, 2.53, 1.26 Hz, 1 H) 8.50 (d, J = 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

The title compound was obtained as described in Example 4-1 from ethyl 2- (naphthalene-3-sulfonamido) thiazole-4-carboxylate and ethylmagnesium bromide. 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.63 (t, J = 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, J = 8.59 Hz, 1 H) 8.00 (d, J = 7.07 Hz, 1 H) 8.06 (d, J = 8.59 Hz, 1 H) 8.15 (d, J = 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

The title compound was obtained as described in Example 4-1 from ethyl 2- (2,3-dichlorophenylsulfonamido) thiazol-4-carboxylate and ethylmagnesium bromide. 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.67 (t, J = 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, J = 7.96, 1.01 Hz, 1 H) 7.87 (dt, J = 8.02, 1.29 Hz, 1 H) 8.04 (dt, J = 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

The title compound was obtained as described in Example 4-1 from ethyl 2- (benzofuran-2-sulfonamido) thiazol-4-carboxylate and ethylmagnesium bromide. 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.65 (t, J = 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, J = 7.45 Hz, 1 H) 7.42-7.51 (m, 2 H) 7.66 (d, J = 8.59 Hz, 1 H) 7.76 (d, J = 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

The title compound was obtained as described in Example 4-1 from ethyl 2- (benzo [d] thiazole-6-sulfonamido) thiazol-4-carboxylate and ethylmagnesium bromide. 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.64 (t, J = 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, J = 8.59, 1.52 Hz, 1 H) 8.20 (d, J = 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

The title compound was obtained as described in Example 4-1 from ethyl 2- (benzo [b] thiophene-2-sulfonamido) thiazol-4-carboxylate and ethylmagnesium bromide. 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.65 (t, J = 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, J = 7.33 Hz, 1 H) 8.02 (d, J = 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-1-sulfonamide

The title compound was obtained as described in Example 4-1 from ethyl 2- (naphthalene-1-sulfonamido) thiazol-4-carboxylate and ethylmagnesium bromide. 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.61 (t, J = 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, J = 8.08 Hz, 1 H) 8.14-8.19 (m, 2 H) 8.70 (d, J = 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

The title compound was obtained as described in Example 4-1 from ethyl 2- (5-methylbenzo [b] thiophene-2-sulfonamido) thiazol-4-carboxylate and ethylmagnesium bromide. 1H NMR (400 MHz, CHLOROFORM-D) δ, ppm 0.88 (t, J = 7.33 Hz, 6 H) 1.78 (q, J = 7.58 Hz, 4 H) 2.45 (s, 3 H) 6.12 (s, 1 H 7.22 (d, J = 8.34 Hz, 1 H) 7.53 (d, J = 8.34 Hz, 1 H) 7.59 (s, 1 H) 7.81 (s, 1 H), no NH protons were 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

Ethyl-2-aminothiazole-4-carboxylate (0.861 g, 5.00 mmol) was suspended in THF (10 mL) and treated with ethylmagnesium chloride (2 M in ethyl ether, 10 mL, 20.0 mmol) for 3 min. . After the exothermic reaction had ceased, the mixture was stirred for 30 minutes and quenched with NaHCO 3 (saturated aqueous solution, 10 mL). The resulting mixture was extracted with EtOAc (6 × 3 mL). The combined extracts were dried (MgSO 4 ), filtered and concentrated under reduced pressure. The crude material was purified by HPLC (5-15% acetonitrile in water, 0.05% TFA) to give the title compound as an off-white solid (0.267 g, 29%). 1 H NMR (400 MHz, DMSO-D6) δ, ppm 0.65 (t, J = 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

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) was dissolved in pyridine and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the crude material was purified using HPLC (35-50% acetonitrile in water, 0.05% TFA) to give the title compound as a white solid (24.4 mg, 66%). 1 H NMR (400 MHz, DMSO-D6) δ, ppm 0.65 (t, J = 7.33 Hz, 6 H) 1.55-1.66 (m, 4 H) 3.21 (t, J = 8.72 Hz, 2 H) 4.59 (t , J = 8.84 Hz, 2 H) 4.94 (br s, 1 H) 6.39 (s, 1 H) 6.84 (d, J = 8.34 Hz, 1 H) 7.55 (dd, J = 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

The title compound was prepared as described in Example 4-15 from ethyl-2-aminothiazole-4-carboxylate and p-tolylmethanesulfonyl chloride. 1 H NMR (400 MHz, DMSO-D6) δ, ppm 0.67 (t, J = 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, J = 7.58 Hz, 2 H) 7.18 (d, J = 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

The title compound was prepared from ethyl-2-aminothiazole-4-carboxylate and 2-oxo-2H-chromene-6-sulfonyl chloride as described in Example 4-15. 1 H NMR (400 MHz, DMSO-D6) δ, ppm 0.64 (t, J = 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, J = 9.35 Hz, 1 H) 7.52 (d, J = 8.84 Hz, 1 H) 7.94 (dd, J = 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

The title compound was prepared from ethyl-2-aminothiazole-4-carboxylate and 2,4-dimethylthiazole-5-sulfonyl chloride as described in Example 4-15. 1 H NMR (400 MHz, DMSO-D6) δ, ppm 0.66 (t, J = 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, J = 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

The title compound was prepared from ethyl-2-aminothiazole-4-carboxylate and 5- (oxazol-5-yl) thiophene-2-sulfonyl chloride as described in Example 4-15. 1 H NMR (400 MHz, DMSO-D6) δ, ppm 0.65 (t, J = 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, J = 3.79 Hz, 1 H) 7.56 (d, J = 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

The title compound was prepared from ethyl-2-aminothiazole-4-carboxylate and 5-chloronaphthalene-2-sulfonyl chloride as described in Example 4-15. 1 H NMR (400 MHz, DMSO-D6) δ, ppm 0.63 (t, J = 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, J = 7.83 Hz, 1 H) 7.85 (dd, J = 7.45, 1.14 Hz, 1 H) 7.96 (dd, J = 9.09, 1.77 Hz, 1 H) 8.19 (d, J = 8.34 Hz, 1 H) 8.31 (d, J = 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

The title compound was prepared from ethyl-2-aminothiazole-4-carboxylate and benzo [b] thiophene-3-sulfonyl chloride as described in Example 4-15. 1 H NMR (400 MHz, DMSO-D6) δ, ppm 0.62 (t, J = 7.45 Hz, 6 H) 1.55-1.66 (m, 4 H) 4.95 (br s, 1 H) 6.46 (d, J = 1.52 Hz, 1 H) 7.43-7.51 (m, 2 H) 8.07 (dd, J = 7.33, 1.26 Hz, 1 H) 8.11 (dd, J = 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] dioxin-6-sulfonamide

The title compound was prepared from ethyl-2-aminothiazole-4-carboxylate and 2,3-dihydrobenzo [b] [1,4] dioxin-6-sulfonyl chloride as described in Example 4-15. . 1 H NMR (400 MHz, DMSO-D6) δ, ppm 0.65 (t, J = 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, J = 8.34 Hz, 1 H) 7.19 (d, J = 2.27 Hz, 1 H) 7.25 (dd, J = 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

The title compound was prepared from ethyl-2-aminothiazole-4-carboxylate and 2-chloro-4,5-difluorobenzene-1-sulfonyl chloride as described in Example 4-15. 1 H NMR (400 MHz, DMSO-D6) δ, ppm 0.67 (t, J = 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, J = 10.23, 6.95 Hz, 1 H) 8.03 (dd, J = 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

The title compound was obtained in Example 4-15 from ethyl-2-aminothiazole-4-carboxylate and 4-methyl-3,4-dihydro-2H-benzo [b] [1,4] oxazine-6-sulfonyl chloride. Prepared as described. 1 H NMR (400 MHz, DMSO-D6) δ, ppm 0.66 (t, J = 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, J = 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

The title compound was prepared from ethyl-2-aminothiazole-4-carboxylate and 5-chloro-3-methylbenzo [b] thiophene-2-sulfonyl chloride as described in Example 4-15. 1 H NMR (400 MHz, DMSO-D6) δ, ppm 0.65 (t, J = 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, J = 1.77 Hz, 1 H) 7.53 (dd, J = 8.59, 2.02 Hz, 1 H) 7.98 (d, J = 1.52 Hz, 1 H) 8.05 (d, J = 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

The title compound was prepared as described in Example 4-15. 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.66 (t, J = 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

The title compound was prepared as described in 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

The title compound was prepared as described in Example 4-15. ESI-MS: m / z 387.3 (M + H) + .

