WO2006134481A1 - Inhibitors of 11-beta hydroxysteroid dehydrogenase type 1 - Google Patents

Abstract

The present invention relates to compounds of formula (I): or a pharmaceutically acceptable salts or solvates thereof, wherein n, X, Y, R1, R2, R3 and R4 are as described in the specification. The invention also relates to pharmaceutical compositions comprising the compounds of formula (I) and methods of treating conditions that are mediated by the modulation of 11 βHSD1 , the method comprising administering to a mammal an effective amount of a compound of formula (I).

Description

INHIBITORS OF 11 -BETA HYDROXYSTEROID DEHYDROGENASE TYPE 1

Field of the Invention

The present invention relates to novel compounds, pharmaceutical compositions comprising these compounds, and methods of using these compounds and compositions for the treatment of conditions mediated by 11 β-hydroxysteroid dehydrogenase type 1 enzyme (11 βHSD1).

Background of the Invention

Type 2 diabetes is a major health concern with an estimated 150 million people affected worldwide. Characteristics of Type 2 diabetes are insulin resistance, hyperglycemia and hyperinsulinaemia. Although there are several marketed drugs that partially lower plasma glucose levels and improved insulin sensitivity, there is still a need for more effective therapies with fewer side effects. Many research labs are studying novel biological mechanisms that influence this disease. One biological target that has gained a lot of attention is 11 βHSD1 because of the role it plays in gluconeogenesis and insulin sensitivity.

Gluconeogenesis, the de novo synthesis of glucose from non-carbohydrate precursors, primarily occurs in the liver and is abnormally high in Type 2 diabetes. Hepatic glucose output is poorly regulated by insulin in the late stages of the disease, which results in higher serum glucose levels. Hepatic glucose output attributed to gluconeogenesis in Type 2 diabetic patients may reach as high as 90%, whereas in healthy patients only 25% of glucose output is a result of gluconeogenesis. This process is regulated by the glucocorticoid receptor (GR), which drives the expression of two enzymes involved in rate limiting steps of the gluconeogenic pathway: phosphoenolpyruvate carboxykinase (PEPGK) and glucose-6- phosphatase (GΘPase).

In the liver, 11 βHSD1 plays a role in ligand-induced activation of GR by raising the tissue specific concentration of Cortisol. It does this by catalyzing the reduction of the 11-keto group found on inactive cortisone using NAD(P)H as the cofactor. Increased activity of 11 βHSD1 therefore leads to an increase In GR activation. In adipose tissue, 11 βHSD1 activity affects adipocytes where, for example, it decreases insulin-dependent glucose uptake and increases lipolysis. Expression of 1 1 βHSD1 in visceral fat is higher than in subcutaneous fat. Visceral obesity is strongly correlated with insulin resistance and the metabolic syndrome. Therefore, increased activity in adipose 11 βHSD1 could play a role in these conditions. Thus, there is a need for new drugs which inhibits and/or modulates the activity of 11 βHSD1. The discussion of the background of the invention is included herein to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known or part of the common general knowledge in the United States or in any foreign country as of the priority date of any of the claims.

Summary of the Invention The compounds and compositions of the present invention inhibit and/or modulate the activity of

11βHSD1 and therefore, are useful in the treatment of type 2 diabetes, obesity, ophthalmic diseases, glaucoma, osteoporosis, cognitive disorders, immune disorders, depression, hypertension, and metabolic diseases. In one aspect, the present invention provides compounds having formula (I):

I or a pharmaceutically acceptable salt or solvate thereof, wherein; R¹ is pyridine substituted with 1 to 3 R⁷ groups; or R¹ is

wherein W is C or N, and R¹ is substituted with O to 3 R⁷ groups;

R² and R³ are optionally each independently selected from hydrogen, hydroxyl, (C₁-C₆)BIkOXyI, (Ci-CβJalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (CR^δR⁶)_n(C₃-C₁₀)cycloalkyl, (C=O)O(C₁-C₆)BIkVl and SO₂(C₁-C₆)alkyl, and R² and R³ are each independently substituted with O to 4 R⁷ groups; or

R² and R³ form a 5, 6 or 7-membered saturated ring containing 1 or 2 heteroatoms each independently selected from N, O or S₁ and the 5, 6 or 7 membered saturated ring is substituted with O to 4 R⁷ groups;

R⁴ is selected from hydrogen, hydroxyl, halogen, (C₁-C₆JaIkOXy and

and R⁴ is optionally substituted with O to 4 R⁷ groups;

R⁵ and R⁶ are each independently selected from hydrogen and (C^C^alkyl; each R⁷ is independently selected from hydroxyl, halogen, cyano, amino, azido, nitro, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, (C_rC₆)alkoxy, (C^C^alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C=O)R⁸, (C=O)OR⁸, 0(C=O)R⁸, NR⁸(C=O)R⁹, (C=O)NR⁸R⁹, NR⁸R⁹, NR⁸OR⁹, S(O)_jNR⁸R⁹, S(O)_j(C₁-C₆)aikyl, OSO₂R⁸, NR⁸S(O)_jR⁹, (CR⁸R⁹)_k(C₆-C₁₀aryl), (CR⁸R⁹)_k(5-10)-membered heterocyclyl, (CR⁸R⁹)_k(C=O)(CR⁸R⁹)_m(C₆-C₁₀)aryl, (CR⁸R⁹)_k(C=O)(CR⁸R⁹)_m(5-10)-membered heterocyclyl, (CR⁸R⁹)_kO(CR⁸R⁹)_m(C₆-C₁₀)aryl, (CR⁸R⁹)_kO(CR⁸R⁹)_m(5-10)-membered heterocyclyl,

(CR⁸R⁹)_kS(O)_j(CR⁸R⁹)_m(C₆-C₁₀)aryl and (CR⁸R⁹)_kS(O)_j(CR⁸R⁹)_m(5-10)-membered heterocyclyl; and each R⁷ is substituted with O to 4 R¹⁰ groups; each j, k and m are independently O, 1 , 2 or 3; and each R⁸ and R⁹ are independently selected from hydrogen, (C_rC₆)alkyl, (CR⁵R⁶)_p(C₆-C₁₀)aryl or (CR⁵R⁶)p(5-10)-membered heterocyclyl; each R¹⁰ is independently selected from hydroxyl, halogen, cyano, amino, azido, nitro, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, (C_rC₆)alkoxy, (C^CeJalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C=O)R⁸, (C=O)OR⁸, 0(C=O)R⁸, NR⁸(C=O)R⁸, (C=O)NR⁸R⁹, NR⁸R⁹, NR⁸OR⁹,

S(O)₁NR⁸R⁹, S(O)_j(C_rC₆)alkyl, OSO₂R⁸, NR⁸S(O)_jR⁹, (CR⁸R⁹)_k(C₆-C₁₀aryl), (CR⁸R⁹)_k(5-10)-membered heterocyclyl, (CR⁸R⁹)_k(C=O)(CR⁸R⁹)_m(C₆-C₁₀)aryl, (CR⁸R⁹)_k(.C=O)(CR⁸R⁹)_m(5-10)-membered heterocyclyl, (CR⁸R⁹)_kO(CR⁸R⁹)_m(C₆-C₁₀)aryl, (CR⁸R⁹)_kO(CR⁸R⁹)_m(5-10)-membered heterocyclyl,

and (CR⁸R⁹)_kS(O)_j(CR⁸R⁹)_m(5-10)-membered heterocyclyl

In another aspect, the present invention provides compounds of formula I, wherein R¹ is pyridine

In still another aspect, the present invention provides compounds of formula I, wherein R¹ is benzo[b]thιophene

In another aspect, the present invention provides compounds of formula I, wherein R² and R³ are optionally each independently selected from hydrogen, (CVC^alkyl, (C=O)O(C₁-C₆)alkyl and SO₂(C₁- CβJalkyl, or R² and R³ form a 5 or 6-membered saturated ring containing 1 or 2 heteroatoms each independently selected from N or O

In yet another aspect, the present invention provides compounds of formula I, wherein R² and R³ form a pyrrolidine, pipeπdine or morpholine ring

In another aspect, the present invention provides compounds of formula I, wherein the compound is selected from

In a still further aspect, the present invention provides compounds of formula I, wherein the compound is selected from - A -

In yet another aspect, the present invention provides compounds of formula I₁ wherein the compound is selected-from:

In a further aspect, the present invention provides compounds having formula (II):

or a pharmaceutically acceptable salt or solvate thereof, wherein;

R¹ is naphthyl or is

wherein Q and Z are each independently C or N, but are not both N, and wherein R¹ is substituted with O to 4 R¹⁰ groups;

R² and R³ are optionally each independently selected from hydrogen, hydroxyl, (Ci-C₆)alkoxyl, (C₁-C₆)SlRy!, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (CR⁵R⁶)_n(C₃-C₁₀)cycloalkyl, (C=O)O(C₁-C₆)alkyl and SO₂(C₁-C₆)alkyl, and R² and R³ are each independently substituted with O to 4 R¹⁰ groups; or ^■ R² and R³ form a 5, 6 or 7-membered saturated ring containing 1 or 2 heteroatoms each independently selected from N, O or S, and the 5, 6 or 7 membered saturated ring is substituted with O to 4 R¹⁰ groups;

R⁴ is selected from hydrogen, hydroxyl, halogen, (C₁-C₆)BIkOXy and (C^CeJalkyl, and R⁴ is optionally substituted with O to 4 R¹⁰ groups; R⁵ and R⁶ are each independently selected from hydrogen and (C₁-C₆)alkyl;

R⁷ is selected from (C₆-C₁₀)aryl or (5-10)-membered heteroaryl, and is substituted with 1 to 4 R¹⁰ groups; each R⁸ and R⁹ are independently selected from hydrogen, (C_rC₆)alkyl, (CR⁵R⁶)_p(C₆-C₁₀)aryI or (CR⁵R⁶)p(5-10)-membered heterocyclyl; each R¹⁰ is independently selected from hydroxyl, halogen, cyano, amino, azido, nitro, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, (C_rC₆)alkoxy, (d-CeJalkyl, (C₂-C₆)alkenyi, (C₂-C₆)alkynyl, (C=O)R⁸, (C=O)OR⁸, 0(C=O)R⁸, NR⁸(C=O)R⁹, (C=O)NR⁸R⁹, NR⁸R⁹, NR⁸OR⁹, S(O)₁NR⁸R⁹, S(O)_j(C_rC₆)alkyl, OSO₂R⁸, NR⁸S(O)_jR⁹, (CR⁸R⁹)_k(C₆-C₁₀aryl)₍ (CR⁸R⁹)_k(5-10)-membered heterocyclyl, (CR⁸R⁹)_k(C=O)(CR⁸R⁹)_m(C₆-C₁₀)aryl, (CR⁸R⁹)_k(C=O)(CR⁸R⁹)_m(5-10)-membered heterocyclyl, (CR⁸R⁹)_kO(CR⁸R⁹)_m(C₆-Cio)aryl, ^! (CR⁸R⁹)_kO(CR⁸R⁹)_m(5-10)-membered heterocyclyl,

(CR⁸R⁹)_kS(O)_j(CR⁸R⁹)_m(C₆-C₁₀)aryl and (CR⁸R⁹)_kS(O)_j(CR⁸R⁹)_m(5-10)-membered heterocyciyl; and each j, k and m are independently O, 1 , 2 or 3.

In one aspect, the present invention provides compounds of formula II, wherein R¹ is

In a further aspect, R⁷ is either benzyl or pyridine. In a still further aspect Q is C and Z is N. In still another aspect of formula II, Q is N and Z is C. In an alternative aspect, R¹ is naphthyl substituted with 1 to 4 R¹⁰ groups.

In another aspect, the present invention provides pharmaceutical compositions comprising an effective amount of the compound of formula 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. In another aspect, the present invention provides methods for treating conditions that are mediated by the modulation of 11 βHSD1 , comprising administering to a mammal an effective amount of the compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides methods for treating conditions that are mediated by the modulation of 11βHSD1 , wherein the condition is diabetes, metabolic syndrome, insulin resistance syndrome, obesity, ophthalmic diseases, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, atherosclerosis, dementia, depression, virus diseases, inflammatory disorders, or diseases in which the liver is a target organ.

In another aspect, the present invention provides methods for treating glaucoma comprising administering to a mammal an effective amount of an inventive compound in combination with a prostanoid receptor agonist, wherein said agonist is latanoprost.

Definitions

For purposes of the present invention, as described and claimed herein, the following terms are defined as follows:

As used herein, the terms "comprising" and "including" are used in their open, non-limiting sense. As used herein, the term "alkyl", unless otherwise indicated, refers to a linear, branched, or cyclic saturated hydrocarbon group containing 1 to about 24 carbon atoms, preferably 1 to about 12 carbon atoms, including groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. The term "lower alkyl" means an alkyl group of 1 to 6 carbon - Q -

atoms. The term "substituted alkyl" refers to an alkyl group which is substituted with one or more substituent groups, and the term "heteroatom containing alkyl" refers to an alkyl group which is substituted with one or more heteroatoms. The terms "alkyl" and "lower alkyl" include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkyl and lower alkyl, respectively. As used herein, the term "alkenyl", unless otherwise indicated, refers to a linear, branched, or cyclic hydrocarbon group of 2 to about 24 carbon atoms containing at least one double bond, such as ethenyi, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl, and the like. Preferred alkenyl groups herein contain 2 to about 12 carbon atoms. The term "lower alkenyl" intends an alkenyl group of 2 to 6 carbon atoms, and the specific term "cycloalkenyl" intends a cyclic alkenyl group, preferably having 5 to 8 carbon atoms. The term "substituted alkenyl" refers to alkenyl substituted with one or more substituent groups, and the terms "heteroatom- containing alkenyl" and "heteroalkenyl" refer to alkenyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms "alkenyl" and "lower alkenyl" include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkenyl and lower alkenyl, respectively. As used herein, the term "alkynyl", unless otherwise indicated refers to a linear or branched hydrocarbon group of 2 to about 24 carbon atoms containing at least one triple bond, such as ethynyl, n- propynyl, and the like. Preferred alkynyl groups herein contain 2 to about 12 carbon atoms. The term "lower alkynyl" intends an alkynyl group of 2 to 6 carbon atoms. The term "substituted alkynyl" refers to alkynyl substituted with one or more substituent groups, and the terms "heteroatom-containing alkynyl" and "heteroalkynyl" refer to alkynyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms "alkynyl" and "lower alkynyl" include linear, branched, unsubstituted, substituted, and/or heteroatom-containing alkynyl and lower alkynyl, respectively.

As used herein, the term "cycloalkyl", unless otherwise indicated, refers to a non-aromatic, saturated or partially saturated, monocyclic or fused, spiro or unfused bicyclic or tricyclic hydrocarbon referred to herein containing a total of from 3 to 10 carbon atoms, preferably 5-8 ring carbon atoms. Exemplary cycloalkyls include monocyclic rings having from 3-10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; fused rings having from 6 to 10 carbon atoms such tetrahydrodecalin and tetrahydronaphthalene; and bicyclic rings having from 6 to 10 carbon atoms such as norbornane, norbornene and adamantane. Illustrative examples of cycloalkyls include but not limited to:

As used herein, the term "aryl" or "(C₆-C₁₀)aryl", unless otherwise indicated, refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings that are fused together, directly linked, or indirectly linked (such that the different aromatic rings are bound to a common group such as a methylene or ethylene moiety). Preferred aryl groups contain 6 to 10 carbon atoms. Exemplary aryl groups contain one aromatic ring or two fused or linked aromatic rings, e.g., phenyl, naphthyl, biphenyl, and the like. "Substituted aryl" refers to an aryl moiety substituted with one or more substituent groups.

As used herein, the terms "halogen" or "halo", unless otherwise indicated, refers to fluoro, chloro, bromo or iodo. As used herein, the term "heteroaryl" or "(5-10)-membered heteroaryl", unless otherwise indicated, includes aromatic heterocyclic groups containing one to four heteroatoms each selected from O, S and N, wherein each heteroaryl group has from 5 to 10 atoms in its ring system. Examples of heteroaryl groups include but are not limited to pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, pyrimidinyl, imidazolyl, 1 ,2,4-triazolyl, tetrazolyl, and the like. As used herein, the term "heterocyclic", unless otherwise indicated, includes aromatic and non- aromatic heterocyclic groups containing 3 to 10 atoms in their ring systems. Non-aromatic heterocyclic groups include groups having only 3 atoms in their ring system, whereas aromatic heterocyclic groups have at least 5 atoms in their ring system. The heterocyclic groups also include benzo-fused ring systems. An example of a 3 membered heterocyclic group is aziridine, an example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5 membered heterocyclic group is thiazolyl, an example of a 7 membered ring is azepinyl, and an example of a 10 membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 ,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3- pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1 ,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3- azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, as derived from the groups listed above, may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached). The 4-7 membered heterocyclic may be optionally substituted on any ring carbon, sulfur, or nitrogen atom(s) by one to two oxo, per ring. An example of a heterocyclic group wherein 2 ring carbon atoms are substituted with oxo moieties is 1 ,1-dioxo-thiomorpholinyl. As used herein, the term "oxo", unless otherwise indicated, refers to =0

As used herein, the term "Boc", unless otherwise indicated, refers to the protecting group: tert- butyl carbonate (-C(=O)0C₄H₉).