Example 4-29: N- (4- (N- (4- (3-hydroxypentan-3-yl) thiazol-2-yl) sulfonyl) phenyl) acetamide

The title compound was prepared as described in 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

The title compound was prepared as described in 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

The title compound was prepared as described in Example 4-15. 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.66 (t, J = 7.45 Hz, 6 H) 1.55-1.75 (m, 4 H) 5.01 (s, 1 H) 6.53 (d, J = 1.26 Hz, 1 H) 7.89 (d, J = 8.34 Hz, 1 H) 7.99 (dd, J = 8.34, 2.27 Hz, 1 H) 8.24 (d, J = 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

The title compound was prepared as described in Example 4-15. 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.67 (t, J = 7.33 Hz, 6 H) 1.56-1.73 (m, J = 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

The title compound was prepared as described in 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

The title compound was prepared as described in 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] [1,2,5] thiadiazole-5-sulfonamide

The title compound was prepared as described in Example 4-15. 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.64 (t, J = 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, J = 9.09, 1.77 Hz, 1 H) 8.25 (d, J = 9.35 Hz, 1 H) 8.46 (d, J = 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] [1,4] dioxepin-7-sulfone Amide

The title compound was prepared as described in 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

The title compound was prepared as described in Example 4-15. 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.65 (t, J = 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, J = 7.96 Hz, 1 H) 7.77-7.83 (m, J = 7.83, 7.83, 1.64, 0.88 Hz, 2 H) 7.87 (t, J = 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) -1,2,3,4- Tetrahydroisoquinoline-7-sulfonamide

The title compound was prepared as described in Example 4-15. 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.65 (t, J = 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, J = 8.08 Hz, 1 H) 7.63 (td, J = 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) -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide

The title compound was prepared as described in Example 4-15 (TFA salt). 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.65 (t, J = 7.33 Hz, 6 H) 1.53-1.71 (m, 4 H) 3.02 (t, J = 6.44 Hz, 2 H) 3.39 (t, J = 5.94 Hz, 2 H) 4.35 (s, 2 H) 4.97 (s, 1 H) 6.44 (s, 1 H) 7.39 (d, J = 7.83 Hz, 1 H) 7.66 (dd, J = 7.83, 1.77 Hz, 1 H) 7.69 (d, J = 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

The title compound was prepared as described in 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

The title compound was prepared as described in Example 4-15. 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.65 (t, J = 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, J = 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

The title compound was prepared as described in Example 4-15. 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.66 (t, J = 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, J = 1.77 Hz, 1 H) 7.56 (ddd, J = 8.40, 2.08, 0.63 Hz, 1 H) 7.60-7.64 (m, 1 H) 7.79 (d, J = 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-hydroxypentan-3-yl) thiazol-2-yl) benzenesulfonamide

The title compound was prepared as described in Example 4-15. 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.66 (t, J = 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, J = 8.34, 2.02 Hz, 1 H) 7.92 (d, J = 2.02 Hz, 1 H) 7.95 (d, J = 8.34 Hz, 1 H) 12.70 (s, 1 H)
ESI-MS: m / z 439.0 (M + H) + .

Example 4-44: 4-bromo-N- (4- (3-hydroxypentan-3-yl) thiazol-2-yl) -2- (trifluoromethyl) benzenesulfonamide

The title compound was prepared as described in Example 4-15. ESI-MS: m / z 472.9 (M + H) + .

Example 4-45: 4-bromo-5-chloro-N- (4- (3-hydroxypentan-3-yl) thiazol-2-yl) thiophene-2-sulfonamide

The title compound was prepared as described in 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

The title compound was prepared as described in 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

The title compound was prepared as described in 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

The title compound was prepared as described in 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

The title compound was prepared as described in 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

The title compound was prepared as described in Example 4-15. ESI-MS: m / z 405.2 (M + H) + .

Example 4-51: N- (4- (3-hydroxypentan-3-yl) thiazol-2-yl) -4-methoxybenzenesulfonamide

The title compound was prepared as described in 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

The title compound was prepared as described in 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

The title compound was prepared as described in 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

The title compound was prepared as described in 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

The title compound was prepared as described in 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

The title compound was prepared as described in Example 4-15. 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.66 (t, J = 7.33 Hz, 6 H) 1.55-1.75 (m, 4 H) 5.01 (s, 1 H) 6.52 (d, J = 1.52 Hz, 1 H) 7.91 (d, J = 8.34 Hz, 1 H) 8.06 (s, 1 H) 8.24 (d, J = 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

The title compound was prepared as described in 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] [1,3] dioxol-5-sulfonamide

The title compound was prepared as described in Example 4-15. 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.65 (t, J = 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, J = 8.34 Hz, 1 H) 7.19 (d, J = 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] [1,4] oxazine -6-sulfonamide

The title compound was prepared as described in 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

The title compound was prepared as described in 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

The title compound was prepared as described in Example 4-15. 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.64 (t, J = 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, J = 8.59 Hz, 2 H) 8.08 (d, J = 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

The title compound was prepared as described in Example 4-15. 1H NMR (400 MHz, DMSO-D6) δ, ppm 0.66 (t, J = 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, J = 8.59 Hz, 1 H) 8.31 (dd, J = 8.46, 2.40 Hz, 1 H) 8.60 (d, J = 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

The title compound was prepared as described in 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

The title compound was prepared as described in 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

The title compound was prepared as described in 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

Ethyl 2- (2- (3-chloro-2-methylphenylsulfonamido) thiazol-4-yl) acetate (1.51 g, 4.03 mmol) was dissolved in THF (8 mL) and ethyl magnesium chloride (in ethyl ether). 2M, 8 mL, 16 mmol). The reaction mixture was stirred for 5 minutes, cooled to 0 ° C., carefully quenched with a cooled (0 ° C.) NH 4 Cl (saturated aqueous solution, 5 mL) -water (5 mL) mixture, stirred vigorously for 5 minutes, Extracted with ethyl acetate (15 mL). The organic extract was dried (MgSO 4 ), filtered and concentrated under reduced pressure. Flash column chromatography (250 mL SiO 2, hexane - ethyl acetate 1: 1, 1 L) was passed through to give the title compound as an off-white solid (0.210mg, 13%). 1 H NMR (400 MHz, CHLOROFORM-D) δ, ppm 0.87 (t, J = 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, J = 8.08 Hz, 1 H) 7.53 (d, J = 7.33 Hz, 1 H) 8.03 (d, J = 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

The title compound was prepared as described in Example 5-1. 1 H NMR (400 MHz, CHLOROFORM-D) δ, ppm 0.90 (t, J = 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, J = 7.96 Hz, 1 H) 7.52 (d, J = 8.08 Hz, 1 H) 8.02 (d , J = 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

4- (Chloromethyl) thiazol-2-amine hydrochloride (2.0 g, 11 mmol) was suspended in CH 2 Cl 2 at 0 ° C. and neutralized with ice-cold saturated NaHCO 3 . This mixture was extracted twice with CH 2 Cl 2 . The combined organic layers were then dried over MgSO 4 , filtered and concentrated to about 30 ml. To this solution was added 3-chloro-2-methylbenzene-1-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 hours. Saturated NaHCO 3 was added and the mixture was extracted 3 times with EtOAc. The combined organic layers were washed with 1N HCl and then with brine. The crude product was purified on a SiO 2 column eluted with EtOAc / hexane (1: 1) to give a yellow solid. The product was further purified by trituration with Et 2 O; filtration to give 1.1 g (30%) of the title compound as a yellow solid. 1 H NMR (400 MHz, d 6 -DMSO) δ, ppm: 2.62 (s, 3 H), 4.24 (d, J = 3.5 Hz, 2 H), 5.38 (s, 1 H), 6.58 (s, 1 H), 7.36 (t, J = 8.0 Hz, 1 H), 7.65 (d, J = 7.8 Hz, 1 H), 7.88 (d, J = 8.1 Hz, 1 H), 12.84 (s, 1 H); ESI-MS: m / z 337.2 (M + H) + .

Step B: 3-Chloro-N- (4-((1-hydroxycyclobutyl) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide

A solution of cyclobutanone (22 ml, 0.30 mmol) and 3-chloro-N- (4- (chloromethyl) thiazol-2-yl) -2-methylbenzenesulfonamide (100 mg, 0.30 mmol) in tetrahydrofuran (3 ml) To was added sodium iodide (8 mg, 0.06 mmol). To this mixture was added dropwise a 0.05M solution of samarium (II) iodide in THF (ca. 3 ml) at room temperature until the dark blue color no longer disappeared (persist). Then another 18 ml of SmI 2 / THF solution (0.90 mmol) was added dropwise along a portion. The reaction mixture was stirred at room temperature for about 30 minutes until the blue mixture turned yellow. Sodium potassium tartrate aqueous solution (1.0 M) was added and the bilayer was vigorously stirred for 30 minutes. Brine was added and the aqueous phase was extracted twice with EtOAc. The combined organic layers were dried over MgSO 4 , filtered and concentrated. The crude product was HPLC (C-18, isocratic, 45% ACN / H 2 O ) to afford the title compound 15mg (14%). 1 H NMR (400 MHz, CDCl 3 ) 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, J = 8.0 Hz, 1 H), 7.53 (d, J = 8.1 Hz, 1 H), 8.01 (d, J = 7.8 Hz, 1 H ); ESI-MS: m / z 373.2 (M + H) + .

Example 5-4: 3-chloro-N- (4-((1-hydroxycyclopentyl) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide

The title compound was prepared from cyclopentanone and 3-chloro-N- (4- (chloromethyl) thiazol-2-yl) -2-methylbenzenesulfonamide according to the procedure described in Example 5-3. The crude product was HPLC (C-18, gradient, 45-60% ACN / H 2 O ) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) 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, J = 7.8 Hz, 1 H), 7.54 (d, J = 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

The title compound was obtained from ethyl 2- (2- (4-fluoro-2-methylphenylsulfonamido) thiazol-4-yl) acetate (Example 2-21-A) as described in Example 5-1. And purified. 1 H 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

N, N-dimethylethanolamine (122 iL, 1.21 mmol) was added at 0 ° C. to a stirred solution of sodium hydride (0.031 g, 95% dry, 1.21 mmol) in 2 mL of tetrahydrofuran. After stirring for 0.5 hour, the resulting solution was diluted with N- (4- (2-ethyl-2-hydroxybutyl) thiazol-2-yl) -4-fluoro-2-methylbenzene in THF (2 mL). To the sulfonamide (Example 5-5, 0.075 g, 0.20 mmol) was added. The resulting reaction mixture was microwaved at 150 ° C. After 45 minutes, the reaction was concentrated and the resulting residue was purified by SiO 2 column chromatography eluting with methylene chloride / methanol (9: 1) to give 0.065 g (74%) of the title compound. Obtained as a white foam. 1 H 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

The title compound was obtained from commercially available N- (2-hydroxyethyl) morpholine and N- (4- (2-ethyl-2-hydroxybutyl) thiazol-2-yl) -4-fluoro-2-methylbenzenesulfonamide. Purified from 5-5 as described in Example 5-6. 1 H 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

The title compound was obtained from commercially available 3-dimethylamino-1-propanol and N- (4- (2-ethyl-2-hydroxybutyl) thiazol-2-yl) -4-fluoro-2-methylbenzenesulfonamide. Prepared from -5. 1 H 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: 2- (2- (3-Chloro-4-fluorophenylsulfonamido) thiazol-4-yl) ethyl acetate

The title compound was prepared as described in Example 2-1-A. 1 H NMR (400 MHz, DMSO-d6) δ, 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

The title compound was prepared as described in Example 5-1. 1 H NMR (400 MHz, DMSO-d6) δ, ppm: 0.78 (t, J = 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, J = 9.09 Hz, 1 H), 7.77-7.85 (m, 1 H), 7.91 (dd, J = 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) -N- (4- (2-ethyl-2-hydroxybutyl) thiazol-2-yl) benzenesulfonamide

The title compound was described in 3-chloro-N- (4- (2-ethyl-2-hydroxybutyl) thiazol-2-yl) -4-fluorobenzenesulfonamide from Example 5-9 to Example 5-6. Were prepared as described. 1 H 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-N- (4- (2-ethyl-2-hydroxybutyl) thiazol-2-yl) -4- (2-morpholinoethoxy) benzenesulfonamide

The title compound was obtained from commercially available N- (2-hydroxyethyl) morpholine and 3-chloro-N- (4- (2-ethyl-2-hydroxybutyl) thiazol-2-yl) -4-fluorobenzenesulfonamide. Prepared from 5-9 as described in Example 5-6. 1 H 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-N- (4- (2-ethyl-2-hydroxybutyl) thiazol-2-yl) -4- (3-morpholinopropoxy) benzenesulfonamide

The title compound is obtained from commercially available 3-morpholinopropanol and 3-chloro-N- (4- (2-ethyl-2-hydroxybutyl) thiazol-2-yl) -4-fluorobenzenesulfonamide from Example 5-9. Prepared as described in Examples 5-6. 1 H 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- (dimethylamino) propoxy) -N- (4- (2-ethyl-2-hydroxybutyl) thiazol-2-yl) benzenesulfonamide

The title compound was obtained from commercially available 3-dimethylamino-1-propanol and 3-chloro-N- (4- (2-ethyl-2-hydroxybutyl) thiazol-2-yl) -4-fluorobenzenesulfonamide Example 5 Prepared from -9 as described in Example 5-6. 1 H NMR (400 MHz, Chloroform-d) δ, 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: N- (4- (2-ethyl-2-hydroxybutyl) thiazol-2-yl) -2-methyl-4- (3-morpholinopropoxy) benzenesulfonamide

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 did. 1 H 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

The title compound was prepared as described in Example 5-1. 1 H 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

The title compound was prepared as described in Example 5-1. 1 H 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

The title compound was obtained from commercially available 3-morpholinopropanol and N- (4- (2-ethyl-2-hydroxybutyl) thiazol-2-yl) -3-fluorobenzenesulfonamide from Example 5-16 to Example 5- Prepared as described in 6. 1 H 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: N- (4- (2-ethyl-2-hydroxybutyl) thiazol-2-yl) -4- (3-morpholinopropoxy) benzenesulfonamide

The title compound was obtained from commercially available 3-morpholinopropanol and N- (4- (2-ethyl-2-hydroxybutyl) thiazol-2-yl) -4-fluorobenzenesulfonamide from Example 5-15 to Example 5- Prepared as described in 6. 1 H 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

The title compound is obtained from commercially available 3-dimethylamino-1-propanol and N- (4- (2-ethyl-2-hydroxybutyl) thiazol-2-yl) -4-fluorobenzenesulfonamide from Example 5-15. Prepared as described in Examples 5-6. 1 H NMR (400 MHz, Chloroform-d) δ, 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

The title compound was obtained from commercially available 3-dimethylamino-1-propanol and N- (4- (2-ethyl-2-hydroxybutyl) thiazol-2-yl) -3-fluorobenzenesulfonamide from Example 5-16. Prepared as described in Examples 5-6. 1 H 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

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 in Example 5-3. did. The crude product was purified by column chromatography (SiO 2, gradient, 0-0.5% MeOH / EtOAc) to afford the title compound (24%). 1H 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, J = 6.44 , 2.40 Hz, 4 H) 6.14 (s, 1 H) 7.24 (t, J = 7.96 Hz, 1 H) 7.57 (dd, J = 8.10, 1.30 Hz, 1 H) 8.00 (dd, J = 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-((1-hydroxycyclobutyl) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide

Step A: tert-Butyl 4- (chloromethyl) thiazol-2-ylcarbamate

4- (Chloromethyl) thiazol-2-amine hydrochloride (2.7 g, 15 mmol) was suspended in CH 2 Cl 2 (150 ml) at 0 ° C. and neutralized with ice-cold saturated NaHCO 3 . This mixture was extracted twice with CH 2 Cl 2 . The combined organic layers were then dried over MgSO 4 , 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 hours. Diluted HCl (0.1 M) was added, and then CH 2 Cl 2 was removed under reduced pressure. The aqueous residue was extracted 3 times with EtOAc. The combined organic layers were washed with saturated NaHCO 3 , dried over MgSO 4 , filtered and concentrated. The crude product was purified by column chromatography (SiO 2 30% EtOAc / hexane) to give the title compound as a white solid (1.7 g, 45%).