As used herein, the term "Ms", unless otherwise indicated, refers to the mesylate group (- SO₂CH₃). As used herein, the terms "optional" or "optionally", unless otherwise indicated means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not. For example, the phrase "optionally substituted" means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present.

As used herein, the term "solvate", unless otherwise indicated, refers to pharmaceutically acceptable solvate forms of a specified compound that retains the biological effectiveness of such compound. Examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO (dimethylsulfoxide), ethyl acetate, acetic acid, or ethanolamine.

As used herein, the phrase "pharmaceutically acceptable salt(s)", unless otherwise indicated, refers to salts of acidic or basic groups which may be present in the compounds of formula (I). The compounds of formula (I) that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula (I) are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edeta.te, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate^', malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phospate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts.

Certain compounds of formula (I) may have asymmetric centers and therefore exist in different diastereomeric and/or enantiomeric forms. All optical isomers and stereoisomers of the compounds of formula (I), and mixtures thereof, are considered to be within the scope of the invention. With respect to the compounds of formula (I), the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof. The compounds of formula (I) may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof. The compounds of the present invention may have asymmetric carbon atoms. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixtures into a diastereomric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered as part of the invention.

As used herein, the term "chiral", unless otherwise indicated, refers to a structure that does not have an improper rotation axis (S_n), i.e., it belongs to point group C_n or D_n. Such molecules are thus chiral with respect to an axis, plane or center of asymmetry. Preferred "chiral" molecules herein are in enantiomerically pure form, such that a particular chiral molecule represents at least about 95 wt. % of the composition in which it is contained, more preferably at least about 99 wt. % of that composition.

As used herein, the term "enantioselective", unless otherwise indicated, refers to a chemical reaction that preferentially results in one enantiomer relative to a second enantiomer, i.e., gives rise to a product of which a desired enantiomer represents at least about 50 wt. %. Preferably, in the enantioselective reactions herein, the desired enantiomer represents at least about 80 wt. % of the product, more preferably at least about 85 wt. % of the product, optimally at least about 95 wt. % of the product.

In the molecular structures herein, the use of bold and dashed lines to denote particular conformation of groups follows the IUPAC convention. A bond indicated by a broken line indicates that the group in question is below the general plane of the molecule as drawn (the "α" configuration), and a bond indicated by a bold line indicates that the group at the position in question is above the general plane of the molecule as drawn (the "β" configuration).

When a functional group, e.g., a hydroxyl, sulfhydryl, or amino group, is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site. Suitable protecting groups for the compounds of the present invention will be recognized from the present application taking into account the level of skill in the art, and with reference to standard textbooks, such as Greene et al., Protective Groups in Organic Synthesis (New York: Wiley, 1991).

Certain functional groups contained within the compounds of the present invention can be substituted for bioisosteric groups, that is, groups which have similar spatial or electronic requirements to the parent group, but exhibit differing or improved physicochemical or other properties. Suitable examples are well known to those of skill in the art, and include, but are not limited to moieties described in Patini et al., Chem. Rev, 1996, 96, 3147-3176 and references cited therein.

The subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶CI, respectively. Compounds of the present invention and pharmaceutically acceptable salts or solvates of said compounds which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances, lsotopically labeled compounds of formula (I) of this invention thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non- isotopically labelled reagent. As used herein, the term "diseases in which the liver is a target organ", unless otherwise indicated means diabetes, hepatitis, liver cancer, liver fibrosis, and malaria.

As used herein, the term "metabolic syndrome", unless otherwise indicated means psoriasis, diabetes mellitus, wound healing, inflammation, neurodegenerative diseases, galactosemia, maple syrup urine disease, phenylketonuria, hypersarcosinemia, thymine uraciluria, sulfinuria, isovaleric acidemia, saccharopinuria, 4-hydroxy butyric aciduria, glucose-6-phosphate dehydrogenase deficiency, and pyruvate dehydrogenase deficiency.

As used herein, the term "modulate" or "modulating", unless otherwise indicated, refers to the ability of a modulator for a member of the steroid/thyroid superfamily to either directly (by binding to the receptor as a ligand) or indirectly (as a precursor for a ligand or an inducer which promotes production of ligand from a precursor) induce expression of gene(s) maintained under hormone expression control, or to repress expression of gene(s) maintained under such control.

As used herein, the term "obesity" or "obese", unless otherwise indicated, refers generally to individuals who are at least about 20-30% over the average weight for his/her age, sex and height. Technically, "obese" is defined, for males, as individuals whose body mass index is greater than 27.8 kg/ m², and for females, as individuals whose body mass index is greater than 27.3 kg/m². Those of skill in the art readily recognize that the invention method is not limited to those who fall within the above criteria. Indeed, the method of the invention can also be advantageously practiced by individuals who fall outside of these traditional criteria, for example, by those who may be prone to obesity. As used herein, the term "inflammatory disorders", unless otherwise indicated, refers to disorders such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, chondrocalcinosis, gout, inflammatory bowel disease, ulcerative colitis, Crohn's disease, fibromyalgia, and cachexia.

As used herein, the phrase "therapeutically effective amount", unless otherwise indicated, refers to that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other.

As used herein, the term "treating", unless otherwise indicated, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above.

As used herein, the phrase "amount . . . effective to lower blood glucose levels", unless otherwise indicated, refers to levels of compound sufficient to provide circulating concentrations high enough to accomplish the desired effect. Such a concentration typically falls in the range of about 10 nM up to 2 μM; with concentrations in the range of about 100 nM up to 500 nM being preferred. As noted previously, since the activity of different compounds which fall within the definition of formula (I) as set forth above may vary considerably, and since individual subjects may present a wide variation in severity of symptoms, it is up to the practitioner to determine a subject's response to treatment and vary the dosages accordingly.

As used herein, the phrase "insulin resistance", unless otherwise indicated, refers to the reduced sensitivity to the actions of insulin in the whole body or individual tissues, such as skeletal muscle tissue, myocardial tissue, fat tissue or liver tissue. Insulin resistance occurs in many individuals with or without diabetes mellitus.

As used herein, the phrase "insulin resistance syndrome", unless otherwise indicated, refers to the cluster of manifestations that include insulin resistance, hyperinsulinemia, non insulin dependent diabetes mellitus (NIDDM), arterial hypertension, central (visceral) obesity, and dyslipidemia.

As used herein, the phrase "ophthalmic diseases", unless otherwise indicated, refers to diseases of the eye including but not limited to glaucoma, age related macular degeneration including exudative (wet AMD) and non-exudative (dry AMD), choroidal neovascularization, retinopathies such as diabetic retinopathy, retinitis pigmentosa and retinopathy of prematurity, diabetic macular edema, retinitis, uveitis, cystoid macular edema, glaucoma, and other diseases or conditions of the eye.

For example, the inventive compositions may be used to form a drug depot behind the eye and may include one or more pharmaceutically active agents, in addition to one or more non-active excipients as described herein. Examples of pharmaceutically active agents useful in the inventive compositions includes anti-infectives, including, without limitation, antibiotics, antivirals, and antifungals; antiallergenic agents and mast cell stabilizers; steroidal and nonsteroidal anti-inflammatory agents (such as nepafenac); cyclooxygenase inhibitors, including, without limitation, Cox I and Cox Il inhibitors; combinations of anti- infective and anti-inflammatory agents; decongestants; anti-glaucoma agents, including, without limitation, adrenergics, beta-adrenergic blocking agents, alpha-adrenergic agonists, parasypathomimetic agents, cholinesterase inhibitors, carbonic anhydrase inhibitors, and prostaglandins; combinations of anti- glaucoma agents; antioxidants; nutritiopal supplements; drugs for the treatment of cystoid macular edema including, without limitation, non-steroidal anti-inflammatory agents; drugs for the treatment of age related macular degeneration including nonexudative (dry AMD) and exudative (wet AMD), including, without limitation, angiogenesis inhibitors, including angiogenesis inhibitors that inhibit protein kinase receptors, including protein kinase receptors that are VEGF receptors; and nutritional supplements; drugs for the treatment of herpetic infections and CMV ocular infections; drugs for the treatment of proliferative vitreoretinopathy including, without limitation, antimetabolites and fibrinolytics; wound modulating agents, including, without limitation, growth factors; antimetabolites; neuroprotective drugs, including, without limitation, eliprodil; and angiostatic steroids for the treatment of diseases or conditions of posterior segment 26, including, without limitation, age related macular degeneration including nonexudative (dry AMD) and exudative (wet AMD), choroidal neovascularization, retinopathies, retinitis, uveitis, macular edema, and glaucoma. Such angiostatic steroids are more fully disclosed in U.S. Patent Nos. 5,679,666 and 5,770,592. A non-steroidal anti-inflammatory for the treatment of cystoid macular edema is nepafenac.

For administration to the eye, a compound of the present invention is delivered in a pharmaceutically acceptable ophthalmic vehicle such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the cornea and/or sclera and internal regions of the eye, including, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/ciliary's, lens, choroid/retina and sclera. The pharmaceutically acceptable ophthalmic vehicle may be an ointment, vegetable oil, or an encapsulating material. A compound of the invention may also be injected directly into the vitreous humor or aqueous humor.

Further, a compound of the present invention may be also be administered by well known, acceptable methods, such as sub-Tenon and/or subconjunctival injections. As is well known in the ophthalmic art, the macula is comprised primarily of retinal cones and is the region of maximum visual acuity in the retina. A Tenon's capsule or Tenon's membrane is disposed on the sclera. A conjunctiva covers a short area of the globe of the eyeposterior to the limbus (the bulbar conjunctiva) and folds up (the upper cul-de-sac) or down (the lower cul-de-sac) to cover the inner areas of the upper eyelid and lower eyelid, respectively. The conjunctiva is disposed on top of Tenon's capsule. The sclera and Tenon's capsule define the exterior surface of the globe of the eye. For treatment of ocular diseases such as age related macular degeneration including nonexudative (dry AMD) and exudative (wet AMD), choroidal neovascularization, retinopathies (such as diabetic retinopathy, retinopathy of prematurity), diabetic macular edema, retinitis, uveitis, cystoid macular edema (CME), glaucoma, and other diseases or conditions of the posterior segment of the eye, it is preferable to dispose a depot of a specific quantity of an ophthalmically acceptable pharmaceutically active agent directly on the outer surface of the sclera and below Tenon's capsule. In addition, in cases of age related macular degeneration including nonexudative (dry AMD) and exudative (wet AMD) and CME it is most preferable to dispose the depot directly on the outer surface of the sclera, below Tenon's capsule, and generally above the macula.

The compounds may be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) intramuscular injection or by the above mentioned sub-Tenon or intravitreal injection. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

Within particularly preferred embodiments of the invention, the compounds may be prepared for topical administration in saline (combined with any of the preservatives and antimicrobial agents commonly used in ocular preparations), and administered in eye-drop form. The solution or suspension may be prepared in its pure form and administered several times daily. Alternatively, the present compositions, prepared as described above, may also be administered directly to the cornea.

Within preferred embodiments, the composition is prepared with a muco-adhesive polymer that binds to cornea. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

A pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system may be a VPD co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD:5W) contains VPD diluted 1 :1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used iπstead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes' and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are known by those skilled in the art. Sustained- release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

The pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

Some of the compounds of the invention may be provided as salts with pharmaceutically compatible counter ions. Pharmaceutically compatible salts may be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free-base forms. The preparation of preferred compounds of the present invention is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other compounds of the invention. For example, the synthesis of non- exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.

Other aspects, advantages, and features of the invention will become apparent from the detailed description below. Detailed Description Of The Invention

The following reaction Schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated, R¹ - R⁴, X and Y in the reaction schemes and the discussion that follows are as defined above.

The compounds described herein are prepared according to the following general schemes. As shown below, coupling of the sulfonyl chloride compound of formula A with the pyrrolidine compound of formula B provides the pyrrolidine sulfonyl compound of formula C:

A B C

This coupling step is accomplished using a suitable solvent such as CH₂CI₂ or DMF, and advantageously, in the presence of a suitable base such as pyridine or triethylaπnine, and at temperatures ranging from about -78 ⁰C to about 10O ⁰C. The choice of R¹, R² and R³ groups is dependent upon which starting materials are used.

Alternatively, the R¹ and pyrrolidine amino group may be functionalized by first coupling the sulfonyl chloride compound of formula D with the amino protected pyrrolidine compound of formula E (the use of amino protecting groups (PG) and their subsequent removal are well known to those skilled in the art), using suitable reaction conditions such as those described above, to provide the pyrrolidine sulfonyl compound of formula F:

D E F

The R¹ group may be functionalized using Suzuki or Heck reaction conditions. For example, reaction of the compound of formula F under Suzuki conditions using the boronic acid R⁷B(OH)₂, and catalyzed by metal catalysts such as [1 ,1-bis(diphenylphosphino)ferrocene]-dichloropalladium (II) dichloromethane complex or bis(triphenylphosphine)dichloropalladium, in a suitable solvent such as DMF or DMCA and water, in the presence of a base such as potassium carbonate or cesium carbonate and at a temperature ranging from about room temperature to about 140 ⁰C under conventional conditions or microwave conditions, provides the R⁷ substituted compound of formula G:

F G Removal of the protecting group, PG, on the compound of formula G then provides the secondary amino compound of formula H:

Functionalization of the secondary amino group is accomplished by exposure of the compound of formula H to R³X, wherein X is a leaving group as described above, in a suitable solvent such as CH₂Cl₂ or DMF, and advantageously, in the presence of a base such as potassium carbonate, sodium bicarbonate or triethylamine, ranging from about room temperature to about the boiling point of the solvent, typically from about 20 degrees ⁰C to about 100 ⁰C, to provide the compound of formula I.

Alternatively, the compounds described herein may be prepared through use of the hydroxy pyrrolidine compound of formula J. Coupling of the sulfonyl chloride compound of formula D with the hydroxyl pyrrolidine compound of formula J, using suitable reaction conditions as described above, provides the pyrrolidine sulfonyl compound of formula K

D J K

Alternatively, the use of hydroxy protecting groups (PG) may be used in these steps as the use of such groups are well known to those skilled in the art. As discussed above, the R¹ aryl or heteroaryl group may be functionalized using Heck or Suzuki reaction conditions to provide the compound of formula L

K L

Treatment of the compound of formula L with mesyl chloride in a suitable solvent such as dichloromethane or DMF, and advantageously, in the presence of a base such as potassium carbonate, sodium bicarbonate or triethylamine, and ranging from room temperature to the boiling point of the solvent, typically from about 20 ⁰C to about 100 ⁰C, provides the compound of formula M. Treatment of the compound M with an amine of formula R₂R₃NH in a suitable solvent, e.g. dichloromethane or N₁N- dimethyl formamide, and advantageously, in the presence of a base, e.g. potassium carbonate, sodium bicarbonate or triethylamine, from room temperature to the boiling point of the solvent, typically from about 20 ⁰C to about 100 ⁰C, provides the amino compound of formula N

Further, the compound of formula Q may be prepared by oxidation of the compound of formula O using methods well known to those skilled in the art to provide the keto compound of formula P. Reductive amination of the compound of formula P with an amine of formula R²R³NH in a suitable solvent such as CH₂CI₂, methanol (MeOH) or tetrahydrofuran (THF), in the presence of an acid such as acetic acid and a reducing agent such as NaBCNH₃ or NaB(OAc)₃H at a temperature ranging from about room temperature to about 60 ⁰C, provides the tertiary amino compound of formula Q

The compounds of formula (I) that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula (I) from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.

Those compounds of formula (I) that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline- earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula (I). Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium, and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.

The compounds of the present invention may be modulators of 11 βHSD1. The compounds of the present invention may modulate processes mediated by 1 1βHSD1 , which refer to biological, physiological, endocrinological, and other bodily processes which are mediated by receptor or receptor combinations which are responsive to the 11 (3HSD1 inhibitors described herein (e.g., diabetes, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, diabetic complications (e.g. retinopathy, nephropathy, neurosis, cataracts and coronary artery diseases and the like), arteriosclerosis, pregnancy diabetes, polycystic ovary syndrome, cardiovascular diseases (e.g. ischemic heart disease and the like), cell injury (e.g.) brain injury induced by strokes and the like) induced by atherosclerosis or ischemic heart disease, gout, inflammatory diseases (e.g. arthrosteitis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergosis, asthma, Gl ulcer, cachexia, autoimmune diseases, pancreatitis and the like), cancer, osteoporosis and cataracts. Modulation of such processes can be accomplished in vitro or in vivo. In vivo modulation can be carried out in a wide range of subjects, such as, for example, humans, rodents, sheep, pigs, cows, and the like.

The compounds according to the present invention may be used in several indications which involve modulations of 11 βHSD1 enzyme. Thus, the compounds according to the present invention may be used against dementia (see WO97/07789), osteoporosis (see Canalis E 1996, Mechanisms of glucocorticoid action in bone: implications to glucocorticoid-induced osteoporosis, Journal of Clinical

Endocrinology and Metabolism, 81 , 3441-3447) and may also be used disorders in the immune system

(see Franchimont, et. al, "Inhibition of Th1 immune response by glucocorticoids: dexamethasone selectively inhibits IL-12-induced Stat 4 phosphorylation in T lymphocytes", The journal of Immunology 2000, Feb 15, vol 164 (4), pages 1768-74) and also in the above listed indications.