Step B: tert-Butyl 4-((1-hydroxycyclobutyl) methyl) thiazol-2-ylcarbamate

Cyclobutanone (1.0 ml, 13 mmol) and tert-butyl 4- (chloromethyl) thiazol-2-ylcarbamate in tetrahydrofuran (20 ml) Example 5-22-A (1.1 g, 13 mmol) was iodinated. Samarium (II) solution (0.1 M in THF, 88 ml, 8.8 mmol) was added. The reaction mixture was stirred at room temperature for about 30 minutes until the blue mixture turned yellow. 0.1M HCl solution was added and THF was removed under reduced pressure. The aqueous residue was extracted 3 times with EtOAc. The combined organic layers were dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO 2, gradient, 5-10% Et 2 O / CH 2 Cl 2), to give the title compound as a white solid (790mg, 63%). 1H NMR (400 MHz, CHLOROFORM-D) δ, 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: 1-((2-Aminothiazol-4-yl) methyl) cyclobutanol

To a solution of tert-butyl 4-((1-hydroxybutyl) methyl) thiazol-2-ylcarbamate in CH 2 Cl 2 (15 ml) Example 5-22-B (600 mg, 2.1 mmol) (5 ml) was added at room temperature. The reaction mixture was stirred at room temperature for 5 hours. All volatiles were then removed under reduced pressure. The residue was then re-diluted in saturated NaHCO 3 and extracted twice with EtOAc. The combined organic layers were dried over MgSO 4 , filtered and concentrated under reduced pressure 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

1-((2-Aminothiazol-4-yl) methyl) cyclobutanol in pyridine (5 ml) To a solution of Example 5-22-C (100 mg, 0.54 mmol) 4-dimethylaminopyridine (catalytic amount) and 2-Bromo-4-methylphenylsulfonyl chloride (146 mg, 0.54 mmol) was added. The yellow solution was stirred at room temperature for 18 hours. The pyridine was then removed under reduced pressure. The residue was diluted with 1N HCl and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated. The crude product was purified by column chromatography (SiO 2, gradient, 50-60% EtOAc / hexanes) to afford the title compound as a pink solid (135 mg, 60%). 1H 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, J = 8.1 Hz, 1 H) 7.42 (s, 1 H) 7.91 (d, J = 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

Triethylsilane (0.270 mL, 1.69 mmol) was added to 3-chloro-N- (4-((4-fluorophenyl) (hydroxy) methyl) thiazol-2-yl) -2- in trifluoroacetic acid (1 mL). Methylbenzenesulfonamide Added to a solution of Example 1-16 (0.070 g, 0.170 mmol). After stirring overnight, the reaction mixture was concentrated under reduced pressure, dissolved in dichloromethane (5 mL) and washed with saturated aqueous NaHCO 3 . The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by SiO 2 column chromatography eluting with hexane / ethyl acetate (2: 1) to give 0.052 g (77%) of the title compound as a white foam. 1 H 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, J = 8.97 Hz, 2 H ), 7.28 (dd, J = 8.34, 5.81 Hz, 2 H), 7.37 (t, J = 8.08 Hz, 1 H), 7.66 (d, J = 7.83 Hz, 1 H), 7.87 (d, J = 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

The title compound was prepared according to the procedure described in Example 6-1 from 3-Chloro-N- (4- (hydroxy (phenyl) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide. Prepared. 1 H NMR (400 MHz, DMSO-d6) δ, ppm: 2.62 (s, 3 H), 3.77 (s, 2 H,) 6.33 (s, 1 H), 7.23 (d, J = 3.28 Hz, 1 H ), 7.24 (s, 2 H), 7.28-7.39 (m, 3 H), 7.65 (d, J = 8.08 Hz, 1 H), 7.87 (d, J = 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

The title compound was converted from 3-chloro-N- (4-((4-chlorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide from Example 1-18 to Example 6-1. Prepared according to the described procedure. 1 H 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, J = 8.08 Hz, 1 H), 7.87 (d, J = 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

The title compound is described in 3-chloro-N- (4-((3-chlorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide Example 1-19 to Example 6-1. Prepared according to the procedure described. 1 H NMR (400 MHz, DMSO-d6) δ, ppm: 2.62 (s, 3 H), 3.79 (s, 2 H), 6.39 (s, 1 H,) 7.21 (d, J = 8.84 Hz, 1 H ), 7.29-7.41 (m, 4 H), 7.66 (d, J = 7.58 Hz, 1 H), 7.87 (d, J = 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

The title compound was prepared from 3-chloro-N- (4-((3-chloro-4-fluorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide Example 1-20 Prepared according to the procedure described in Example 6-1. 1 H 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, J = 5.56 Hz, 1 H), 7.66 (d, J = 8.34 Hz, 1 H), 7.87 (d, J = 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

The title compound was prepared from 3-chloro-N- (4-((3,5-difluorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide Example 1-21 to Example 6- Prepared according to the procedure described in 1. 1 H NMR (400 MHz, DMSO-d6) δ, ppm: 2.62 (s, 3 H), 3.81 (s, 2 H), 6.41 (s, 1 H), 7.02 (d, J = 8.59 Hz, 2 H ), 7.08-7.18 (m, 1 H), 7.37 (t, J = 7.96 Hz, 1 H), 7.66 (d, J = 8.08 Hz, 1 H), 7.88 (d, J = 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

The title compound was prepared according to the procedure described in Examples 1-22 to 6-1. Prepared according to 1 H 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, J = 7.83 Hz, 1 H), 7.36 (t, J = 7.96 Hz, 1 H), 7.65 (d, J = 8.08 Hz, 1 H), 7.87 (d, J = 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

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 Prepared from -C according to the procedure described in Example 1-16. 1 H 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

The title compound was described in 3-chloro-N- (4- (hydroxy (o-tolyl) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide Example 1-10 to Example 6-1. Prepared according to procedure. 1 H 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, J = 7.96 Hz, 1 H), 7.66 (d, J = 7.33 Hz, 1 H), 7.88 (d, J = 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

The title compound was prepared from 3-chloro-N- (4-((4-cyanophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide Example 1-25 to Example 6-1. Prepared according to the procedure described in. 1 H 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, J = 7.96 Hz, 1 H ), 7.44 (d, J = 8.08 Hz, 2 H), 7.66 (d, J = 7.83 Hz, 1 H), 7.79 (d, J = 8.34 Hz, 2 H), 7.86 (d, J = 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-methylphenylsulfonamido) thiazol-4-yl) methyl) benzamide

Potassium carbonate (0.109 g, 0.79 mmol) was added to N- (4- (4-cyanobenzyl) thiazol-2-yl) -3-chloro-2-methylbenzenesulfonamide in dimethyl sulfoxide (0.250 mL). Add to a solution of Example 6-10 (0.040 g, 0.1 mmol) and cool to 10 ° C. Hydrogen peroxide (0.341 mL, 35 wt% solution in water, 3.9 mmol) was added dropwise and the resulting reaction was stirred for 1 hour at 10 ° C. and then allowed to warm to ambient temperature. After 2 hours, the reaction mixture was transferred to brine (1 mL). The resulting solution was extracted with ethyl acetate (2 × 2 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.010 g (24%) of the title compound as a yellow oil. 1 H 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, J = 8.34 Hz, 2 H), 7.77 (d, J = 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

The title compound was prepared from 3-chloro-N- (4-((3-cyanophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide from Example 1-13 to Example 6-1. Prepared according to the procedure described in. 1 H 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 = 8.08 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

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. did. 1 H NMR (400 MHz, DMSO-d6) δ, 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