Inhibition of 11 βHSD1 in mature adipocytes is expected to attenuate secretion of the plasminogen activator inhibitor 1 (PAI-1) an independent cardiovascular risk factor (Haileux, C. M. et al. (1999) J. Clin.

Endocrinol. Metab. 84: 4097-4105). Furthermore, there is a clear correlation between glucocorticoid

"activity" and cardiovascular risk factor suggesting that a reduction of the glucocorticoid effects would be beneficial (Walker, B. R., et al. (1998) Hypertension 31 : 891-895; Fraser, R. et al. (1999) Hypertension 33:

1364-1368).

Adrenalectomy attenuates the effect of fasting to increase both food intake and hypothalamic neuropeptide Y expression. This supports the role of glucocorticoids in promoting food intake and suggests that inhibition of 11 βHSD1 in the brain might increase satiety and therefore reduce food intake (Woods, S. C, et al. 1998) Science, 280: 1378-1383).

Possible Beneficial Effect on the Pancreas

Inhibition of 11 βHSD1 in isolated murine pancreatic β-cells improves the glucose-stimulated insulin secretion (Davani, B., et al. (2000) J. Biol. Chem. Nov. 10, 2000; 275(45): 34841-4).

Glucocorticoids were previously known to reduce pancreatic insulin release in vivo (Billaudel, B. and B. C. J. Sutter (1979) Horm. Metab. Res. 11 : 555-560). Thus, inhibition of 11 βHSD1 is predicted to yield other beneficial effects for diabetes treatment, besides effects on liver and fat.

Stress and glucocorticoids influence cognitive function (de Quervain, D. J.-F., B. Roozendaal, and

J. L. McGaugh (1998) Nature 394: 787-790). The enzyme 11βHSD1 controls the level of glucocorticoid action in the brain and thus contributes to neurotoxicity (Rajan, V., C. R. W. Edwards, and J. R. Seckl, J. (1996) Neuroscience 16: 65-70; Seckl, J. R., Front. (2000) Neuroendocrine/. 18: 49-99). Unpublished results indicate significant memory improvement in rats treated with a non-specific 11βHSD1 inhibitor.

Based the above and on the known effects of glucocorticoids in the brain, it may also be suggested that inhibiting 11 βHSD1 in the brain may result in reduced anxiety (Tranche, F. et al. (1999) Nature Genetics

23: 99-103). Thus, taken together, the hypothesis is that inhibition of 11βHSD1 in the human brain would prevent reactivation of cortisone into Cortisol and protect against deleterious glucocorticoid-mediated effects on neuronal survival and other aspects of neuronal function, including cognitive impairment, depression, and increased appetite (previous section).

The general perception is that glucocorticoids suppress the immune system. But in fact there is a dynamic interaction between the immune system and the HPA (hypothalamo-pituitary-adrenal) axis (Rook, G. A. W. (1999) Baillier's Clin. Endocrinol. Metab. 13: 576-581). The balance between the cell- mediated response and humoral responses is modulated by glucocorticoids. A high glucocorticoid activity, such as at a state of stress, is associated with a humoral response. Thus, inhibition of the enzyme 11βHSD1 has been suggested as a means of shifting the response towards a cell-based reaction.

In certain disease states, including tuberculosis, lepra and psoriasis the immune reaction is normaly biased towards a humoral response when in fact the appropriate response would be cell based. Temporal inhibition of 11 βHSD1 , local or systemic, might be used to push the immune system into the appropriate response (Mason, D. (1991) Immunology Today 12: 57-60; Rook et al., supra).

Recent data suggests that the levels of the glucocorticoid target receptors and the 11 βHSD1 enzymes determine the susceptibility to glaucoma (Stokes, J., et al., (2000) Invest. Ophthalmol. 41 : 1629- 1638). Further, inhibition of 11 βHSD1 was recently presented as a novel approach to lower the intraocular pressure (Walker E. A., et al, poster P3-698 at the Endocrine society meeting Jun. 12-15, 1999, San Diego). Ingestion of carbenoxolone, a non-specific inhibitor of 11 βHSD1 , was shown to reduce the intraocular pressure by 20% in normal subjects. In the eye, expression of 11 βHSD1 is confined to basal cells of the corneal epithelium and the non-pigmented epithelialium of the cornea (the site of aqueous production), to ciliary muscle and to the sphincter and dilator muscles of the iris. In contrast, the distant isoenzyme 11 beta-hydroxysteroid dehydrogenase type 2 is highly expressed in the non-pigmented ciliary epithelium and corneal endothelium. None of the enzymes is found at the trabecular meshwork, the site of drainage. Thus, 11 βHSD1 is suggested to have a role in aqueous production, rather than drainage, but it is presently unknown if this is by interfering with activation of the glucocorticoid or the mineralocorticoid receptor, or both.

Glucocorticoids have an essential role in skeletal development and function but are detrimental in excess. Glucocorticoid-induced bone loss is derived, at least in part, via inhibition of bone formation, which includes suppression of osteoblast proliferation and collagen synthesis (Kim, C. H., S. L. Cheng, and G. S. Kim (1999) J. Endocrinol. 162: 371-379). The negative effect on bone nodule formation could be blocked by the non-specific inhibitor carbenoxolone suggesting an important role of 11 βHSD1 in the glucocorticoid effect (Bellows, C. G., A. Ciaccia, and J. N. M. Heersche, (1998) Bone 23: 119-125). Other data suggest a role of 11 βHSD1 in providing sufficiently high levels of active glucocorticoid in osteoclasts, and thus in augmenting bone resorption (Cooper, M. S. et al. (2000) Bone 27: 375-381). Taken together, these different data suggest that inhibition of 11 βHSD1 may have beneficial effects against osteoporosis by more than one mechanism working in parallel.

Bile acids inhibit 11 β-hydroxysteroid dehydrogenase type 2. This results in a shift in the overall body balance in favor of Cortisol over cortisone, as shown by studying the ratio of the urinary metabolites (Quattropani C, Vogt B, Odermatt A, Dick B, Frey B M, Frey F J. 2001. J Clin Invest. Nov; 108(9):1299- 305. "Reduced activity of 11 beta-hydroxysteroid dehydrogenase in patients with cholestasis"). Reducing the activity of 11 βHSD1 in the liver by a selective inhibitor is predicted to reverse this imbalance, and acutely counter the symptoms such as hypertension, while awaiting surgical treatment removing the biliary obstruction.

All publications mentioned herein are hereby incorporated by reference. By the expression "comprising" means "including but not limited to." Thus, other non-mentioned substances, additives or carriers may be present. The compounds of the present invention may also be useful in the treatment of other metabolic disorders associated with impaired glucose utilization and insulin resistance include major late-stage complications of NIDDM, such as diabetic angiopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy, and diabetic ocular complications such as retinopathy, cataract formation and glaucoma, and many other conditions linked to NIDDM, including dyslipidemia glucocorticoid induced insulin resistance, dyslipidemia, polycysitic ovarian syndrome, obesity, hyperglycemia, hyperlipidemia, hypercholesteremia, hypertriglyceridemia, hyperinsulinemia, and hypertension. Brief definitions of these conditions are available in any medical dictionary, for instance, Stedman's Medical Dictionary (10^th Ed.). Assay. All assays were performed using an Agilent 1100 HPLC with a 96-well plate autosampler accompanied by an IN/US systems β-Ram model 3 Radio-HPLC detector. The 11 βHSD1 assay was performed on a Coming 96-well plate at a total volume of 300μl. The buffer conditions used in this assay are as follows: 10OmM TEA (Triethanolamine), 20OmM NaCI, 0.02% n-dodecyl beta-D-maltoside (NDM), 5% glycerol, 5mM β-M^'E, at a pH of 8.0. The reaction mixture for the assay includes 500μM NADPH, about 6nM 11 βHSD1 (based on active site titration with potent reversible inhibitor), 1 % DMSO (inhibitor), 2mM G6P, 1 U/ml G6P dehydrogenase, and 6mM MgCI₂. G6P, G6P dehydrogenase and MgCI₂ act as a regeneration system to amplify 11 βHSD1 activity.

NADPH and 11 βHSD1 were incubated in buffer for 30 minutes in the presence of inhibitor at 25 celcius prior to the addition of the regeneration system and initiation with ³H-cortisone. Initial reaction velocities were measured by stopping the reaction at various time points between 0 and 60 minutes by mixing 60μl of sample with 60μl of DMSO. These samples were then analyzed by reversed phase liquid chromatography by injecting 15μl of sample into a Jupiter C18, 150 x 4.6mm, 5 micron, 300 A⁰ Phenomenex column, while running an isocratic method of 34:66 methanol to water at 1.25ml/min. The β-Ram model 3 pumps at a 3:1 liquid scintillation cocktail to eluate ratio, and a ³H signal is subsequently measured by the area of the peak observed. ³H-cortisone comes off at approximately 7 minutes, while the ³H-cortisol product of the 11 βHSD1 reaction comes off at approximately 9 minutes. The area of ³H-cortisol is then plotted versus time to determine a linear velocity and this rate can then be plotted to inhibitor concentration to determine a Ki and IC₅₀.

[1 ,2-3H]-cortisone was purchased from American Radiolabeled Chemicals Inc. NADPH, Glucose- 6-Phosphate (G6P), and Glucose-6-Phosphate dehydrogenase were purchased from Sigma.

The K] values of the compounds of the present invention for the 11 βHSD1 enzyme may lie typically between about 10 nM and about 10 μM. The compounds of the present invention that were tested all have Kj's in at least one of the above SPA assays of less than 1 μM, preferably less than 100 nM. Certain preferred groups of compounds possess differential selectivity toward the various H βHSD's. One group of preferred compounds possesses selective activity towards 11 βHSD1 over 11 βHSD2. Another preferred group of compounds possesses selective activity towards 11 βHSD2 over 11 βHSD1. Pharmaceutical Compositions/Formulations. Dosaqinq and Modes of Administration Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be apparent, to those skilled in this art. In addition, those of ordinary skill in the art are familiar with formulation and administration techniques. Such topics would be discussed, e.g. in Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, current edition, Pergamon Press; and Remington's Pharmaceutical Sciences, current edition. Mack Publishing, Co., Easton, Pa. These techniques can be employed in appropriate aspects and embodiments of the methods and compositions described herein. The following examples are provided for illustrative purposes only and are not meant to serve as limitations of the present invention.

The amino heterocyclyl compounds of formula (I) may be provided in suitable topical, oral and parenteral pharmaceutical formulations for use in the treatment of 11 βHSD1 mediated diseases. The compounds of the present invention may be administered orally as tablets or capsules, as oily or aqueous suspensions, lozenges, troches, powders, granules, emulsions, syrups or elixirs. The compositions for oral use may include one or more agents for flavoring, sweetening, coloring and preserving in order to produce pharmaceutically elegant and palatable preparations. Tablets may contain pharmaceutically acceptable excipients as an aid in the manufacture of such tablets. As is conventional in the art these tablets may be coated with a pharmaceutically acceptable enteric coating, such as glyceryl monostearate or glyceryl distearate, to delay disintegration and absorption in the gastrointestinal tract to provide a sustained action over a longer period.

Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil. Aqueous suspensions normally contain active ingredients in admixture with excipients suitable for the manufacture of an aqueous suspension. Such excipients may be a suspending agent, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; a dispersing or wetting agent that may be a naturally occurring phosphatide such as lecithin, a condensation product of ethylene oxide and a long chain fatty acid, for example polyoxyethylene stearate, a condensation product of ethylene oxide and a • long chain aliphatic alcohol such as heptadecaethylenoxycetanol, a condensation product of ethylene oxide and a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate or a fatty acid hexitol anhydrides such as polyoxyethylene sorbitan monooleate.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to know methods using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be formulated as a suspension in a non toxic perenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringers solution and isotonic sodium chloride solution. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition fatty acids such as oleic acid find use in the preparation of injectables.

The amino heterocyclyl compounds of formula (I) may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at about 25 Celcius but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and other glycerides.

For topical use preparations, for example, creams, ointments, jellies solutions, or suspensions, containing the compounds of the present invention are employed. The amino heterocyclyl compounds of formula (I) may also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multimellar vesicles. Liposomes can be formed from a variety of phospholipides, such as cholesterol, stearylamine or phosphatidylcholines.

Dosage levels of the compounds of the present invention are of the order of about 0.5 mg/kg body weight to about 100 mg/kg body weight. A preferred dosage rate is between about 30 mg/kg body weight to about 100 mg/kg body weight. It will be understood, however, that the specific dose level for any particular patient will depend upon a number of factors including the activity of the particular compound being administered, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. To enhance the therapeutic activity of the present compounds they may be administered concomitantly with other orally active antidiabetic compounds such as the sulfonylureas, for example, tolbutamide and the like.

The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art. Where HPLC chromatography is referred to in the preparations and examples below, the general conditions used, unless otherwise indicated, are as follows. The column used is an Alltech Platinum EPS 100A 1.5 micron C18 column; 33mm x 7mm. The samples are run on a Hewlett Packard- 1100 system. A gradient solvent method is used running 5% acetonitrile in water (0.1 % trifluoroacetic acid) to 95% acetonitrile in water (0.1 % trifluoroacetic acid) over 5.5 minutes. The system then proceeds on a wash cycle with 95 percent acetonitrile in water (0.1 % trifluoroacetic acid) for 1.5 minutes. The flow rate over this period is a constant 1.5 mL / minute.

In the following examples and preparations, "Et" means ethyl, "AC" means acetyl, "Me" means methyl, "ETOAC" or "ETOAc" means ethyl acetate, "THF" means tetrahydrofuran, and "Bu" means butyl, DMSO means dimethylsulfoxide. Examples

The invention will now be described in reference to the following Examples. These Examples are not to be regarded as limiting the scope of the present invention, but shall only serve in an illustrative manner. Method A

Example A1: (3R)-1-[(4'-chloro-3-fluorobiphenvl-4-vl)sulfonvl1-N,N-dimethylpyrrolidin-3-amine

A1

Intermediate A1(i) (3R)-1-[(1-bromo-3-fluorophenyl-4-yl)sulfonyl]-N,N-dimethylpyrrolidin-3-amine To a mixture of 4-bromo-2-fluorobenzenesulfonyl chloride (17.51 g, 64.03mmol) in pyridine (100 ml_) at ambient temperature was added (3R)-(+)-3-dimethylaminopyrrolidine (1.2 eq, 8g, 70.44 mmol). The mixture was allowed to stir for 18 hours before the addition of water (400 ml.) and extraction with ethyl acetate (3 x 200 ml_). Combined organic extracts dried (MgSO₄), filtered and concentrated in vacuo. Residue purified via flash column chromatography (SiO₂, dichloromethane/methanol 0-10%) to return named compound AKi) as a tan solid (17.6 g, 50.1 mmol, 78% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.66 - 1.83 (m, 1 H) 2.02 - 2.13 (m, 1 H) 2.20 (s, 6H) 2.63 - 2.76 (m, 1 H) 3.01 - 3.10 (m, 1 H) 3.30 - 3.40 (m, 1 H) 3.51 - 3.59 (m, 1 H) 3.60 - 3.69 (m, J=9.47, 6.95 Hz, 1 H) 7.37 - 7.48 (m, 2 H) 7.71 - 7.81 (m, J=8.59, 7.33 Hz, 1 H)

Example A1: (3R)-1-[(4'-chloro-3-fluorobiphenyl-4-yl)sulfonyl]-N,N-dimethylpyrrolidin-3-amine To a mixture of AKi) (375 mg, 1.06 mmol), (4-chlorophenylboronic acid, 1.2 eq, 200 mg, 1.28 mmol) and cesium carbonate (3eq, 1.03 g, 3.12 mmol) in 1,4-dioxane (6 mL) was added(2-[D-κN)methyl]phenyl- κC](tricyclohexylphosphine)trifluoroacetato-κO-(sp-4-3)-palladium (5mg, 0.5 mol%), (Bedford, R. B.; Cazin, C. S. J.; Gelbrich, T.; Horton, P. N.; Hursthouse, M. B.; Light, M. E. Organometallics 2003, 22, 987). The mixture was heated at reflux for 16 hours. After such time reaction mixture was allowed to cool to room temperature, filtered through a plug of silica (2 gram) eluting with dichloromethane/methanol 90/10 and concentrated in vacuo. The residue was dissolved in dimethylsulfoxide (60 mg/mL) and purified via reverse phase HPLC to return the named compound as the trifluoroacetic acid salt (solid, 234mg, 0.61mmol, 58% yield). Example A2: (3R)-1-{[4-(6-methoxypyridin-3-yl)phenyl]sulfonyi}-N,N-dimethylpyrrolidin-3-amine

Intermediate A2i: (3R)-1-[(1-bromophenyl-4-yl)sulfonyl]-N,N-dimethylpyrrolidin-3-amine

Intermediate A2(i) was prepared using the procedure described for of AKi) above, but substituting 4- bromo-benzenesulfonyl chloride to form a light brown solid A2(i) (17.6 g, 53 mmol, 90% yield). ¹H NMR

(400 MHz, CHLOROFORM-d) δ ppm 1.57 - 1.75 (m, 1 H) 1.97 - 2.10 (m, 1 H) 2.18 (s, 6H) 2.57 - 2.73 (m,

1 H) 2.93 (t, J=8.84 Hz, 1 H) 3.21 - 3.31 (m, J=9.60, 7.33 Hz, 1 H) 3.33 - 3.45 (m, 1 H) 3.46 - 3.58 (m, 1

H) 7.69 (s, 4H)

Example A2: (3R)-1-{[4-(6-methoxypyridin-3-yl)phenyl]sulfonyl}-N,N-dimethylpyrrolidin-3-amine

The title compound was prepared from A2 using the method described for Example A1 above, except substituting A2(i) for AKi) and substituting 4-O-methylphenylboronic acid for 4-chloro-phenylboronic acid.