The title compound was prepared from 3-chloro-N- (4- (hydroxy (3- (trifluoromethyl) phenyl) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide Example 1-26 and Example 6 Prepared according to the procedure described in -1. 1 H 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, J = 7.96 Hz, 1 H ), 7.54-7.57 (m, 2 H), 7.59-7.67 (m, 3 H), 7.87 (d, J = 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

Sodium hydride (0.022 g, 95% dry 0.920 mmol) was added to a stirred solution of 2-hydroxypyridine (0.085 g, 0.89 mmol) in DME (2 mL) and DMF (0.5 mL) at 0 ° C. Added at. After 10 minutes, 3-chloro-N- (4- (chloromethyl) thiazol-2-yl) -2-methylbenzenesulfonamide Example 5-3-A (0.100 g, 0.297 mmol) was added, The resulting reaction mixture was stirred at room temperature for 15 minutes and then refluxed overnight. The reaction was quenched by adding chilled brine solution (10 mL). The resulting solution was extracted with ethyl acetate (2 × 5 mL). The combined organic fractions were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude residue was treated with dichloromethane and the resulting white precipitate was filtered to give 0.087 g (74%) of the title compound as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ, ppm: 2.60 (s, 3 H), 4.77 (s, 2 H), 6.10 (s, 1 H), 6.15 (t, J = 5.94 Hz, 1 H ), 6.33 (d, J = 8.84 Hz, 1 H), 7.20 (t, J = 7.83 Hz, 1 H), 7.33-7.39 (m, 1 H), 7.44 (d, J = 7.58 Hz, 1 H) , 7.57 (dd, J = 6.82, 2.02 Hz, 1 H), 7.82 (d, J = 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

The title compound was prepared from Example 1-33 according to the procedure described in Example 6-1. The crude product was purified by SiO 2 column chromatography eluting with EtOAc / hexane (1: 1) to give 0.089 g (60%) of the title compound. 1 H 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, J = 8.0, 1 H), 7.21 (t, J = 8.0, 1 H), 7.21 (t, J = 8.1, 1 H), 7.53 (d, J = 8.1 Hz , 2 H), 8.00 (d, J = 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) + .

The activity of compounds as biological test 11b-HSD1 inhibitors can be analyzed in vitro, in vivo, or in cell lines. Described below is an analysis of the 11b-HSD1 dehydrogenase activity of the in vitro enzyme (with respect to activity against 11b-HSD1).

  It should be noted that a variety of other expression systems and hosts are also suitable for the expression of 11b-HSD1, as will be readily appreciated by those skilled in the art.

  Purified 11b-HSD1 can be obtained as follows: residues 24-292 of 11-β-hydroxysteroid dehydrogenase isoform 1 are derived from IMAGE clone 5193867 (ATCC clone 7277078) with primer hsd1 — 24-f: 5 Amplification was performed using PCR with '-AACGAGGAATTCAGACCAGGATG-3' (SEQ ID NO: 1) and hsd1-292-r: 5'-TTACTTGTTTTGAATCTTCCAT-3 '(SEQ ID NO: 2). The resulting PCR product was topolocloned into the pBAD-ThioE vector (Invitrogen). This pBAD-ThioE vector was modified by inserting a DNA sequence encoding MKHQHQHQHQHQHQQPL at the cloning site and was compatible with TOPO clone PCR (Invitrogen). Under control of the ara promoter, MKHQHQHQHQHQHQQPL was fused to the N-terminus to produce residues 24-292 of 11-β-hydroxysteroid dehydrogenase isoform 1. Quick change PCR with primers hsdC272Sqcf: 5′-TCAGAAATCCCATCCAGGAAGATC-3 ′ (SEQ ID NO: 3) and hsdC272Sqcr: 5′-GATCTCTCTGGATGGAGTCTGA-3 ′ (SEQ ID NO: 4) in the final construct (final construct) C272S, a one point mutation, was generated.

  An E. coli having the 11b-HSD1 expression plasmid inside; E. coli DH10b-Tir (Invitrogen) was grown in Luria medium (LB) at 37 ° C. with addition of 0.05 mg / ml kanamycin (Km). Then 15 ml of saturated culture was used to inoculate 1 liter of fresh LB (0.05 mg / ml Km). When the culture reached an optical density of 0.4 (λ = 600 nm), the growth temperature was changed from 37 ° C. to 25 ° C. After an additional 2 hours of growth, arabinose and corticosterone were added to final concentrations of 0.2% (w / w) and 0.25 mM, respectively. After approximately 14 hours induction, the cells were harvested and quickly cooled at -80 ° C. The cell pellet from each liter of cell culture is thawed and 50 ml of lysis buffer (30 mM CHAPS, 50 mM Tris-HCl, pH 7.9, 0.15 M NaCl, 0.5 μl / ml benzonase). Resuspended in 1 μl / ml ReadyLyse). Subsequently, after 30 minutes of incubation at room temperature, the lysate was clarified by centrifugation. The resulting supernatant was loaded onto 6 ml of Probond resin (Invitrogen) and then equilibrated with wash buffer (4 mM CHAPS, 50 mM Tris-HCl, pH 7.9, 0.25 M NaCl, 40 mM imidazole), then Washed with 10 column volumes of wash buffer. 11b-HSD1 was then eluted with 3 column volumes of wash buffer supplemented with 0.2M imidazole. The elution of purified 11b-HSD1 was dialyzed extensively 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 purification method yielded a single sporadic 11b-HSD1.

  It should be noted that a variety of other expression systems and hosts are also suitable for the expression of 11b-HSD1, as will be readily appreciated by those skilled in the art.

The inhibitory properties of the compounds for 11b-HSD1 are determined in the following reaction conditions using a white 384 well plate format: 50 mM Tris pH 7.5, 150 mM NaCl, 0.1 mM EDTA, 0.01% Brij 35, 10 μM each. Of cortisol and NADP + , 1% DMSO. The reaction product was quantitatively determined by fluorescence intensity using a fluorescence plate reader (Molecular Devices Gemini) at 340 nm excitation wavelength and 460 nm emission wavelength.

The assay reaction was initiated as follows: 4 μl of buffer containing 25 μM cortisol and 25 μM NADP + was added to each well of the plate, followed by 2 μl inhibitor containing 5% DMSO ( For eleven data points, each inhibitor was serially diluted twofold). 125 nM 11b-HSD1 enzyme solution (4 μl) can be added to initiate the reaction (final enzyme concentration was 50 nM). The fluorescence intensity of the resulting reaction mixture can be measured after 60 minutes incubation at room temperature.

  IC50 values can be calculated by fitting a compound concentration and fluorescence intensity to a standard IC50 equation by a non-linear curve. In the measurement of 11b-HSD1 dehydrogenase, carbenoxolone and BVT14225 exhibited IC50 of 100 nM and 500 nM, respectively, as reference points for this measurement.

The following abbreviations are used:
ATP adenosine triphosphate BSA bovine serum albumin EDTA ethylenediaminetetraacetic acid MOPS morpholine propane sulfonic acid SPA scintillation proximity assay

  It will be apparent to those skilled in the art that various modifications and variations can be made to 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 modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.

FIG. 1 shows SEQ ID NOs: 1, 2, 3, and 4 referred to herein.