See Table 1 for NMR data.

Example A3: (R)-4-(4-(3-(dimethylamino)pyrrolidin-1-ylsulfonyl)-2,5-difluorophenyl)benzonitrile

A3(i)

Intermediate A3i: (3R)-1-[(4-bromo-2,5-difluorophenyl)sulfonyl]-N,N-dimethylpyrrolidin-3-amine

Intermediate A3(i) was prepared by the procedure described for AKi) above, but substituting 4-bromo-2,5- difluorobenzenesulfonyl chloride to form light brown solid (4.8 g, 13 mmol, 89% yield). ¹H NMR (400 MHz,

CHLOROFORM-d) δ ppm 7.60 - 7.69 (m, 1 H) 7.52 (dd, J=8.6, 5.1 Hz, 6 H) 3.81 - 3.86 (m, 1 H) 3.64 -

3.78 (m, 3 H) 3.36 - 3.43 (m, 1 H) 2.84 (s, 6 H) 2.37 - 2.56 (m, 2 H).

Example A3: (R)-4-(4-(3-(dimethylamino)pyrrolidln-1-ylsulfonyl)-2,5-difluorophenyl)benzonitrile

The title compound was prepared by the procedure described for AJ. above, except substituting A3(i) for

AKi) and 4-cyanophenylboronic acid for 4-chlorophenylboronic acid. See Table 1 for NMR data.

Example A4: 4'-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]sulfonyl}-2',5'-difluorobiphenyl-4-carbonitrile

Intermediate A4i: (3R)-1-[(1-bromo-3,5-difluorophenyl-4-yl)sulfonyl]-N,N-dimethylpyrrolidin-3-amine Intermediate A4(i) was prepared by the procedure described for AKi) above, but substituting 4-bromo-3,5- difluorobenzenesulfonyl chloride. Low resolution mass spectroscopy APCI⁺ 370 [M+H⁺]⁺ 100%. Example A4: 4'-{[(3R)-3-(dimethylamino)pyrroiidin-1-yl]sulfonyl}-2',5'-difluorobiphenyl-4-carbonitrile The title compound was prepared by the procedure described for A3 above, except substituting A4(i) for Aim. See Table 1 for NMR data.

Example A5: (R)-1-(5-(4-fluorophenyl)pyridin-2-ylsulfonyl)-N,N-dimethylpyrrolidin-3-amine

Intermediate A5(i): 2-(benzylthio)-5-bromopyridine

To a solution of benzyl mercaptan (13.61 g, 100 mmol) in tetrahydrofuran (200 mL, anhydrous) at ambient temperature was added sodium hydride (3.63 g, 120 mmol, 95% in mineral oil) in 3 portions over 20 minutes. The thick slurry was agitated for 30 minutes at ambient temperature, then 2,5-dibromopyridine (23.69 g, 100 mmol) was added in one portion. The reaction was stirred at ambient temperature for 3 hours. The solution was quenched with water and diluted with diethyl ether. The organic layer was washed with saturated aqueous bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue wεis purified by flash column chromatography (SiO₂) eluting with 2-10% ethyl acetate in hexane to give the desired product A5(i) as yellow oil. (26.2 g, yield 94%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.52 (d, J=1.8 Hz, 1 H) 7.58 (dd, J=8.6, 2.5 Hz, 1 H) 7.37 - 7.43 (m, 2 H) 7.31 - 7.36 (m, 2 H) 7.23 - 7.28 (m, 1 H) 7.06 (d, J=9.1 Hz, 1 H) 4.41 (s, 2 H) Intermediate Aδ(ii): 5-bromopyridine-2-sulfonyl chloride

To a solution of A5(i) (8.87 g, 32 mmol) in CH₂CI₂ (96 ml) and water (22 ml) at 0 ⁰C was added sulfuryl chloride (18 ml, 221 mmol). The reaction was stirred at 0 ⁰C for 20 minutes and then diluted with water. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the named compound A5(ii) which was taken on directly to the next step.

Intermediate A5(iii): (3R)-1-[(5-bromopyridin-2-yl)sulfonyl]-N,N-dimethylpyrrolidin-3-amine

To a solution of A5(ii) (7.62 g, 30 mmol) in anhydrous CH₂CI₂ (120 mL) at 0 ⁰C was added (R)-N, N- dimethylpyrrolidin-3-amine (3.43 g, 30 mmol) and triethyiamine (12.5 mL, 90 mmol). The mixture was allowed to reach ambient temperature and stirred for 18 hours. The reaction mixture was diluted with

CH₂Cl₂ (100 mL) and water (50 mL), and extracted with CH₂CI₂ (2 x 50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (SiO₂) eluting with 2-10% methanol in CH₂CI₂ to give desired product A5(iii) (4.43 g, yield

48%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.75 (d, J=1.8 Hz, 1 H) 8.04 (dd, J=8.3, 2.3 Hz, 1 H)

7.85 (d, J=8.3 Hz, 1 H) 3.67 - 3.79 (m, 2 H) 3.46 (td, J=10.1 , 7.1 Hz, 1 H) 3.17 (t, J=9.1 Hz, 1 H) 2.67 -

2.75 (m, 1 H) 2.19 - 2.22 (m, 6 H) 2.03 - 2.12 (m, 1 H) 1.69 - 1.82 (m, 1 H). ^'

Example A5: (R)-1-(5-(4-fluorophenyl)pyridin-2-ylsulfonyl)-N,N-dimethylpyrrolidin-3-amine

The title compound was prepared by the procedure described for Al above, except substituting A5(iii) for

A1(D and 4-fluorophenylboronic acid for 4-chlorophenylboronic acid. See Table 1 for NMR data.

Example A6: 4-(5-{[3-(4,4-difluoropiperidin-1-yi)pyrrolidin-1-yl]sulfonyl}pyridin-2-yl)benzonitrile

A6(iii)

Intermediate A6(i) and A6(ii): benzyl (3R)-3-(4,4-difluoropiperidin-1-yl)pyrrolidine-1-carboxylate and benzyl (3S)-3-(4,4-difluoropiperidin-1-yl)pyrrolidine-1-carboxylate

To a solution 4,4-difluoropiperidine (11.68 g, 53.5 mmol) in tetrahydrofuran (250 ml) was added benzyl 3- oxopyrrolidine-1-carboxylate (1 mol eq), acetic acid (2 mol eq.). After stirring for 10 min at room temperature sodium triacetoxyborohydride (2 mol eq) was added and the mixture stirred at ambient temperature for 20 hours. After such time the mixture was concentrated in vacuo and treated with aqueous K₂CO₃ (200 ml), extracted with dichloromethane (3 x 400 ml), dried over Na₂SO₄., filtered and concentrated in vacuo. The residue was purified via flash column chromatography (SiO₂, petroleum etherethyl acetate 100:0 to 70:30) to return desired product as a 1 :1 mixture of enantiomers. The enantiomers were resolved via super critical fluid chromatography (Chiralpak IA, 20% 1 :1 methanol:acetonitrile @ 140 bar, 2.5 mL/min. prep: 20% methanol:acetonitrile @ 140 bar, 55 mL/min) to afford first peak at 2.833 min. designated as S enantiomer. Low resolution mass spectrometry APCI⁺ 325 [M+H⁺]⁺ 100% and second peak at 3.806 min designated as R enantiomer Low resolution mass spectrometry APCI⁺ 325 [M+H⁺]⁺ 100%.

Intermediate A6(iii): 4,4-difluoro-1-[(3R)-pyrrolidin-3-yl]pipeήdine

Benzyl A6(i) (3R)-3-(4,4-Difluoropiperidin-1-vl)pvrrolidine-1-carboxylate (3.71 g, 11.5 mmol) in methanol (200 ml) was degassed with nitrogen and to the mixture was added palladium on carbon (0.4 g, 10 wt/wt %). The nitrogen atmosphere was replaced with hydrogen and the mixture shaken vigorously at 40 psi and ambient temperature for 6 hours. After such time the mixture and concentrated in vacuo to return title compound A6(iii) as a colorless oil (2.2 g, 100%). Low resolution mass spectrometry APCI⁺ 191 [M+H⁺]⁺ 100%

Intermediate A6(iv): 2-chloro-5~{[(3R)-3-(4,4-difluoropiperidin-1-yl)pyrrolidin-1-yl]sulfonyl}pyridine 6-Chloropyridine-3-sulfonyl chloride (424 mg, 2.0 mmol, 2.0 eq) and A6(iiD (150 mg, 0.8 mmol, 1.0 eq) in 2.0 mL anhydrous pyridine were mixed and stirred at room temperature overnight. After removing pyridine in vacuo, the resulting residue was purified via silica gel column chromatography eluting with 40% ethyl acetate in petroleum ether to afford the title compound A6(iv) (163 mg, 56% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm: 8.83 (d, J=2.27 Hz, 1 H), 8.06 (dd, J=8.31 , 1.76 Hz, 1 H), 7.52 (d, .7=8.31 Hz, 1 H), 3.55 (dd, J=9.06, 7.30 Hz, 1 H), 3.40 - 3.48 (m, 1 H), 3.23 - 3.34 (m, 1 H), 3.03 (t, J=8.69 Hz, 1 H), 2.84 - 2.95 (m, 1 H), 2.41 - 2.62 (m, 4 H), 2.05 - 2.16 (m, 1 H), 1.88 - 2.03 (m, 4 H), 1.68 - 1.82 (m, 1 H). Example A6: 4-(5-{[3-(4,4-difluoropiperidin-1-yl)pyrrolidin-1-yl]sulfonyl}pyridin-2-yl)benzonitrile The title compound was prepared by the procedure described for Al above, except substituting A6(iv) for AKi) and 4-cyanophenylboronic acid for 4-chlorophenylboronic acid. See Table 1 for NMR data.

Method B

Example B1 : (3R)-Λ/,N-dimethyl-1-(1-naphthylsulfonyl)pyrrolidin-3-amine

To a solution containing naphthalene-1-sulfonyl chloride (0.30 g, 1.0 mmol) in anhydrous CH₂CI₂ (2 mL) was added a solution of (R)-Λ/,Λ/-dimethylpyrrolidin-3-amine (95 mg, 0.83 mmol) in anhydrous CH₂CI₂ (2mL) and PS-DIEA (50 mg, 4.1 mmol). The reaction of mixture was stirred at room temperature overnight. Then PS-trisamine (100 mg) was added to the reaction mixture and stirred for another 2 hours. The reaction mixture was passed through a pre-packed silica column (0.5 g), washed with CH₂CI₂ (4 mL) and methanol (4 mL). The filtrate was concentrated and then diluted with CH₂CI₂ (40 mL) and saturated NaHCO₃ (10 mL), and extracted twice with CH₂CI₂. The combined organic layer was washed with H₂O and brine, and then dried with magnesium sulfate. The desired product Bl was obtained as a white solid (0.1O g, yield 40%) without further purification. See Table 1 for NMR data.

Example B2: 4'-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]sulfonyl}-3'-methylbiphenyl-4-carbonitrile

Intermediate B2(l:) 3'-methylhiphenyl-4-carbonitήle A solution of 4-cyanophenylboronic acid (3.60 g, 24.5 mmol, 1.94 equiv) and sodium carbonate (5.2 g, 49 mmol, 3.9 equiv) in dimethylformamide (41 mL) and water (13 mL) was deoxygenated by alternate evacuation (<1 mm Hg) and argon fill (5 x). 3-Bromotoluene (1.50 mL, 12.6 mmol, 1 equiv) and tetrakistriphenylphosphine palladium (0) (720 mg, 0.62 mmol, 0.049 equiv) were sequentially added to the reaction, and the resulting suspension was deoxygenated by alternate evacuation (<1 mm Hg) and argon fill (2 x). The reaction mixture was heated to 8O⁰C. After 17 h, the mixture was cooled to 24°C and diluted with water (400 mL). The resulting solution was extracted with 3:2 diethyl ether / hexanes (4 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (SiO₂, 0 → 4% ethyl acetate in hexanes; 100% dichloromethane) provided product B2(i) (1.7 g, 72%). ¹H NMR (400 MHz, CDCI₃), δ: 7.67-7.74 (m, 4 H), 7.34-7.44 (m, 3 H), 7.25 (m, 1 H), 2.45 (s, 3H). Intermediate B2(ii): 4'-cyano-3-methylbiphenyl-4-sulfonyl chloride

To an ice-cooled solution of B2(i), 3'-methylbiphenyl-4-carbonitrile, (210 mg, 1.09 mmol, 1 equiv) in dichloromethane (3.6 mL) was added chlorosulfonic acid (145 μL, 2.17 mmol, 2.00 equiv) drop wise. The reaction mixture was allowed to warm to 24 ⁰C over 1 h. After 15 h, excess chlorosulfonic acid was quenched by slow addition of a saturated aqueous sodium bicarbonate solution (7 mL) at 0 ⁰C. The resulting mixture was stirred vigorously until the orange oil was dissolved. The resulting solution was extracted with dichloromethane (50 mL). The collected organics were dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product B2(ii) (42 mg). ¹H NMR (400 MHz, DMSO-Cf₆), δ: 7.75-7.94 (m, 5 H), 7.74-7.53 (m, 2 H), 2.59 (s, 3 H). Example B2: 4'-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]sulfonyl}-3'-methylbiphenyl-4-carbonitrile

The title compound was prepared using the method described in Example B1 above, except substituting

B2(ii) for naphthalene-1-sulfonyl chloride. See Table 1 for NMR data.

Example B3: 4-{(3R)-1-[(5-chloro-1-naphthyl)sulfonyl]pyrrolidin-3-yl}morpholine

B3

Intermediate B3(i): tert-butyl (3S)-3-{[(4-methylphenyl)sulfonyl]oxy}pyrrolidine-1-carboxylate

To a solution of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (10 g, 0.053 mol) in anhydrous dichloromethane (120 ml_) were added Λ/,Λ/-dimethylpyridin-4-amine (0.65 g, 0.0053 mol) and triethylamine (16.1 g, 0.160 mol). The mixture was cooled to O⁰C and toluenesulfonyl chloride (20.3 g, 0.106 mol) was added under N₂. The reaction mixture was stirred at room temperature for 48 h. After such time aqueous Na₂CO₃ was added. After stirring for 0.5 h the organic layer was separated and washed with 10% aqueous citric acid, water, then dried over anhydrous Na₂SO₄, concentrated to return title compound (17.4 g, 95.6%) as an oil. %). ¹H NMR (400 MHz, CDCI₃), δ: 7.78 (d, 2 H), 7.34 (d, 2 H), 5.10- 5.00 (m, 1 H), 3.44-3.37 (m, 4 H), 2.43 (s, 3H), 2.25-1.85 (m, 2 H), 1.41 (s, 9 H). Intermediate B3(ii): 4-[(3R)-pyrrolidin-3-yl]morpholine dihydrochlόride

A mixture of B3(0 (70 g, 0.21 mol) and morpholine (340 ml_) was heated at 85°C for 7 hours. After such time the mixture was allowed to cool to room temperature and water (200 ml.) added. The mixture was stirred for several minutes and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with water (200 mL), dried over anhydrous MgSO₄ and concentrate to yield a yellow oil, which was purified via silica gel column chromatography eluting with petroleum etheπethyl acetate10:1 to 2:1 to give tert-butyl (3R)-3-morpholin-4-ylpyrrolidine-1-carboxylate (21 g, 40.4%) as a white solid. Hydrochloric acid in methanol (8 M, 70 mL) was added into a solution of tert-butyl (3R)-3-morpholin-4- ylpyrrolidine-1-carboxylate (21 g, 0.082 mol) in methanol (70 mL) cooled with ice-water. The mixture was stirred at ambient temperature for 14 hours. After such time the mixture was evaporated and ethyl ether

(200 mL) was added. The precipitate was filtered and dried in vacuo to afford title compound B3(ii) (13.4 g, 71.4%) as a white solid. %). ¹H NMR (400 MHz, D₂O), δ: 4.07-3.76 (m, 6 H), 3.54-3.25 (m, 8 H), 2.57-

2.48 (m, 2 H), 2.17-2.07 (m, 2H).

Example B3: 4-{(3R)-1-[(5-chloro-1-naphthyl)sulfonyl]pyrrolidin-3-yl}morpholine

The title compound was prepared using the method described in Example B1 above, except substituting

B3(ii) for (R)-Λ/,Λ/-dimethyIpyrrolidin-3-amine and 5-chloro-1-naphthylsulfonyl chloride for naphthalene-1- sulfonyl chloride. See Table 1 for NMR data.

Example B4: 2-[{(3R)-1-[(5-chloro-2-naphthyl)sulfonyl]pyrrolidin-3-yl}(methyl)amino]ethanol

B4(ii) B4(iii)

Intermediate B4(i): benzyl (SRyS-Ktert-butoxycarbonyWmethytyaminojpyrrolidine-i-carboxylate

Title compound was prepared following the procedure described in WO Publication Number

WO2003106462A1.

Intermediate B4(ii): benzyl (3R)-3-(methylamino)pyrrolidine-1-carboxylate hydrochloride

To a solution of B4(i) (400 g, 1.2 mol) in methanol (3 L) was added dropwise hydrochloric acid in methanol (8 M, 200 mL) at 0 ⁰C. After the addition, the mixture was gradually warmed to 10 °C and stirred overnight. After such time the mixture was evaporated under reduced pressure and ethyl acetate (1 L) was added to the residue and stirred for 1 h. The mixture was filtered and the cake was washed with diethyl ether (100 mL) and dried under reduced pressure to afford title compound B4(ii) (21 O g, 65 % yield) as a white solid. ¹H NMR: DMSO-d₆ δ 8.30 (m, 3H), 7.28-7.36 (m, 5H), 5.05 (s, 2H), 3.74-3.75 (m,

1 H), 3.33-3.60 (m, 4H), 2.09-2.16 (m, 1 H), 1.93-1.98 (m, 1 H).

Intermediate B4(iii): benzyl (3R)-3-[(2-ethoxy-2-oxoethyl)(methyl)amino]pyrrolidine-1 -carboxylate

To a suspension of B4(ii) (200 g, 0.855 mol) and K₂CO₃ (476 g 3.4 mol) in CH₃CN (2 L) was added bromo-acetic acid ethyl ester (285.6 g, 1.71 mol) in one portion. The mixture was stirred at room temperature overnight. After such time the mixture was filtered and the cake was washed with CH₃CN (100 ml_). The filtrate was concentrated under reduced pressure to afford intermediate B4(iifl (240 g, 88% yield) as brown liquid.¹H NMR: CDCI₃ δ 7.30-7.36 (m, 5H), 5.12 (s, 2H), 4.26 (q, J=8, 2H), 3.66-3.75 (m, 2H), 3.28-3.39 (m, 4H), 2.41 (d, J=8, 3H), 2.04-2.09 (m, 1H), 1.28 (t, J=6, 3H). Intermediate B4(iv): benzyl (3R)-3-[(2-hydroxyethyl)(methyl)amino]pyrrolidine-1-carboxylate

To a solution of B4(iifl (180 g, 0.563 mol) in anhydrous tetrahydrofuran (2 L) was added portionwise lithium aluminium hydride (22 g, 0.563 mol) at -40 ⁰C. After The mixture was gradually warmed to -10.⁰C and stirred for 1 h. After such time the reaction was quenched with ethyl acetate (50 mL) and water (20 ml_). The mixture was filtered and the filtrate was concentrated and the residue purified by column chromatography (SiO₂, dichloromethane/methanol = 10:1) to afford intermediate B4(iv) (60 g, 38.5% yield) as an off-yellow liquid. ¹H NMR: CDCI₃ δ 7.33 (m, 5H), 5.16 (s, 2H), 3.59-3.74 (m, 4H), 3.39 (m, 1 H), 3.08- 3.19 (m, 2H) 2.5-2.7 (m, 2H), 2.27 (s, 3H), 2.10-2.19 (m, 1 H), 1.65-1.75 (m, 1 H) Intermediate B4(v): 2-{meihyl[(3R)-pyrrolidin-3-yl]amino}ethanol To a solution of B4(iv) (42 g, 0.150 mol) in methanol (200 mL) was added palladium hydroxide on carbon (1 % water, 3.5 g). The resulting mixture was stirred under 40 Psi of H₂ ^'at 40 ⁰C for 24 h. After such time the mixture was filtered and the filtrate concentrated under reduced pressure to afford intermediate B4(v) (20 g, 92.6% in yield) as dark-red liquid. ¹H NMR: CDCI₃ δ 5.04 (m, 2H), 3.55-3.60 (m, 2H), 2.93-3.16 (m, 5H), 2.51-2.54 (m, 2H), 2.24 (s, 3H), 1.77-1.96 (m, 2H). Example B4: 2-[{(3R)-1-[(5-chloro-2-naphthyl)sulfonyl]pyrrolidin-3-yl}(methyl)amino]ethanol The title compound was prepared using the method described in Example B1 above, except substituting B4(iv) for (R)-Λ/,Λ/-dimethylpyrrolidin-3-amine and 5-chloro-2-naphthylsulfonyl chloride for naphthalene-1- sulfonyl chloride. See Table 1 for NMR data.

B<arnpJe_B5: 2-[{(3R)-1-[(5-bromo-3-methyl-1-benzothien-2-yl)sulfonyl]pyrrolidin-3- yl}(methyl)amino]ethanol

The title compound was prepared in a manner similar to methods B1 to B4 above, except using 5-bromo- 3-methyl-1-benzothiophene-2-sulfonyl chloride and for B4(iv). See Table 1 for NMR data.

Example B6: 1-f(3ffl-1-[(5-bromo-3-methvl-1-benzothien-2-yl)sulfonyl]pyrrolidin-3-yl}piperidin-4-ol

The title compound was prepared in a manner similar to method B5 above, except using 5-bromo-3- methyl-1-benzothiophene-2-sulfonyl chloride and 1-[(3R)-pyrrolidin-3-yl]piperidin-4-ol, white solid (487 mg, 71% yield). See Tablei for NMR data.

Example B7: (3R)-1-[(5-bromo-3-methyl-1-benzothien-2-yl)sulfonyl]-N,N-dimethylpyrrolidin-3-amine

The title compound was prepared in a manner similar to methods B5 to B6 above, except using 5-bromo- 3-methyl-1-benzothiophene-2-sulfonyl chloride and (3R)-Λ/,Λ/-dimethylpyrrolidin-3-amine. See Table 1 for NMR data.

Example B8: (3'R)-1 '-[(5-bromo-3-methyl-1 -benzothien-2-yl)sulfonyl]-1 ,3'-bipyrrolidine

The title compound was prepared in a manner similar to methods B5 to B6 above, except using 5-bromo- 3-methyl-1-benzothiophene-2-sulfonyl chloride and (3'R)-1 ,3'-bipyrrolidine. See Table 1 for NMR data.

Method C

Example C1 : 4'-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]sulfonyl}-2'-(trifluoromethyl)biphenyl-4-carbonitrile

Intermediate C1(i): (3R)-1-{[4-bromo-3-(trifluoromethyl)phenyl]sulfonyl}-N,N-dimethylpyrrOlidin-3-amine (Step A) To a solution containing 4-bromo-3-fluorobenzene-1-sulfonyl chloride (0.24 g, 1.0 mmol) in anhydrous CH₂CI₂ (2 mL) was added a solution of (R)-N, N-dimethylpyrrolidin-3-amine (95 mg, 0.83 mmol) in anhydrous CH₂CI₂ (2 mL) and PS-DIEA (50 mg, 4.1 mmol). The reaction mixture was stirred at room temperature overnight. Then PS-Trisamine (100 mg) was added to the reaction mixture and stirred for another 2 hours. The reaction mixture was passed through pre-packed silica columns, washed with CH₂CI₂ (4 mL) and methanol (4 mL). The filtration was concentrated and then diluted with CH₂CI₂ (40 mL) and saturated NaHCO₃ (10 mL) and extracted with CH₂CI₂ (2 x 30 mL). The combined organic extracts were washed with H₂O and brine and dried with magnesium sulfate to obtain product CKi) as a white solid (0.28 g) which was used directly in step B. Example C1 :

Example C1; 4'-{[(3R)-3-(dimeihyIamino)pyrrolidin-1-yl]suIfonyl}-2'-(trιϊluoromethyl)biphen

(Step B)

To a mixture of CKi) (0.23 g, 0.65 mmol) and cyanophenylboronic acid (0.10 g, 0.66 mmol) in dioxane was added Cs₂CO₃ (0.63 g, 1.94 mmol) followed by ([2-[(D-κN)methyl]phenyl- κC](tricyclohexylphosphine)(trifluoroacetato-κO-(sp-4-3)-palladium (0.002 g, 0.1 mol% ), (Bedford, R. B.; Cazin, C. S. J.; Gelbrich, T.; Horton, P. N.; Hursthouse, M. B.; Light, M. E. Organometallics 2003, 22, 987). The resulting mixture was heated at 100 ⁰C for 3 hours. The mixture was cooled down and partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by reverse phase chromatography eluting with acetonitrile in H₂O to give the title product as a white solid CJ. (227 mg, 0.54 mmol, 65% over 2 steps). See Table 1 for NMR data.

Method D

Example D1 : 4'-(1 ,3'-bipyrrolidin-1'-ylsulfonyl)biphenyl-4-carbonitrile

lntermediate D1(i): 4'-isocyanobiphenyl-4-sulfonyl chloride

Intermediate DKi) was prepared following the procedure described in European Patent Application EP483667A2. Intermediate D1(ii): 4'-[(3-hydroxypyrrolidin-1-yl)sulfonyl]blphenyl-4-carbonitrile

A solution of D1 fi) (500 mg, 1.8 mmol), 3-pyrrolidinol (200 mg, 2.3 mmol) and triethylamine (0.5 mL) in anhydrous dichloromethane (10 mL) was stirred for 2 hours at room temperature. The mixture was concentrated under reduced pressure, diluted with CH₂CI₂ (200 mL) and washed with saturated NaHCO₃. The organic layer was dried with K₂CO₃, filtered and concentrated under reduced pressure to provide a yellow solid. The solid was triturated with CH₂CI₂ to obtain the desired product (200 mg). The mother liquor was purified via flash chromatography eluting with 0-7% methanol in CH₂Cl₂ to afford a second batch of desired product (270 mg). The total weight of the desired product D1 (ii) was 470 mg (80%). ¹H NMR (400 MHz₁ CHLOROFORM-d) δ ppm 1.84 - 1.93 (m, 1 H) 1.93 - 2.04 (m, J=13.45, 8.91 , 8.72, 4.80 Hz, 1 H) 3.31 (d, J=11.12 Hz, 1 H) 3.40 - 3.50 (m, 3 H) 4.44 (tt, J=4.55, 2.27 Hz, 1 H) 7.70 - 7.79 (m, 6H) 7.96 (d, J=8.59 Hz, 2 H).

Intermediate DI(Hi): 4'-[(3-oxopyrrolidin-1-yl)sulfonyl]biphenyl-4-carbonitήle

Intermediate DKiii) was obtained by oxidation of DKii) using the method described in J. Org. Chem 1997, (p1795). ¹H NMR (400 MHz, DMSO-d_s) δ ppm 2.44-2.5 (m, 2 H) 3.49 - 3.57 (m, 4 H) 7.93 - 8.05 (m, 8 H). Example DV. 4'-(1 ,3'-bipyrrolidin-1 '-ylsulfonyl)biphenyl-4-carbonitrile To a mixture of pyrrolidine (65.4 mg, 0.92 mmol), DKiii) (100 mg, 0.31 mmol) and molecular sieves in methanol (3.5 mL) was added NaCNBH₃ (57.8 mg, 0.92 mmol). The mixture was stirred for 16 hours at room temperature. The mixture was quenched with water then concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (40 mL), filtered through a Celite^® pad and washed with water. The organic layer was dried with K₂CO₃, filtered and concentrated under reduce pressure. The residue was purified using prep-plate TLC by elution with 0-5% methanol in CH₂CI₂ to obtain the desired product Dl (20 mg, 24%). See Table 1 for NMR data.

Method E

Example E1 : 4-(5-{[(3R)-3-piperidin-1-ylpyrrolidin-1-yl]sulfonyl}pyridin-2-yl)benzonitrile

Intermediate E1(i): 1-(6-chloro-pyridine-3-sulfonyl)-pyrrolidin-3-ol

A solution of 3(R)-hydroxy-pyrrolidine (615 mg, 7.06 mmol), 2-chloropyridine-5-sulphonyl chloride (1.57 g, 7.41 mmol) and pyridine (15 ml_) was stirred at O⁰C and allowed to warm to ambient temperature over 1 hour. The mixture was partitioned between ethyl acetate and saturated NaHCO₃ and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to obtain the desired product EKi) as a yellow solid (1.82 g, 94%). ¹H NMR (300 MHz, CDCI₃) δ ppm 8.84 (d, J=2.45 Hz, 1 H) 8.59 - 8.66 (m, 1 H) 8.07 (dd, J=8.29, 2.45 Hz, 1 H) 4.45 (d, J=1.88 Hz, 1 H) 3.43 - 3.56 (m, 2 H) 3.26 - 3.42 (m, 2 H) 1.82 - 2.11 (m, 2 H).

Intermediate EI(H): 4-(5-{[(3S)-3-hydroxypyrrolidin-1-yl]sulfonyi}pyridin-2-yl)benzonitrile A solution of EKi) (326 mg, 2.22 mmol), Pd(PPh₃)₂CI₂ (74 mg, 0.11 mmol) and Cs₂CO₃ (1.64 g in 1 mL water, 5 mmol) in N,N-dimethylformamide (4 mL) was heated in a microwave oven at 140 ⁰C for 30 min. The mixture was partitioned between ethyl acetate and saturated NaHCO₃ and the layers separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography eluting with 60 to 100% ethyl acetate/hexane to obtain the desired product as a white solid (100 mg, 14%). Low resolution mass spectrometry: APCI⁺ 330 [M+H⁺]⁺ 100%. Intermediate EI(Hi): (3S)-1-{[6-(4-cyanophenyl)pyridin-3-yl]suifonyl}pyrrolidin-3-yl methanesulfonate A solution of EKJi) (49 mg, 0.15 mmol), triethylamine (40 μL, 0.3 mmol), methanesulfonyl chloride (13 μL, 0.16 mmol) and CH₂CI₂ (3 mL) was stirred for 30 minutes at O⁰C. The mixture was partitioned between CH₂CI₂ and saturated NaHCO₃ solution and the layers separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated to obtain the desired product EKiii) as a yellow solid (62 mg, 100%). The product was used directly in the next step. ¹H NMR (300 MHz, CDCI₃) δ ppm 8.84 (d, J=2Λ5 Hz, 1 H) 8.59 - 8.66 (m, 1 H) 8.07 (dd, J=8.29, 2.45 Hz, 1 H) 8.01 (m, 2 H), 7.64 (m, 2 H),4.45 (d, J=1.88 Hz, 1 H) 3.43 - 3.56 (m, 2 H) 3.26 - 3.42 (m, 2 H) 1.85 (s, 3H)1.82 - 2.11 (m, 2 H). Example E1: 4-(5-{[(3R)-3-piperidin-1-ylpyrrolidin-1-yl]sulfonyl}pyridin-2-yl)benzonitrile A solution of E1 (iii) (20 mg, 0.05 mmol) and piperidine (0.1 mL) in acetonitrile (2 mL) was heated in a microwave oven at 170 ⁰C for 30 minutes. The mixture was then concentrated and the residue purified by silica gel chromatography eluting with 60% ethyl acetate/hexane to obtain the desired product EJ. (11 mg, 50%) as a white solid. See Table 1 for NMR data.

Method F

Example F1 : 2-[{(3R)-1-[(4'-chlorobiphenyl-4-yl)sulfonyl]pyrrolidin-3-yl}(methyl)amino] ethanol

F1

Intermediate F1(i): tert-butyl {(3R)-1-[(4-bromophenyl)sulfonyl]pyrrolidin-3-yl}carbamate A solution of tert-butyl (3R)-pyrrolidin-3-ylcarbamate (803 mg, 4.3 mmol) in anhydrous CH₂CIa (1OmL) and triethylamine was slowly added to solution of 4-bromobenzenesulfonylchloride (1.Og, 3.9 mmol) in anhydrous CH₂CI₂ (10 ml) at 3°C. The reaction mixture was stirred for 10 minutes at room temperature under nitrogen for 1.5 hours, diluted with CH₂CI₂ (120 ml.) and washed with saturated aqueous NaHCO₃ (20 mL). The organic layer was dried over K₂CO₃, filtered and concentrated in vacuo to return the desired product FM as a white solid (1.5g, 95%). ¹H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.41 (s, 9 H) 1.76 (br, 1 H) 2.02 - 2.11 (m, J=13.14, 8.08, 6.57, 6.57 Hz, 1 H) 3.14 - 3.24 (m, 2 H) 3.32 - 3.43 (m, 2 H) 4.09 (br, 1 H) 4.46 (br, 1 H) 7.68 (s, 4 H). Intermediate F1 (H): tert-butyl {(3R)-1-[(4-bromophenyl)sulfonyl]pyrrolidin-3-yl}methylcarbamate

A solution of fert-butyl FKi) (800 mg, 1.97 mmol) in anhydrous dimethylformamide (8 mL) and sodium hydride (95% suspension in mineral oil, 75 mg, 2.96 mmol) was stirred at room temperature, lodomethane (700.5 mg, 4.94 mmol) was added and the mixture was stirred at 60⁰C for 16 hours. The reaction mixture was cooled to a temperature and diluted with 2:1 ethyl acetateibenzene (200 mL), washed with 1 N aqueous hydrochloric acid (15 ml_), saturated aqueous NaHCO₃ (15 mL) and brine (15 mL). The organic layer was dried over K₂CO₃, filtered and concentrated in vacuo to obtain the desired product FKii) as a gum (830 mg). The gum was used in the next reaction without further purification. ¹H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.41 (s, 9 H) 1.89 (td, J=8.53, 4.17 Hz, 1 H) 1.94 - 2.02 (m, 1 H) 2.71 (s, 3 H) 2.93-3.02 (m, 1 H) 3.09 - 3.16 (m, 1 H) 3.27-3.48 (m, 1 H) 3.47 (d, J=4.80 Hz, 1 H) 4.59 (br, 1 H) 7.67 (s, 4 H).