Claims (70)

  1. formula:

    (Where
    J is selected from the group consisting of CR 6 and N (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
    K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
    L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
    M is selected from the group consisting of S, O and NR 15 ;
    R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
    R 2 is

    Selected from the group consisting of:
    R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
    R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
    R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
    R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) each independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any one of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The two together form a ring;
    R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, or is selected from the group consisting of (C 9-12) bicycloaryl and hetero (C 4-12) bicycloaryl, or R 13 and R 7, Any one of R 9 and R 11 together forms a ring;
    R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl;
    X is selected from the group consisting of unsubstituted or substituted C 1-6 alkylene; and
    Y is (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl each of which is unsubstituted or substituted. , Aryl, heteroaryl, (C 9-12 ) bicycloaryl and hetero (C 4-12 ) bicycloaryl)
    A compound comprising
  2. formula:

    (Where
    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 (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
    K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
    L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
    M is selected from the group consisting of S, O and NR 15 ;
    R 2 is

    Selected from the group consisting of:
    R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
    R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
    R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
    R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) each independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any one of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The two together form a ring;
    R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, or is selected from the group consisting of (C 9-12) bicycloaryl and hetero (C 4-12) bicycloaryl, or R 13 and R 7, Any one of R 9 and R 11 together forms a ring;
    Each R 14 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, each substituted or unsubstituted Imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicyclo Alkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1 -10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfo Le (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
    R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl;
    X is selected from the group consisting of unsubstituted or substituted C 1-6 alkylene; and
    Y is each substituted or unsubstituted (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, Selected from the group consisting of aryl, heteroaryl, (C 9-12 ) bicycloaryl and hetero (C 4-12 ) bicycloaryl)
    The compound of claim 1 comprising:
  3. formula:

    (Where
    J is selected from the group consisting of CR 6 and N (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
    K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
    L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
    M is selected from the group consisting of S, O and NR 15 ;
    R 2 is

    Selected from the group consisting of:
    R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
    R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
    R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
    R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any two of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 Together form a ring;
    R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, or is selected from the group consisting of (C 9-12) bicycloaryl and hetero (C 4-12) bicycloaryl, or R 13 and R 7, Any one of R 9 and R 11 together forms a ring;
    R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl;
    X is selected from the group consisting of unsubstituted and substituted C 1-6 alkylene; and
    Y is (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, each substituted or unsubstituted. , Aryl, heteroaryl, (C 9-12 ) bicycloaryl and hetero (C 4-12 ) bicycloaryl)
    The compound of claim 1 comprising:
  4. formula:

    (Where
    R 2 is

    Selected from the group consisting of:
    R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
    R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
    R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any two of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 Together form a ring;
    R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, or is selected from the group consisting of (C 9-12) bicycloaryl and hetero (C 4-12) bicycloaryl, or R 13 and R 7, Any one of R 9 and R 11 together forms a ring;
    X is selected from the group consisting of unsubstituted and substituted C 1-6 alkylene; and
    Y is (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, each substituted or unsubstituted. , Aryl, heteroaryl, (C 9-12 ) bicycloaryl and hetero (C 4-12 ) bicycloaryl)
    The compound of claim 1 comprising:
  5. formula:

    (Where
    R 2 is

    Selected from the group consisting of:
    R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl; and
    R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) each independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any one of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The two together form a ring)
    The compound of claim 1 comprising:
  6. formula:

    (Where
    R 2 is

    Selected from the group consisting of:
    R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl; and
    R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) each independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any one of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The two together form a ring)
    The compound of claim 1 comprising:
  7. formula:

    (Where
    R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
    R 2 is

    Selected from the group consisting of:
    R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
    R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
    R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) each independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any one of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The two together form a ring;
    R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, or is selected from the group consisting of (C 9-12) bicycloaryl and hetero (C 4-12) bicycloaryl, or R 13 and R 7, Any one of R 9 and R 11 together forms a ring;
    X is selected from the group consisting of unsubstituted and substituted C 1-6 alkylene; and
    Y is (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, each substituted or unsubstituted. , Aryl, heteroaryl, (C 9-12 ) bicycloaryl and hetero (C 4-12 ) bicycloaryl)
    The compound of claim 1 comprising:
  8. formula:

    (Where
    R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
    R 2 is

    Selected from the group consisting of:
    R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl; and
    R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) each independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any one of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The two together form a ring)
    The compound of claim 1 comprising:
  9. formula:

    (Where
    R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
    R 2 is

    Selected from the group consisting of:
    R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl; and
    R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) each independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any one of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The two together form a ring)
    The compound of claim 1 comprising:

  10. (Where
    J is selected from the group consisting of CR 6 and N (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
    K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
    L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
    M is selected from the group consisting of S, O and NR 15 ;
    R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
    R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
    R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
    R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl, or R 7 and R 8 together form a ring;
    R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) or is selected from the group consisting of bicycloaryl, or R 13 and R 7 Together form a ring; and
    R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl)
    The compound of claim 1 comprising:
  11. formula:

    (Where
    J is selected from the group consisting of CR 6 and N (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
    K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
    L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
    M is selected from the group consisting of S, O and NR 15 ;
    R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
    R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
    R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
    R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl, or R 7 and R 8 together form a ring;
    R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) or is selected from the group consisting of bicycloaryl, or R 13 and R 7 Together form a ring; and
    R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl)
    The compound of claim 1 comprising:
  12. formula:

    (Where
    J is selected from the group consisting of CR 6 and N (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
    K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
    L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
    M is selected from the group consisting of S, O and NR 15 ;
    R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
    R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
    R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
    R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
    R 9 and R 10 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, Ruhoniru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl, or any two of R 7 , R 8 , R 9 and R 10 together form a ring And
    R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero (C 4-12) or is selected from the group consisting of bicycloaryl, or R 13 and R 7 and Together with any one of R 9 to form a ring; and
    R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl)
    The compound of claim 1 comprising:
  13. formula:

    (Where
    J is selected from the group consisting of CR 6 and N (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
    K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
    L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
    M is selected from the group consisting of S, O and NR 15 ;
    R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
    R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
    R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
    R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
    R 9 and R 10 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, Ruhoniru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl, or any two of R 7 , R 8 , R 9 and R 10 together form a ring And
    R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero (C 4-12) or is selected from the group consisting of bicycloaryl, or R 13 and R 7 and Together with any one of R 9 to form a ring; and
    R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl)
    The compound of claim 1 comprising:
  14. formula:

    (Where
    J is selected from the group consisting of CR 6 and N (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
    K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
    L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
    M is selected from the group consisting of S, O and NR 15 ;
    R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
    R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
    R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
    R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
    R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) each independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any one of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The two together form a ring;
    R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, or is selected from the group consisting of (C 9-12) bicycloaryl and hetero (C 4-12) bicycloaryl, or R 13 and R 7, Any one of R 9 and R 11 together forms a ring; and
    R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl)
    The compound of claim 1 comprising:
  15. formula:

    (Where
    J is selected from the group consisting of CR 6 and N (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
    K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
    L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
    M is selected from the group consisting of S, O and NR 15 ;
    R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
    R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
    R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
    R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
    R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) each independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any one of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The two together form a ring;
    R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, or is selected from the group consisting of (C 9-12) bicycloaryl and hetero (C 4-12) bicycloaryl, or R 13 and R 7, Any one of R 9 and R 11 together forms a ring; and
    R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl)
    The compound of claim 1 comprising:
  16. formula:

    (Where
    J is selected from the group consisting of CR 6 and N (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
    K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
    L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
    M is selected from the group consisting of S, O and NR 15 ;
    R 1 is (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, each substituted or unsubstituted. Selected from the group consisting of hetero (C 3-12 ) bicycloalkyl, aryl, heteroaryl, (C 9-12 ) bicycloaryl, hetero (C 4-12 ) bicycloaryl;
    R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
    R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
    R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl;
    X is selected from the group consisting of unsubstituted and substituted C 1-6 alkylene; and
    Y is (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, each substituted or unsubstituted. , Aryl, heteroaryl, (C 9-12 ) bicycloaryl and hetero (C 4-12 ) bicycloaryl)
    The compound of claim 1 comprising:
  17. formula:

    (Where
    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 (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
    K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
    L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
    M is selected from the group consisting of S, O and NR 15 ;
    R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
    R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
    R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl, or R 7 and R 8 together form a ring;
    R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, or is selected from the group consisting of (C 9-12) bicycloaryl and hetero (C 4-12) bicycloaryl, or R 13 and R 7 is Together form a ring;
    Each R 14 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, each substituted or unsubstituted Imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicyclo Alkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1 -10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfo Le (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl; and
    R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl)
    The compound of claim 1 comprising:
  18. formula:

    (Where
    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 (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
    K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
    L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
    M is selected from the group consisting of S, O and NR 15 ;
    R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
    R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
    R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
    R 9 and R 10 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, Ruhoniru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl, or any two of R 7 , R 8 , R 9 and R 10 together form a ring And
    R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero (C 4-12) or is selected from the group consisting of bicycloaryl, or R 13 and R 7 and Any one of R 9 together forms a ring;
    Each R 14 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, each substituted or unsubstituted Imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicyclo Alkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1 -10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfo Le (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl; and
    R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl)
    The compound of claim 1 comprising:
  19. formula:

    (Where
    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 (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
    K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
    L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
    M is selected from the group consisting of S, O and NR 15 ;
    R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
    R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
    R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 7 and R 8 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfone Amido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) Bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo ( C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, scan Honiru (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Each independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
    R 9 , R 10 , R 11, and R 12 are each substituted or unsubstituted hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1- 10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, ( C1-10 ) alkyl, ( C3-12 ) cycloalkyl, hetero ( C3-12 ) cycloalkyl, ( C9-12 ) bicycloalkyl, Hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1- 10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C -3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9- 12 ) each independently selected from the group consisting of bicycloaryl and hetero (C 4-12 ) bicycloaryl, or any one of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The two together form a ring;
    R 13 is each substituted or unsubstituted hydrogen, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3- 12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) Alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) A Kill, imino (C 1-3) alkyl, aryl, heteroaryl, or is selected from the group consisting of (C 9-12) bicycloaryl and hetero (C 4-12) bicycloaryl, or R 13 and R 7, Any one of R 9 and R 11 together forms a ring;
    Each R 14 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, each substituted or unsubstituted Imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicyclo Alkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1 -10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfo Le (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
    R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl)
    The compound of claim 1 comprising:
  20. formula:

    (Where
    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 (provided that when J forms part of a double bond, J is CR 6 and R 6 is absent);
    K is selected from the group consisting of CR 6 and N (provided that when K forms part of a double bond, K is CR 6 and R 6 is absent);
    L is selected from the group consisting of CR 6 and N (provided that when L forms part of a double bond, L is CR 6 and R 6 is absent);
    M is selected from the group consisting of S, O and NR 15 ;
    R 3 is hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (substituted, each substituted or unsubstituted. C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroari Is selected from the group consisting of Le and hetero (C 4-12) bicycloaryl;
    R 4 is each substituted or unsubstituted hydrogen, nitro, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) Alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, hetero aryl (C 1-5) alkyl, (C 3-12) cycloalkyl (C 1-10) alkyl, halo (C 1-10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1- ) Alkyl, aryl, heteroaryl, and (C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl (however, N to R 4 are bonded forms part of a double bond If R 4 is not present);
    R 5 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    R 6 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, imino, each substituted or unsubstituted , Sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl , Aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1- 10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfonyl C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and hetero ( C 4-12 ) selected from the group consisting of bicycloaryl;
    Each R 14 is hydrogen, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 ) alkylamino, sulfonamide, each substituted or unsubstituted Imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicyclo Alkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1-5 ) alkyl, perhalo (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1 -10) alkyl, carbonyl (C 1-3) alkyl, thiocarbonyl (C 1-3) alkyl, sulfo Le (C 1-3) alkyl, sulfinyl (C 1-3) alkyl, amino (C 1-10) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl and Independently selected from the group consisting of hetero (C 4-12 ) bicycloaryl;
    R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3-12 ) cycloalkyl, hetero ( C 3-12) cycloalkyl, (C 9-12) bicycloaryl alkyl, hetero (C 3-12) bicycloalkyl, aryl (C 1-10) alkyl, heteroaryl (C 1-5) alkyl, (C 3- 12 ) Cycloalkyl ( C1-10 ) alkyl, halo ( C1-10 ) alkyl, carbonyl ( C1-3 ) alkyl, thiocarbonyl ( C1-3 ) alkyl, sulfonyl ( C1-3 ) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, (C 9-12) Bishikuroa Lumpur and hetero (C 4-12) selected from the group consisting of bicycloaryl;
    X is selected from the group consisting of unsubstituted and substituted C 1-6 alkylene; and
    Y is (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, each substituted or unsubstituted. , Aryl, heteroaryl, (C 9-12 ) bicycloaryl and hetero (C 4-12 ) bicycloaryl)
    The compound of claim 1 comprising:
  21.   21. A compound according to any one of claims 1-3 and 10-20, wherein M is S.
  22.   21. A compound according to any one of claims 1-3 and 10-20, wherein M is O.
  23. M is NR 15 and R 15 is each substituted or unsubstituted hydrogen, nitro, carbonyl, amino, sulfonamide, imino, sulfonyl, sulfinyl, (C 1-10 ) alkyl, (C 3 -12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicycloalkyl, aryl (C 1-10 ) alkyl, heteroaryl (C 1- 5 ) alkyl, (C 3-12 ) cycloalkyl (C 1-10 ) alkyl, halo (C 1-10 ) alkyl, carbonyl (C 1-3 ) alkyl, thiocarbonyl (C 1-3 ) alkyl, sulfonyl ( C 1-3) alkyl, sulfinyl (C 1-3) alkyl, imino (C 1-3) alkyl, aryl, heteroaryl, C 9-12) bicycloaryl and hetero (C 4-12) selected from the group consisting of bicycloaryl A compound according to any one of claims 1-3 and 10-20.
  24. J, K and L are CR 6, compounds according to any one of claims 1 to 3 and 10 to 23.
  25. R 1 is each substituted or unsubstituted (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3-12 ) bicyclo. alkyl, aryl, heteroaryl, (C 9-12) bicycloaryl, is selected from the group consisting of hetero (C 4-12) bicycloaryl, compounds according to any one of claims 1 and 7 to 24.
  26. R 1 is selected from the group consisting of (C 3-6 ) alkyl, aryl, (C 3-9 ) cycloalkyl, bicycloalkyl and adamantyl, each substituted or unsubstituted. 25. The compound according to any one of -24.
  27. R 1 is each substituted or unsubstituted alkylphenyl, halophenyl, alkylhalophenyl, alkoxyphenyl, alkylaminoalkoxyphenyl, heterocycloalkylalkoxyphenyl, alkylaminoalkylphenyl, heterocycloalkylalkylphenyl, cycloalkyl 25. A compound according to any one of claims 1 and 7-24, selected from the group consisting of:
  28. R 1 is each substituted or unsubstituted cyano, carboxamide, aminoalkyl, aminoalkoxy, heterocycloalkyl, heterocycloalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aryloxy, heteroaryloxy, bicyclo 25. A compound according to any one of claims 1 and 7-24, substituted with a substituent selected from the group consisting of aryl, heterobicycloaryl, bicycloaryloxy and heterobicycloaryloxy.
  29. R 3 is H, A compound according to any one of claims 1~4,7 and 10 to 28.
  30. R 7 is H, A compound according to any one of claims 1~15,17~19 and 21-29.
  31. R 7 and R 8 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heteroaryl, each substituted or unsubstituted. The compound according to any one of 21 to 29.
  32. R 7 and R 8 are each substituted or unsubstituted hydrogen, methyl, ethyl, propyl, isopropyl, butyl, alkylaminoalkyl, dialkylaminoalkyl, benzyl, halobenzyl, dihalobenzyl, phenylethyl, pyrimidinylalkyl, pyrazolyl Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methylphenyl, dimethylphenyl, ethylphenyl, halophenyl, dihalophenyl, methoxyphenyl, cyanophenyl, haloalkylphenyl, pyridinyl, halopyridinyl, alkoxypyridinyl, tetrahydropyranyl, pyrazolyl and 30. A compound according to any one of claims 1 to 15, 17 to 19 and 21 to 29, each independently selected from the group consisting of pyrimidinyl.
  33. R 7 and R 8 are each substituted or unsubstituted (C 3-12 ) cycloalkyl, hetero (C 3-12 ) cycloalkyl, (C 9-12 ) bicycloalkyl, hetero (C 3- 12 ) The ring selected from the group consisting of bicycloalkyl, aryl, heteroaryl, ( C9-12 ) bicycloaryl and hetero ( C4-12 ) bicycloaryl are formed together, The compound according to any one of 17 to 19 and 21 to 29.
  34. The compound according to any one of claims 1 to 4, 7, 10 to 15, 17 to 19, and 21 to 33, wherein R 13 is H.
  35. R 14 is each substituted or unsubstituted cyano, carboxamide, aminoalkyl, aminoalkoxy, heterocycloalkyl, heterocycloalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aryloxy, heteroaryloxy, bicyclo 35. A compound according to any one of claims 2, 17-20 and 21-34, selected from the group consisting of aryl, heterobicycloaryl, bicycloaryloxy and heterobicycloaryloxy.
  36.   The compound according to any one of claims 2, 17 to 20, and 21 to 35, wherein n is 0, 1 or 2.
  37.   37. A compound according to any one of claims 1-4, 7, 16, 20, and 21-36, wherein X is methylene.