Intermediate FI(Hi): iert-butyl {(SRj-iW-chlorobiphenyM-ylJsulfonylJpyrrolidinS-ylJmethylcarbamate A solution of F1 (ii) (280 mg, 0.668 mmol), 4-chlorophenylboronic acid (125.3 mg, 0.8 mmol) in DMAC (4.0 mL), water (0.75 mL) and cesium carbonate (652.9 mg, 2.004 mmol) was degassed by alternating between nitrogen and vacuum three times. To this mixture was added [1 ,1-bis(diphenylphosphino)- ferrocene]dichloropalladium (ll)-dichloromethane complex (21.8 mg, 0.027 mmol). Again the reaction mixture was degassed by alternating between nitrogen and vacuum three times and heated at 80⁰C for 19 hours. The mixture was cooled to ambient temperature, diluted with ethyl acetate (50 mL), saturated aqueous NH₄CI (10 mL) and stirred at for 2 minutes. The mixture was filtered and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 10 mL) and the combined organic layers dried over K₂CO₃ and filtered. The filtrate was concentrated in vacuo and the residue was purified via flash column chromatography eluting with 0-50% ethyl acetate in hexane to give the desired product FKiiO (248 mg, 79 %). ¹H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.43 (s, 9 H) 1.86 - 1.95 (m, 1 H) 1.97 - 2.05 (m, 1 H) 2.72 (s, 3 H) 3.07 (br, 1 H) 3.18 (br, 1 H) 3.32 (br, 1 H) 3.53 (br, 1 H) 4.62 (br, 1 H) 7.43 - 7.47 (m, 2 H) 7.51 - 7.56 (m, 3 H) 7.69 (t, J=9.09 Hz, 2 H) 7.87 (d, J=8.34 Hz, 2 H).

Example F2: 2-[{(3R)-1-[(4'-chlorobiphenyI-4-yl)sulfonyl]pyrrolidin-3-yl}(methyl)amino] ethanol Step A. A solution of FKiii) (240 mg, 0.53 mmol) and trifluoroacetic acid (2.0 mL) in CH₂CI₂ (4 mL) was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with CH₂CI₂ (150 mL), washed with saturated NaHCO₃ (15 mL), dried with K₂CO₃ and filtered. The filtrate was concentrated in vacuo to obtain FKiv). (3R)-1-[(4'-chlorobiphenyl-4-yl)sulfonyl]-Λ/-methylpyrrolidin-3-amine trifluoroacetic acid salt (150 mg).

Step B. A solution of FKiv) (100 mg, 0.285 mmol) ), iodoethanol (245 mg, 1.425 mmol) and triethylamine (0.196 mL) in anhydrous dimethylformamide (1.0 mL) was stirred at 6O⁰C for 3.5 days, cooled to ambient temperature, diluted with 2:1 ethyl acetate:benzene (100 mL) and washed with saturated aqueous NaHCO₃ (10 mL). The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic extracts were dried with K₂CO₃ and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified via flash column chromatography eluting with 0-6% methanol in CH₂CI₂ to return the title compound FJ. (41.5 mg, 37%). See Table 1 for NMR data.

Example F2: 2-[{(3R)-1-[(4'-isocyanobiphenyl-4-yl)-sulfonyl]pyrrolidin-3-yl}(methyl)amino]ethanol

F2(i)

Intermediate F2(i): tert-butyl {(3R)-1-[(4'<yano-biphenyl-4-yl)sulfonyl]pyrrolidin-3-yl}methylcarbamate Intermediate F2(i) was prepared in a manner similar to FKiii) above, except using 4-cyanophenylboronic acid for 4-chlorophenylboronic acid. Low resolution mass spectrometry APCI⁺ 342 [M+H⁺-boc] ^+' Example F2: 2-[{(3R)-1-[(4'-isocyanobiphenyl-4-yl)-sulfonyl]pyrrolidin-3-yl}(methyl)amino]ethanol The title compound was prepared using the method described for preparing F1 above, except substituting F2(i) for FKiii). See Table 1 for NMR data.

Example F3: 2-[{(3R)-1 -^'-isocyano-S'-methylbiphenyl^-yOsulfonyljpyrrolidin-S-ylXmethyOaminolethanol

Intermediate F3(i): iert-butyl {(3R)-1-[(4'-cyano-3'-methylbiphenyl-4-yl)sulfonyl]pyrrolidin-3- yl}methylcarbamate

Intermediate F3(i) was prepared in a manner similar to FKiii) above, except substituting 4-cycano-3- methylphenylboronic acid for 4-chlorophenylboronic acid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm

1.43 (s, 9 H) 1.94 - 1.97 (m, 1 H) 1.98 - 2.04 (m, 1 H) 2.65 (s, 3 H) 2.74 (s, 3 H) 3.09 (d, J=4.55 Hz, 1 H)

3.16 - 3.26 (m, 1 H) 3.34 (t, J=8.46 Hz₁ 1 H) 3.4 - 3.57 (m, 1 H) 4.58 - 4.70 (m, 1 H) 7.51 (d, J=8.08 Hz, 1

H) 7.56 (s, 1 H) 7.73 (dd, J=7.96, 5.68 Hz, 3 H) 7.92 (d, J=8.08 Hz, 2 H).

Example F3: 2-[{(3R)-1-[(4'-isocyano~3'-methylbiphenyl-4-yl)sulfonyl]pyrrolidin-3-yl}(methyl)amino]ethanoi The title compound was prepared using the method described for preparing F1 above, except substituting F3(i) for FKiii). See Table 1 for NMR data.

Example F4: 2-[{(3R)-1-[(4'-chloro-3'-methylbiphenyl-4-yl)sulfonyl]pyrrolidin-3-yl}(methyl)amino]ethanol

Intermediate F4(i): tert-butyl {(3R)-1-[(4'-chloro-3'-methylbiphenyl-4-yl)sulfonyl]pyrrolidin-3- yl}methylcarbamate

Intermediate F4(i) was prepared in a manner similar to FKiii) above, except substituting 4-chloro-3- methylphenylboronic acid for FKM. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (s, 9 H) 1.93 (td,

J=8.59, 4.04 Hz, 1 H) 1.97 - 2.07 (m, 1 H) 2.49 (s, 3 H) 2.74 (s, 3 H) 3.02 - 3.14 (m, 1 H) 3.15 - 3.25 (m, 1

H) 3.34 (t, J=8.34 Hz, 1 H) 3.50 -3.58 (m, 1 H) 4.59 - 4.71 (m, 1 H) 7.36 - 7.40 (m, 1 H) 7.44 - 7.49 (m, 2

H) 7.71 (d, J=8.08 Hz, 2 H) 7.88 (d, J=8.34 Hz, 2 H).

Example F4: 2^{(3R)-1-[(4'-chloro-3'-methylbiphenyl-4-yl)sulfonyl]pyrrolidin-3-yl}(methyl)amino]ethanol The title compound was prepared using the method described for preparing F1 above, except substituting

F4(i) for FKiii). See Table 1 for NMR data.

Example F5: 2-[{(3R)-1-[(4'-isocyano-3-methylbiphenyl-4-yl)sulfonyl]pyrrolidin-3-yl}(methyl)amino]ethanol

F5(i)

F5

Intermediate F5(i): tert-butyl {(3R)-1-[(4-bromo-2-methylphenyl)sulfonyl]pyrrolidin-3-yl}carbamate

Intermediate F5(0 was prepared in a manner similar to FKi) above, using terf-butyl (3R)-pyrrolidin-3- ylcarbamate and 4-bromo-2-methylbenzenesulfonyl chloride. ¹H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.45 (s, 9 H) 1.80 - 1.90 (m, 1 H) 2.16 (ddd, J=14.65, 13.14, 6.57 Hz, 1 H) 2.60 (s, 3 H) 3.18 - 3.30

(m, 2 H) 3.38 - 3.49 (m, 2 H) 4.20 (br, 1 H) 4.67 (br, 1 H) 7.45 (dd, J=8.34, 2.02 Hz, 1 H) 7.48 (s, 1 H) 7.77

(d, J=8.34 Hz, 1 H).

Intermediate F5(ii): tert-butyl {(3R)-1-[(4-bromo-2-methylphenyl)sulfonyl]pyrrolidin-3-yl}methylcarbamate Intermediate F5(ii) was prepared in a manner similar to F1 (ii) above, except using instead F5(i). ¹H NMR

(400 MHz, CHLOROFORM-D) δ ppm 1.45 (s, 9 H) 1.92 - 2.01 (m, 1 H) 2.02 - 2.12 (m, 1 H) 2.59 (s, 3 H)

2.74 (s, 3 H) 3.10 - 3.21 (m, 2 H) 3.36 (t, J=8.84 Hz, 1 H) 3.50 (t, J=6.95 Hz, 1 H) 4.73 (br, 1 H) 7.42 -

7.46 (m, 1 H) 7.47 (s, 1 H) 7.75 (d, J=8.34 Hz, 1 H).

Intermediate F5(iii): tert-butyl {(3R)-1-[(4'-cyano-3-methyIbiphenyl-4-yl)sulfonyl]pyrrolidin-3- yljmethylcarbamate

Intermediate F5(iii) was prepared in a manner similar to F1 (iii). using instead F5(ii) and 4-cyano-phenyl boronic acid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 10 H) 2.71 (s, 3 H) 2.77 (s, 3 H) 3.15 -

3.27 (m, 2 H) 3.41 (t, J=8.34 Hz₁ 1 H) 3.51 - 3.62 (m, 1 H) 4.70 - 4.82 (m, 1 H) 7.48 - 7.53 (m, 2 H) 7.67 -

7.71 (m, 2 H) 7.74 - 7.78 (m, 2 H) 8.00 (d, J=8.84 Hz, 1 H). Example F5: 2-[{(3R)-1-[(4'-isocyano-3-meihylbiphenyl-4-yl)sulfonyl]pyrrolidin-3-yl}(methyl)amino]ethanol

The title compound was prepared using the method described for preparing F1 above, except substituting

F5(iiπ for FKiii). See Table 1 for NMR data. Example F6: 2-[{(3R)-1-[(4'-chloro-3-methylbiphenyl-4-yl)sulfonyl]pyrrolidin-3-yl}(methyl)amino]ethanol

Intermediate F6(i) tert-butyl {(3R)-1-[(4'-chloro-3-methylbiphenyl-4-yl)sulfonyl]pyrrolidin-3- yl}methylcarbamate The title compound was prepared in a manner similar to FKiii) above but using instead F5(ii) and A- chlorophenyl boronic acid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9 H) 1.96 - 2.05 (m, 1 H) 2.08 - 2.15 (m, 1 H) 2.71 (s, 3 H) 2.78 (s, 3 H) 3.17 - 3.28 (m, 2 H) 3.37 - 3.47 (m, 1 H) 3.51 - 3.62 (m, 1 H) 4.72 - 4.84 (m, 1 H) 7.43 - 7.51 (m, 4 H) 7.54 (ddd, J=8.78, 2.40, 2.21 Hz, 2 H) 7.98 (d, J=8.84 Hz, 1 H). Example F6: 2-[{(3R)-1-[(4'-chloro-3-methylbiphenyl-4-yl)sulfonyl]pyrrolidin-3-yl}(methyl)amino]ethanol The title compound was prepared using the method described for preparing F1 above, except substituting F6(i) for F1 (iii). See Table 1 for NMR data.

Example F7: 4-[5-({(3R)-3-[(2-hydroxyethyl)(methyl)amino]pyrrolidin-1-yl}sulfonyl)pyridin-2-yl]-2- methylbenzonitrile

F7(ii)

F7

Intermediate F7(i): tert-butyl {(3R)-1-[(6-chloropyridin-3-yl)sulfonyl]pyrrolidin-3-yi}carbamate

Intermediate F70) was prepared in a manner similar to F Ki) above, except using terf-butyl (3R)-pyrrolidin-

3-ylcarbamate and 6-chloropyridine-3-sulfonyl chloride. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9 H) 1.77 - 1.86 (m, 1 H) 2.08 - 2.17 (m, 1 H) 3.23 - 3.32 (m, 2 H) 3.39 - 3.48 (m, 2 H) 4.07 - 4.17

(br, 1 H) 4.44 - 4.53 (m, 1 H) 7.52 (d, J=8.34 Hz, 1 H) 8.06 (dd, J=8.34, 2.53 Hz, 1 H) 8.83 (d, J=2.02 Hz,

1 H).

Intermediate FT(H): tert-butyl {(3R)-1-[(6~chloropyridin-3-yl)sulfonyl]pyrrolidin-3-yl}methylcarbamate

Intermediate F7(ii) was prepared in a manner similar to FKiQ using instead F7(i). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9 H) 1.95 - 1.99 (m, 1 H) 2.02 - 2.10 (m, 1 H) 2.75 (s, 3 H) 3.08 - 3.15

(m, 1 H) 3.20 (dd, J=9.85, 7.07 Hz, 1 H) 3.31 - 3.39 (m, 1 H) 3.49 - 3.59 (m, 1 H) 4.58 - 4.69 (m, 1 H) 7.52

(d, J=8.34 Hz, 1 H) 8.05 (dd, J=8.34, 2.53 Hz, 1 H) 8.83 (d, J=2.53 Hz, 1 H).

Intermediate F7(iii): tert-buiyl ((3R)-1-{[6-(4-cyano-3-methylphenyl)pyridin-3-yl]sulfonyl}pyrrolidin-3- yl)methylcarbamate Intermediate F7(iii) was prepared in a manner similar to FKiii) above, using instead F7(iO and 4-cyano-3- methyl-phenyl boronic acid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (s, 9 H) 1.98 - 2.07 (m, 2

H) 2.66 (s, 3 H) 2.75 (s, 3 H) 3.10 - 3.18 (m, 1 H) 3.23 (dd, J=9.73, 7.20 Hz, 1 H) 3.34 - 3.42 (m, 1 H) 3.50

-3.59 (m, 1 H) 4.64 (br, 1 H) 7.75 (d, J=8.08 Hz, 1 H) 7.91 - 7.97 (m, 2 H) 8.05 (s, 1 H) 8.20 (dd, J=8.34,

2.27 Hz, 1 H) 9.11 (d, J=2.02 Hz, 1 H). Example Fl: 4-[5-({(3R)-3-[(2-hydroxyeihyl)(meihyl)amino]pyrroiidin-1-yl}sulfonyl)pyridin-2-yl]-2- methylbenzonitrile

The title compound was prepared using the method described for preparing F1 above, except substituting

F7(iii) for FKiii). See Table 1 for NMR data.

Method G Example G1 : 2-({(3R)-3-[(2-hydroxyethyl)(methyl)amino]pyrrolidin-1-yl}sulfonyl)-3-methyl-1- benzothiophene-5-carbonitrile

B5 G1

To a solution of B5 I (0.22 g, 0.5 mmol) in dimethylformamide (2 mL) was added copper (I) cyanide (0.007 mg, 0.75 mmol). The mixture was heated to 250 ⁰C for 15 minutes by microwave and then cooled to room temperature. Water (10 mL) was added and the mixture and extracted with ethyl acetate (2x 15 ml). The combined organics were washed with brine (10 mL), dried over magnesium sulfate and concentrated. The residue was purified by reverse phase chromatography eluting with acetonitrile in water to give the title compound Gl (20 mg, yield 11 %). See Table 1 for NMR data.

Examples G2 - G5:

The compounds G2 through G5 were prepared using the method described in Example G1 above, except using compounds B6 through B8 as starting reagents. See Table 1 for NMR data.

Method H Example H1 : 4'-({(3R)-3-[[(2R)-2-hydroxypropyl](methyl)amino]pyrroiidin-1-yl}sulfonyl)biphenyl-4- carbonitrile

Intermediate H1(i): 4'-{[(3R)-3-(methylamino)pyrrolidin-1-yl]sulfonyl}biphenyl-4-carbonitrile.

To a solution of F2(0 (0.88 g, 2 mmol) in an anhydrous CH₂CI₂ (7 mL) at 0 ⁰C was added trifluoroacitic acid (3 ml). The mixture was allowed to reach ambient temperature and stirred for 3 hours. After such time the reaction mixture was concentrated in vacuo, then saturated aqueous solution of NaHCO₃ (20 mL) was added and the mixture extracted with ethyl acetate (2x 100 ml). The combined organics were washed with brine (10 mL), dried over magnesium sulfate and concentrated. The residue was purified by reverse phase chromatography to give the title compound Hl (0.54 mg, yield 79%). ¹H NMR (400 MHz, CHLOROFORM-d) d ppm 7.91 - 7.99 (m, 2 H) 7.70 - 7.81 (m, 6 H) 3.49 (dd, J=9.9, 6.1 Hz, 1 H) 3.31 - 3.43 (m, 2 H) 3.17 - 3.25 (m, 1 H) 3.06 (dd, J=9.9, 5.1 Hz, 1 H) 2.34 (s, 3 H) 2.00 - 2.10 (m, 1 H) 1.62 - 1.71 (m, 1 H) Example H1: 4'-({(3R)-3~[[(2R)-2-hydroxypropyl](methyl)amino]pyrrolidin-1-yl}suifonyl)biphenyl-4~ caώonitrile

To a solution of HKi) (0.15 g, 0.33 mmol) and triethylamine (0.23 mL, 1.65 mmol) in methanol (1.3 mL) at 0 °C was added (R)-(+)-propylene oxide (0.19 g, 3.3 mmol). The mixture was allowed to reach ambient temperature with stirring in a sealed tube for 72 hours. Water (10 mL) was added and the mixture extracted with ethyl acetate (2x 25 ml). The combined organics were washed with brine (10 mL), dried over magnesium sulfate and concentrated. The residue was purified by reverse phase chromatography eluting with acetonitrile in water to give the title compound Hl (17 mg, yield 13%). See Table 1 for NMR data.

Method I Example 11 4'-({(3R)-3-[isopropyl(methyl)amino]pyrrolidin-1-yl}sulfonyl)biphenyl-4-carbonitrile

To a solution of HKi) (0.12 g, 0.34 mmol) in formic acid (3 ml_) was added acetaldehyde (1 mL). The reaction mixture was heated at 100 ⁰C for 18 hours. The cooled reaction mixture was quenched with a cold saturated aqueous NaHCO₃ and extracted with CH₂CI₂ (2 x 50 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by reverse phase chromatography eluting with acetonitrile in water to give the title compound (14 mg, yield 11 %). See Table 1 for NMR data.

Method J

Example J1 : (3R)-1-[(5-chloro-1W-indol-2-yl)sulfonyl]-N,N-dimethylpyrrolidin-3-amine

J 1(i)

Intermediate J1(i): tert-butyl 5-chioro-2-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]sulfonyl}-1H-indole-1- carhoxylate

Intermediate J1 (i) (449 mg, 1.05 mmol, 36% yield) was prepared according to the methods described in methods B1 through B4 above, using tert-butyl 5-chloro-2-(chlorosulfonyl)-1H-indoie-1-carboxylate (prepared as described in WO 2001007436) and (3R)-N,N-dimethylpyrrolidin-3-amine. Example J1: (3R)-1-[(5-chloro-1H-indol-2-yl)sulfonyl]-N,N-dimethylpyrrolidin-3-amine lntermediate JKi) (449mg, 1.04 mmol) was taken up in dichloromethane (4 mL) to which trifluoroacetic acid (2 mL) was added. The mixture was stirred at ambient temperature for 18 hours. After such time the mixture was concentrated in vacuo, the residue taken up in water (20 mL) and washed with diethyl ether (20 mL), neutralized via addition of sodium hydrogen carbonate and extracted with dichloromethane (3 x 20 mL). Combined organic extracts were dried over magnesium sulfate, concentrated in vacuo and the residue purified via flash column chromatography (SiC>2, dichloromethane/methanol 10%) to return named compound as a light red solid Jl (291 mg, 0.90 mmol, 90% yield). See Table 1 for NMR data.

Method K

Example K1 4'-{[(3R)-3-(dimethylamino)pyrrolidin-1-vl]sulfonyl)-3'-hydroxybiphenyl-4-carbonitrile

Intermediate K1(i): (3R)-1-[(4-bromo-2-methoxyphenyl)sulfonyl]-N,N-dimethylpyrrolidin-3-amine Intermediate KKi) was prepared according to the procedure described in method B above, using (3R)- N,N-dimethylpyrrolidin-3-amine and 4-bromo-2-methoxybenzenesulfonyl chloride (prepared as in DE 4117512 A1) ¹H NMR (400 MHz, CHLOROFORM-αQ δ ppm 1.76 - 1.85 (m, J=12.00, 9.22 Hz₁ 1 H) 2.06 - 2.14 (m, J=2.02 Hz, 1 H) 2.22 (s, 6 H) 2.72 - 2.82 (m, 1 H) 3.07 (t, J=8.97 Hz, 1 H) 3.33 - 3.42 (m, 1 H) 3.52 - 3.60 (m, 1 H) 3.64 - 3.72 (m, J=9.09, 7.33 Hz, 1 H) 3.84 - 3.88 (m, 3 H) 6.90 (dd, J=8.84, 2.53 Hz, 1 H) 7.25 (d, J=2.53 Hz, 1 H) 8.03 (d, J=9.09 Hz, 1 H).

Intermediate KI(H): 4'-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]sulfonyl}-3'-methoxybiphenyl-4-carbonitrile Intermediate KKiQ was prepared according to procedure described in method A above using 4-cyano phenyl boronic acid and KKJl. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.68 - 1.82 (m, 1 H) 2.04 - 2.14 (m, 1 H) 2.19 - 2.27 (m, 6 H) 2.63 - 2.78 (m, 1 H) 3.05 (t, J=9.09 Hz, 1 H) 3.35 - 3.45 (m, 1 H) 3.62 - 3.71 (m, 1 H) 3.76 (dd, J=9.35, 7.07 Hz, 1 H) 4.00 - 4.05 (m, 3 H) 7.15 (d, J=1.52 Hz, 1 H) 7.23 (dd, J=8.08, 1.52 Hz, 1 H) 7.64 - 7.82 (m, 4 H) 8.03 (d, J=8.34 Hz, 1 H).

Example K1: 4'-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]sulfonyl}-3'-hydroxybiphenyl-4-carbonitrile To a mixture of sodium hydride (60% suspension in oil, 37 mg, 1.55mmol) and 2-mercaptoethanol (0.052 mL, 0.778 mmol) in dimethylformamide (0.8 mL) was added a solution of KKii) (150 mg, 0.39 mmol) in dimethylformamide (0.2 mL). The mixture was heated to 135°C for 18 hours. After such time the mixture was taken up in water (20 mL) and extracted with ethyl acetate (2 x 20 mL). Combined organic extracts were dried over magnesium sulfate, concentrated in vacuo and the residue purified via preparative thin layer chromatography (SiO₂, dichloromethane/methanol 10%) to return named compound as an oil (15 mg, quantitative yield). See Table 1 for NMR data.

Method L

Examples L1 and L2: 4'-{K3f?)-3-(4-fluoropiperidin-1-vl)pyrrolidin-1-yi1sulfonvl}biphenvl-4-carbonitrile and 4'-{[(3S)-3-(4-fluoropiperidin-1-yl)pyrrolidin-1-yl]sulfonyl}biphenyl-4-carbonitrile

To a solution of DKiiQ (prepared as described in Example D1 above) (0.98 g, 3.0 mmol, 1.0 eq) in anhydrous dimethyl sulfoxide/tetrahydrofuran(1 :1 v/v, 20 mL) was added a solution of 4-fluoropiperidine hydrochloride in 20 mL anhydrous dimethyl sulfoxide/tetrahydrofuran (0.42 g, 3.0 mmol, 1.0 eq, neutralized by 3.0 mmol K₂CO₃), sodium triacetoxyborohydride (1.60 g, 7.5 mmol, 2.5 eq), acetic acid (0.35 mL, 6 mmol, 2.0 eq). The resulting reaction mixture was stirred at room temperature for 16 h, and then quenched with 1.0 M aqueous K₂CO₃ (20 mL) diluted with additional 200 mL water. The aqueous solution was extracted with ethyl acetate (2 x 30OmL). The combined organic phases were dried over sodium sulfate, concentrated to dryness, and purified by silica gel column chromatography eluting with 40% ethyl acetate in petroleum ether -> 80% ethyl acetate in petroleum ether to afford a racemic mixture. The racemates were resolved by super critical fluid chromatography (Chiralpak IA, 20% 1 :1 methanol:acetonitrile @ 140 bar, 2.5 mL/min. prep: 20% methanokacetonitrile @ 140 bar, 55 mL/min) to afford first peak at 2.981 min. designated as S enantiomer, example L1 (209 mg, 100%EE, 51% yield); ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm: 7.94 (d, J=8.06 Hz, 2 H), 7.77 - 7.83 (m, 2 H), 7.68 - 7.78 (m, 4 H), 4.56 - 4.77 (m, 1 H), 3.62 (dd, J=8.94, 7.18 Hz, 1 H), 3.38 - 3.46 (m, 1 H), 3.28 - 3.37 (m, 1 H), 2.99 (t, J=8.81 Hz, 1 H), 2.77 - 2.88 (m, 1 H), 2.27 - 2.62 (m, 4 H), 2.05 - 2.16 (m, 1 H), 1.77 - 1.93 (m, 4 H), 1.64 - 1.77 (m, 1 H) and second peak at 4.816 min. designated as R enantiomer, example L2 (209 mg, 100%EE, 51 % yield).¹H NMR (400 MHz, CHLOROFORM-d) δ ppm: 7.94 (d, J=8.31 Hz, 2 H)₁ 7.77 - 7.83 (m, 2 H), 7.69 - 7.77 (m, 4 H), 4.56 - 4.77 (m, 1 H), 3.62 (dd, J=9.06, 7.05 Hz, 1 H), 3.37 - 3.46 (m, 1 H), 3.28 - 3.37 (m, 1 H), 2.98 (t, J=8.94 Hz, 1 H), 2.77 - 2.88 (m, 1 H), 2.26 - 2.62 (m, 4 H), 2.05 - 2.16 (m, 1 H), 1.77 - 1.94 (m, 4 H), 1.65 - 1.77 (m, 1 H).

Examples L3 and L4: 4'-{[(3/^:?)-3-(4,4-difluoropiperidin-1-yl)pyrrolidin-1-yl]sulfonyl}biphenyl-4-carbonitrile and 4'-{[(3S)-3-(4,4-difluoropiperidin-1-yl)pyrrolidin-1-yl]suifonyl}biphenyl-4-carbonitrile

Example L3 Example L4

Examples L3 and L4 were prepared according to method L substituting 4-fiuoropiperidine for 4,4'- difluoropiperidine. The racemates were resolved by supercritical_, fluid chromatography to afford first peak at 2.981 min. designated as S enantiomer, example L4 (209 mg, 100%EE, 51% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm: 7.94 (d, J=8.06 Hz, 2 H), 7.77 - 7.83 (m, 2 H), 7.68 - 7.78 (m, 4 H), 4.56 - 4.77 (m, 1 H), 3.62 (dd, J=8.94, 7.18 Hz, 1 H), 3.38 - 3.46 (m, 1 H), 3.28 - 3.37 (m, 1 H), 2.99 (t, J=8,81 Hz, 1 H), 2.77 - 2.88 (m, 1 H), 2.27 - 2.62 (m, 4 H), 2.05 - 2.16 (m, 1 H), 1.77 - 1.93 (m, 4 H), 1.64 - 1.77 (m, 1 H) and second peak at 7.859 min. designated as R enantiomer, example L3 (119 mg, 100%EE, 28% yield). ¹H NMR (400 MHz, CHLOROFORM-D) δ ppm: 7.92 (d, J=6.55 Hz, 2 H), 7.75 - 7.83 (m, 2 H), 7.66 - 7.75 (m, 4 H), 3.56 (t, .7=8.18 Hz, 1 H), 3.42 (t, J=9.32 Hz, 1 H), 3.23 - 3.34 (m, 1 H), 3.00 (t, .7=8.31 Hz, 1 H), 2.81 - 2.93 (m, 1 H), 2.39 - 2.60 (m, 4 H), 2.02 - 2.12 (m, 1 H), 1.85 - 2.01 (m, 4 H), 1.64 - 1.79 (m, 1 H).

Method M

Example M2: 4'-{[3-(4,4-difluoropiperidin-1-yl)pyrrolidin-1-yl]sulfonyl}biphenyl-4-carboxamide

To a solution of trifluoroacetic acid : concentrated sulfuric acid (4:1 v/v, 2.0 rtiL) was added 4'-{[3-(4,4- difluoropiperidin-1-yl)pyrrolidin-1-yl]sulfonyl}biphenyl-4-carbonitrile (racemic mixture of examples L3 and L4) (50 mg, 0.12 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 16 h and then heated at 60^cC for additional 4 h. After cooling to room temperature, ice water (4.0 mL ) was added and a suspension with precipitates was formed. The suspension was diluted with additional water (30 mL) and extracted with ethyl acetate (2 x 3OmL). The combined organic phases were dried over sodium sulfate and concentrated to dryness. The resulting residue was purified via silica gel column chromatography eluting with ethyl acetate to afford the title compound Ml (10 mg, 19% yield). ¹H NMR (400 MHz, DMSO- Gf₆) δ ppm: 8.01 (br. s., 1 H), 7.90 - 7.97 (m, 4 H), 7.84 (d, J=8.31 Hz, 2 H), 7.78 (d, J=8.06 Hz, 2 H), 7.39 (br. s., 1 H), 3.34 - 3.44 (m, 1 H), 3.09 (q, J=8.73 Hz, 1 H), 2.82 - 2.92 (m, 1 H), 2.68 - 2.79 (m, 1 H), 2.24 - 2.41 (m, 5 H), 1.85 - 1.98 (m, 1 H), 1.69 - 1.83 (m, 4 H), 1.47 - 1.61 (m, 1 H). Method N Example N1: 4'-{t(3R)-3-(4-fluoropiperidin-1-yl)pyrrolidin-1-yl]sulfonyl}biphenyI-4-carboxylic acid

To a mixture of 2.0 M aqueous sodium hydroxide (1 ml.) and methanol (2 mL) was added Ll (10 mg, 0.024 mmol, 1.0 eq). The reaction mixture was refluxed for 3 h. After removing the solvents in vacuo, the resulting residue was acidified with 1.0 M aqueous hydrochloric acid to pH=1 , and precipitates were formed filtered and washed with water to remove sodium chloride, and dried in vaco at 6O⁰C overnight to afford the title compound Nl ( 8.0 mg, 80% yield). ¹H NMR (400 MHz, MeOD) δ ppm: 8.05 (d, J=8.31 Hz, 2 H), 7.84 - 7.92 (m, 4 H), 7.72 (d, J=8.31 Hz, 2 H), 4.87 (s, 2 H), 3.71 - 3.81 (m, 1 H), 3.59 (dd, J=10.70, 7.68 Hz, 1 H), 3.39 - 3.53 (m, 2 H), 3.25 (s, 4 H), 3.07 .- 3.17 (m, 1 H), 2.25 - 2.37 (m, 1 H), 2.04 (dd, J=12.84, 8.56 Hz, 5 H).

Compounds in Table 1 below which were not specifically described in the preceding examples were prepared using one of methods A through N above, but with routine modification apparent to one skilled in the art. All starting reagents were commercially available or were made by known methods.

Table 1

1.86 (m, J=12.25, 2.27 (s, 6 H) 2.79 - 1 H) 3.35 - 3.41 (rn, (m, 1 H) 3.63 - 3.72 (s, 3 H) 6.95 (d, 2 H) 7.90 - 7.99 (m, 1 H) 8.53 (d, J=2.78

2.28 (m, J=13.26, 2.93 (s, 6 H) 3.36 - 6.06 Hz, 1 H) (m, J=6.82 Hz, 1 H) - 7.66 (m, 2 H) 8.03 (t,

- 1.89 (m, 1 H) 2.10 - - 2.97 (m, 1 H) 3.15 1 H) 3.53 - 3.72 (m, J=7.33, 5.05 (dd, J=7.33, 2.02 8.22 (dd, J=5.Q5,

- 1.78 (m, J=12.51 , 2.24 (s, 6 H) 2.72 - 8.08 Hz, 1 H) 3.20 - 3.55 (dd, J=9.85, (dd, J=7.45, 4.93 Hz, 7.95 (m, 2 H) 8.15 -

1.76 (m, J=12.38, 2.22 (s, 6 H) 2.69 - 8.08 Hz, 1 H) (m, 2 H) 3.96 (s, 3 H) (m, 4 H) 8.16 (d,

2.20 (m, J=13.64, 2.92 (s, 6 H) 3.16 - 3.68 (m, 2 H) 7.47 - 7.82 - 7.89 (m, 1 H) 4 H) 8.11 - 8.17 (m,

1.72 (m, J=12.51, H) 2.23 (s, 6 H) 2.69 - 8.08 Hz, 1 H) (m, 2 H) 4.08 (s, 3 H) Hz, 1 H) 8.46 (d,

1.78 (m, ./=12.38, Hz, 1 H) 2.26 (s, Hz, 1 H) 3.20 - 3.30 7.84 - 7.99

J=7.07 Hz, 3 H) 1 H) 2.04 - 2.17 (m, 1 H) 2.98 - 3.10 (m, (m, 1 H) 3.44 - 3.61 7.08 (dd, J=7.33, 1.89 Hz, 1 H) 7.81 - 1.89 Hz, 1 H)

J=7.07 Hz, 3 H) 1 H) 2.04 - 2.15 (m, 2.85 (m, 1 H) 2.98 - - 3.30 (m, (m, 2 H) 4.41 (q, Hz, 1 H) 7.83 - 7.97 Hz, 1 H) 8.48 (d, H)

1.77 (m, J=12.38, H) 2.26 (s, 6 H) 2.73 - 8.08 Hz, 1 H) 3.17 - H) 3.99 (d, J=4.55 Hz, - 7.92 (m, 5 H)