  38.   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 substituted or unsubstituted.
  39.   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 phenyl and pyridinyl, each substituted or unsubstituted.
  40.   24. Y 1-4, 7, 16, 20, and 21 wherein Y is selected from the group consisting of phenyl, halophenyl, dihalophenyl, methylphenyl, dimethylphenyl, cyanophenyl, aminocarboxyphenyl, haloalkylphenyl, alkoxyphenyl, and oxopyridinyl. 38. The compound according to any one of -37.
  41. 2. The compound of claim 1, selected from the group consisting of:
    3-chloro-N- (4- (1-hydroxyethyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
    3-chloro-N- (4- (1-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;
    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;
    3-chloro-N- (4-((3-fluorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
    3-chloro-N- (4-((3,4-difluorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
    3-chloro-N- (4-((4-chloro-3-fluorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
    3-chloro-N- (4-((3-chloro-5-fluorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
    3-chloro-N- (4-((4-fluorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
    3-chloro-N- (4- (hydroxy (phenyl) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
    3-chloro-N- (4-((4-chlorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
    3-chloro-N- (4-((3-chlorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
    3-chloro-N- (4-((3-chloro-4-fluorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
    3-chloro-N- (4-((3,5-difluorophenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
    3-chloro-N- (4- (hydroxy (m-tolyl) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
    3-chloro-N- (4-((2,3-dimethylphenyl) (hydroxy) methyl) thiazol-2-yl) -2-methylbenzenesulfonamide;
    3-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-methylbenzenesulfonamide;
    3-chloro-N- (4- (1-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- (1-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- (1-hydroxy-2-pyrimidin-4-yl-ethyl) -thiazol-2-yl] -2-methyl-benzenesulfonamide;
    1- [2- (3-chloro-2-methyl-benzenesulfonylmethyl) -thiazol-4-yl] -2-pyridazin-3-yl-ethanol;
    3-chloro-N- {4- [1-hydroxy-2- (2H-pyrazol-3-yl) -ethyl] -thiazol-2-yl} -2-methyl-benzenesulfonamide; and 3-chloro-N -{4- [1-Hydroxy-2- (1H-pyrazol-4-yl) -ethyl] -thiazol-2-yl} -2-methyl-benzenesulfonamide.
  42. 2. The compound of claim 1, selected from the group consisting of:
    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-1-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-dimethylthiazol-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] dioxin-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] [1,2,5] thiadiazole-5-sulfonamide;
    N- (4- (3-hydroxypentan-3-yl) thiazol-2-yl) -3,4-dihydro-2H-benzo [b] [1,4] dioxepin-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) -1,2,3,4-tetrahydroisoquinoline-7-sulfone An amide;
    N- (4- (3-hydroxypentan-3-yl) thiazol-2-yl) -1,2,3,4-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] [1,3] dioxol-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. 2. The compound of 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-cyclopropyl-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-benzenesulfonamide;
    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) -benzenesulfonamide;
    3-chloro-N- [4- (2-hydroxy-butyl) -thiazol-2-yl] -4- (3-morpholin-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-morpholin-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. 2. The compound of 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-((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-morpholin-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-morpholin-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-morpholinopropoxy) benzenesulfonamide;
    N- (4- (2-ethyl-2-hydroxybutyl) thiazol-2-yl) -4- (3-morpholinopropoxy) 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- (1-hydroxy-cyclopentylmethyl) -thiazol-2-yl] -2-methyl-4- (3-morpholin-4-yl-propoxy) -benzenesulfonamide;
    N- [4- (1-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- (1-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-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-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] -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-morpholin-4-yl-propyl) -2-trifluoromethyl-benzenesulfonamide;
    N- [4- (2-Ethyl-2-hydroxy-butyl) -thiazol-2-yl] -4- (4-morpholin-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- (1-hydroxy-cyclopentylmethyl) -thiazol-2-yl] -amide;
    Ethanesulfonic acid [4- (1-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. 2. The compound of 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. 2. The compound of 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-1 (2H) -yl) methyl) thiazol-2-yl) benzenesulfonamide; and N- (4- (3-methoxybenzyl ) Thiazol-2-yl) -3-chloro-2-methylbenzenesulfonamide.
  47.   47. A compound according to any one of claims 1-46, wherein the compound is in the form of a pharmaceutically acceptable salt.
  48.   48. The compound of any one of claims 1-47, wherein the compound is present in a mixture of stereoisomers.
  49.   48. A compound according to any one of claims 1 to 47, wherein the compound comprises a single stereoisomer.
  50.   50. A pharmaceutical composition comprising the compound according to any one of claims 1 to 49 as an active ingredient.
  51.   51. The pharmaceutical composition according to claim 50, wherein the composition is a solid formulation adapted for oral administration.
  52.   51. The pharmaceutical composition according to claim 50, wherein the composition is a liquid formulation adapted for oral administration.
  53.   51. The pharmaceutical composition according to claim 50, wherein the composition is a tablet.
  54.   51. 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 to 49, wherein the composition is oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, Pharmaceutical suitable for administration by a route selected from the group consisting of rectal, buccal, intranasal, liposome, inhalation, intravaginal, intraocular, topical delivery, subcutaneous, intrafacial, intraarticular and intrathecal Composition.
  56. 50. From the group consisting of the compound of any one of claims 1-49; and indicating the 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. A kit comprising instructions for use comprising one or more selected information forms.
  57.   57. The kit of claim 56, wherein the kit comprises the compound in a multiple dose form.
  58. 50. A product comprising the compound of any one of claims 1-49; and a packaging material.
  59.   59. The product of claim 58, wherein the packaging material comprises a container for housing the compound.
  60.   60. The product of claim 59, wherein the container comprises one or more elements of the group consisting of a disease state to which the compound is to be administered, storage information, dosing information and / or instructions regarding how to administer the compound. Product including label to show.
  61.   59. The product of claim 58, wherein the product comprises the compound in multiple dosage forms.
  62.   50. A method of treatment comprising the step of administering the compound of any one of claims 1-49 to a subject.
  63.   50. A method of inhibiting HSD comprising contacting HSD with a compound of any one of claims 1-49.
  64.   50. A method of inhibiting HSD comprising the step of presenting a compound of any one of claims 1-49 in a subject to inhibit HSD in vivo.
  65.   A method of inhibiting HSD comprising administering a first compound that is converted in vivo to a second compound, wherein the second compound inhibits HSD in vivo, said method comprising: 50. A method wherein the second compound is a compound according to any one of claims 1-49.
  66.   50. A method of treating a disease state wherein HSD has an activity causing pathology and / or symptomatology of said disease state, said method comprising treating the compound of any one of claims 1-49 with said disease A method comprising the step of being present in a subject in a therapeutically effective amount of a condition.
  67.   50. A method of treating a disease state wherein HSD has an activity that causes pathology and / or symptomatology of said disease state, the method comprising: subjecting a compound of any one of claims 1 to 49 to a subject. Administering the compound, wherein the compound is present in the subject in a therapeutically effective amount of the disease state.
  68.   A method of treating a disease state wherein HSD has an activity responsible for the pathology and / or symptomology of said disease state, said method comprising: converting a first compound that is converted in vivo to a second compound 50. A method comprising administering to a subject, wherein the second compound inhibits HSD in vivo, and the second compound is a compound according to any one of claims 1-49. .
  69.   69. The method according to any one of claims 66 to 68, wherein the disease state is selected from the group consisting of metabolic syndrome, Cushing's disease, hypertension, cognitive function and visual function.
  70.   70. The method according to any one of claims 63 to 69, wherein the HSD is 11b-HSD1.
JP2007546949A 2004-12-17 2005-12-16 Hydroxyl steroid dehydrogenase inhibitor Granted JP2008524244A (en)

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