2.20 (m, J=13.52, H) 2.92 (s, 6 H) 3.13 - 3.83 - 3.92 (m, 1 J=8.59 Hz₁ 2 H) 7.87

ppm 1.74- 1.89 (m, 2.27 (m, 6 H) 2.31 (s, J=8.97 Hz, 1 H) (m, 1 H) 3.72 (dd, (m, 2 H) 7.31 (d, 2 H) 7.93 - 8.01 (m, 1

ppm 1.68 - 1.83 (m, (m, 1 H) 2.23 (s, 6 1 H) 2.99 - 3.09 (m, 1 J=9.09, 7.33 Hz, 1 (d, J=8.34 Hz, 2 H) Hz, 2 H)

2.31 (m, J=13.39, H) 2.95 (s, 6 H) 3.35 - 3.76 (m, 2 H) 3.78 - H) 7.35 - 7.46 (m, 3 (t, J=7.45 Hz, 1 H) J=7.45 Hz, 1 H)

2.27 (m, J=13.39, H) 2.93 (s, 6 H) 3.34 - 6.32 Hz, 1 H) 3.65 - H) 3.90 - 4.00 (m, 1 (m, 4 H) 7.96 (t,

2.28 (m, 1 H) 2.39 - 6 H) 3.35 - 3.42 (m, 6.44 Hz, 1 H) 1 H) 3.76 - 3.84 (m, 7.53 (m, 2 H) 7.60 - 1 H) 7.96 (t, J=7.58

231 (m, J=13 14, 2 94 (s, 6 H) 3 35 - 12, 6 32 Hz, 1 H) 1 H) 3 93 - 404 - 761 (m, 1 H)

222 (m, 1 H) 231 - (m, 1 H) 292 (s, J=10 86, 6 32 Hz, 82 (m, 1 H) 3 88 - 84, 884 Hz, 1 H) (m, 1 H) 7 56 - H)

1 H) 293 (s, 1 H)

335 - 1 H) 202 Hz, 1 H) H) 760 -

J=I 58 Hz 3 H) 1 H) 2 38 - 2 49 (m, 2 H) 292 (s, 6 (m, 2 H) 378 (dd, 01 (m, 1 H) 7 34 {d, 4 H) 7 87 - 7 95 (m, 1

1 H) 232 H) 286 - 297 12, 632 1 H)

J=I 58 Hz, 3 H) 1 H) 241 - 2 54 (m, 58 Hz, 2 H) 295 1 H) 3 59 - 374 - 4 06 (m, 1 H) (m, 1 H) 731 -

2 H) 2.19 - 2.29 (m, 1 H) 2.94 (s, 6 {m, 2 H) 3.76 - 7.05 (d, J=7.33 Hz, -7.26 (m, 1 H) (m, 1 H)

2.23 (m, J=13.26, 2.94 (s, 6 H) 3.37 - J=11.12, 6.32 Hz, 3.87 (m, 1 H) 3.92 - 7.79 - 7.87 (m, 1 (t, J=7.83 Hz, 1 H)

2.29 (m, J=13.26, Hz, 1 H)2.93 (s, J=11.12, 6.32 Hz, Hz, 1 H) 3.78 (dd, (m, 1 H) 7.21 - H) 7.71 - 7.80 (m, 2

2.28 (m, 1 H) 2.40 - - 3.42 (m, 1 H) 3.61 - 3.74 (m, 1 H) 3.75 6.32 Hz, 1 H) (m, 3 H) 7.67 - 7.77

2.29 (m, J=13.39, - 2.51 (m, 1 H) 2.93 Hz, 1 H) 3.60 (dd, (m, 1 H) 3.74 - H) 7.29 (d, J=7.58 Hz, - 7.55 (m, 2 H) (m, 1 H)

J=7.33 Hz, 3 H) (m, 1 H) 2.87 - 2.98 7.45 Hz, 2 H) 3.32 - 6.32 Hz, 1 H) 3.64- 7.33 Hz, 1 H) 3.88 - 7.93 - 8.11 (m, 5

2.30 (m, J=13.26, 2.94 (s, 6 H) 3.35 - (dd, J=11.12, 6.32 - 3.83 (m, 1 H) Hz, 2 H) 7.66 - H) 7.98 (I, J=7.96 Hz,

1 H) 241 - 1 H) 367- 1 H) 776 - 2

228 (m, J=1326, 2 94 (s, 6 H) 3 35 - J=10 99, 644 - 385 (m, J=11 12, H) 770- 776 (m, 2 (m, 2 H) 8 00 (t,

228 (m, J=B 08 Hz, H) 291 (s, 6 H) 2 H) 373 - 382 08 (s, 1 H) 726 (s, 2 (m, 1 H)

229 (m, J=13 39, H) 2 93 (s, 6 H) 3 60 - 3 76 - 386 (m, 1 (m, 4 H) 7 84 -

1 H) 236 - 3 34- 342 (m, 1 H) 3 65 - 374 (m, 1 (m, 1 H) 740 (t, H) 787 (dd, (m, 1 H)

229 (m, J=13 26, 2 93 (s, 6 H) 334 - 99, 6 19 Hz, 1 H) 1 H) 3 88 - 3 99 747 - 769 (m, 4 H)

6 H) 334 - 1 Hz, 2 H) 700 - 762 (m, 2

2.28 (m, 1 H) 2.40 - - 3.42 (m, 1 H) 3.61 - 3.73 (m, 1 H) 3.74 H) 7.01 - 7.14 (m, 1 Hz, 2 H) 7.63 - 7.77

2.29 (m, 1 H) 2.40 - - 3.45 (m, J=8.84 Hz, Hz, 1 H) 3.68 - 7.17 (t, J=8.21 Hz, J=8.08 Hz, 1 H)

2.30 (m, J=13.14, 2.94 (s, 6 H) 3.34 - ,/=10.99, 6.44 Hz, 3.86 (m, 1 H) 3.91 - 7.61 (d, J=10.11

2.28 (m, J=13.26, 3.41 Hz, 1 H) Hz, 1 H) 3.62 - 3.74 (m, 1 H) 3.75 1 H) 7.07 - 7.20 (m, 2 Hz, 1 H)

2.27 (m, J=13.39, 2.94 (s, 6 H) 3.35 - (dd, J=11.12, 6.32 - 3.84 (m, 1 H) (m, 3 H) 7.61 - 7.69

2.21 (m, J=13.52, 2.91 (s, 6 H) 3.16 - 3.81 - 3.94 (m, 1 (m, 4 H)

2.21 (m, J=13.52, 3.54 Hz, 1 H) 3.47 - 3.66 (m, 3 H) (m, 2 H) 7.66 - 7.76

1 74 (m, 1 H) 201 - 279 (m, 1 H) 297 - 19 - 3 29 (m, 1 H). J=973, 720 Hz, J=7 58 Hz, 1 H) 4 H)

1 74 (m, J=12 38, 2 19 (s, 6 H) 266 - Hz, 1 H) 3 22 - -758(m, 1 2 H)

1 75 (m, 1 H) 202 - - 241 (m, J=1 77 Hz, 1 H) 3 20 - 3 29 (m, 1 J=S 85, 7 33 Hz, 1 57 (m, 1 H) 7 60 (dd, (m, 4 H)

1 75 (m, 1 H) 201 - 279 (m, 1 H) 3 01 329 (m, 1 H) 340 - Hz, 1 H) 3 86 (ε, 771 (m, 2 H) 777 -

1 75 (m, 1 H) 201 - 281 (m, 1 H) 303 3 28 (m, 1 H) 341 - 733 Hz, 1 H) 3 88 (s, Hz, 1 H) 7 18 - 731 781 - 7 96 (m, 4 H)

J=758 Hz, 3 H) 1 H) 2 30 - 242 (m, 58 Hz, 2 H) 289 - 3 64 (m, 3 H) 378 Hz, 2 H) 7 62 (d, 4 H)

2 18 (m, 1 H) 226 (m, 1 H) 2 89 (S, 6 (m, 3 H) 376 - 1 H) 7 36 - 7 51 (m,

J=7.33 Hz, 3 H) 1 H) 2.12 - 2.23 (m, J=7.58 Hz, 1 H) (m, 2 H) 7.82 - 8.10

(m, 1 H) 2.32 - - 3.25 (m, 1 H) 3.48 - 7.43 (d, J=8.34 Hz, 8.01 (m, 4 H)

1.77 (m, J=12.51, H) 2.26 (s, 6 H) 2.74 - H) 3.20 (s, 3 H) 3.24 - - 3.61 (m, 2 H) Hz, 2 H)

2.21 (m, 1 H) 2.33 - H) 3.18 - 3.27 (m, 1 (m, 1 H) 7.68 -

2.19 (m, J=13.39, H) 2.39 (s, 6 H) 2.89 - 3.64 (m, 3 H) 3.85 (s, 1 H) 7.30 (s, 2 H)

- 1.76 (m, 1 H) 2.03 - - 2.76 (m, 1 H) 3.04 - 3.31 (m, 1 H) 3.43 - 7.20 Hz₁ 1 H) 7.43 (d, Hz, 2 H) 7.64 (t, Hz, 1 H) 7.85 (d, Hz, 2 H)

ppm 1.72 - 1.87 (m, 3 H) 2.41 - 2.60 (m, 2 H) 3.27 - 3.41 (m, 7.77 (m, 2 H) 7.97 (s,

ppm 1.67 - 1.80 (m, (m, 1 H) 2.19 (s, 6 1 H) 3.06 - 3.15 (m, 1 (m, 1 H) 3.67 (dd, J=8.59, 1.77 Hz, 1 H) .7=2.02 Hz, 1 H)

ppm 1.69 - 1.84 (m, 2.51 (m, 4 H) 2.76- 1 H) 3.31 - 3.42 (m, 3.68 (m, 3 H) 7.27 - 1 H) 7.62 - 7.76 (m, - 8.65 (m, 2 H)

ppm 1.71 - 1.86 (m, 2.23 (m, J=5.05 Hz, 3 (m, 2 H) 3.26 - H) 7.50 - 7.62 (m, 1 (m, 1 H) 8.54 - 1 H)

ppm 1.61 - 1.75 (m, 1 H) 2.28 - 2.48 (m, 3 Hz, 1 H) 3.27 - 3.16 Hz, 1 H) Hz, 4 H) 7.55 (t, Hz, 1 H) 7.87 - 7.96

ppm 1.73 - 1.87 (m, (m, 1 H) 2.22 (s, 3 3 H) 3.04 - 3.23 (m, 2 (m, 4 H) 7.22 - 2.53 Hz, 1 H) 7.79

ppm 1.63 - 1.77 (m, (m, 1 H) 2.16 (S₁ 3 (m, 2 H) 3.19 - H) 7.58 - 7.72 (m, 2 H) 7.89 - 8.05 (m, 3

ppm 7.78 (dd, J=8.8, Hz, 1 H) 7.24 - 7.35 2 H) 3.52 - 3.65 (m, 3.09 - 3.22 (m, 1 H) (m, 5 H) 2.07 - 2.26 - 1.62 (m, 2 H)

ppm 8.43 (d, J=8.8 7.75 (d, J=7.3 Hz, 1 1 H) 3.62 (dd, J=9.3, 3.27 - 3.37 (m, 1 H) (m, 1 H) 2.63 - 2.78 - 2.11 (m, 1 H) H) 1.83 - 1.93 (m, 2 H) 1.68 - 1.82 (m, 1 H)

ppm 7.93 (d, J=8.3 - 4.39 (m, 1 H) - 3.44 (m, 2 H) (m, 2 H) 2.79 (d, 1 H) 2.36 - 2.45 (m, 1.92 (m, 2 H) 1.73 - H)

J=9.06, 4.78 Hz, 1 H), 7.30 - 7.38 (m, 1 H), 3.52- 3.60 (m, - 3.14 (m, 1 H), 2.71 - (s, 6 H), 2.05 - 2.14

ppm 1.74 - 1.89 (m, 2.29 (m, 6 H) 2.71 (S₁ J=8.84 Hz₁ 1 H) 3.43 - 3.52 (m, J=9.09, 7.33 Hz, 1 H) (m, 4 H) 8.01 (d,

ppm 7.98 (d, J=2.0 7.59 - 7.67 (m, 1 H) Hz, 1 H) 3.35 - H) 2.69 - 2.85 (m, 25 (m, 3 H) 1.34 (s, 1

1 H), 8.45 (d, Hz, 1 H), 7.99 (dd, Hz, 1 H), 7.61 7.18 Hz, 1 H), (m, 1 H), 2.99 - 3.06 (s, 6 H), 1.97 - - 1.68 (m, 1 H)

ppm 7.8 (d, J=8.3 - 3.66 (m, 1 H), 3.33 1 H), 2.68 - 2.82 (m, 1 H) 1.65 - 1.80 (m,

ppm 1 49 - 1 68 (m, 1 H) 266 - 282 (m, (s, 2 H) 588 (s, 1

ppm 9 12 (d, J=2 27 (d, J=8 34 Hz, 1 H) J=935, 6 82 Hz, 1 (m, 1 H) 305 (t, H) 263 (d, J=10 11 2 02 - 2 14 (m, 1 H) 1 69 - 1 94

δ ppm 1 77 (bs, 5 H) 251 (bs, 4 H) 279 343 (m, 2 H) 772 (t, J=796 Hz, 4 94 (d, J=B 34 Hz, 2

ppm 9 12 (d, J=1 7 (d, J=83 Hz, 1 H) 70 Hz, 1 H) Hz, 1 H) 223 - H) 1 35 - 1 61 (m,

ppm 9 12 (d, J=Z 1 (d, J=8 3 Hz, 1 H) 5 H) 328 - 3 51 - 289 (m, 1 H) 1 H) 1 67 - 1 85

ppm 1 69 - 1 86 (m, (m, J=3 03 Hz, 3 (m, J=Z 78 Hz, 2 342- 3 62 (m, 3 Hz, 1 H) 749 - 760 (m, 2 H) 7 89- 12 - 829 (m, 2 H)

ppm 1 65-1 72 (m, 1 3 H) 234-245 (m, 2 H) 3 28 (td, 278 Hz, 1 H) 748 (dd, J=I 96, -773 (m, 3 H) 7 87

Additional compounds of the present invention were prepared as described in Methods AA through CC below, with corresponding data as shown in Table 2 below.

Method AA

A sulfonyl chloride reagent (200 uL, 0.08 mmol, 0.4 M solution in anhydrous 1 ,2-dιchloroethane), an amine reagent (400 uL, 0.08 mmol, 0.2 M solution in anhydrous dimethoxy ethane), tπethylamine (80 uL, 0.08 mmol, 1.0 M in anhydrous dimethoxy ethane) were placed into a well of a 2 mL deepwell plate. The plate was sealed with an Teflon-lined aluminum plate vice and agitated for 20 sec on a vortexer. The plate was left for 18 h at room temperature. The solvent was evaporated and the residue dissolved in DMSO (containing 0.01 % BHT) to give 0.05 M solution. The solution was injected into an automated HPLC system and the product containing fraction was collected. The solvent was evaporated and the residue dissolved in the appropriate volume of DMSO to give an either 30 mM or 10 mM solution. The product containing solutions were analyzed by LCMS and submitted for screening.

Method BB

A ketone reagent (200 uL, 0.08 mmol, 0.4 M in a mixture of anhydrous THF and anhydrous DMSO (1 :1 ' v:v)), an amine reagent (200 uL, 0.08 mmol, 0.4 M in a mixture of anhydrous THF and anhydrous DMSO (1 :1 v:v)), sodium triacetoxyborohydride (330 uL, 0.20 mmol, 0.6 M dispersion in a mixture of anhydrous THF and anhydrous DMSO (1 :1 v:v)), glacial (pure) acetic acid (10 uL) were placed into the wells of a 2 mL deepwell plate. The plate was sealed with a Teflon-lined aluminum plate vice and agitated on a vortexer for 16-24 h at ambient temperature. K2CO3 (200 uL. 3 M solution in water) and ethanol (550 uL) were added to each well. The plate was sealed.vortexted for 30 min, and then centrifuged for phase separation. The liquid phase was transferred into a test tube and the solvent was evaporated. The solvent was evaporated and the residue dissolved in DMSO (containing 0.01% BHT) to give 0.0572 M solution. The solution was injected into an automated HPLC system and the product containing fraction was collected. The solvent was evaporated and the residue dissolved in the appropriate volume of DMSO to give an either 30 mM or 10 mM solution. The product containing solutions were analyzed by LCMS and submitted for screening.

Method CC

A sulfonyl chloride reagent (104 μmol, 1.3 eq, 400 uL of a 0.26 M solution in anhydrous pyridine) and an amine reagent (80 μmol, 1.0 eq, 400 uL of a 0.2 M solution in anhydrous pyridine) were placed into a test tube (75x10 mm, dried by heating at 110 ⁰C for 16 h) equipped with a stir bar. The test tube was covered with Parafilm and the reaction was stirred for 24 h at ambient temperature. The solvent was evaporated and the residue was dissolved in EtOAc (1 mL). After dissolution was completed or a fine suspension had formed, NaHCO₃ (0.5 mL of a sat. aq. solution) was added. The reaction mixture was vortexed and the phases were separated by centrifugation. The organic layer was transferred into a new test tube (95x10 mm) and the aq. phase was extracted with EtOAc (2x 0.8 mL). The solvent was evaporated and the residue dissolved in DMSO (containing 0.01% BHT) to give 0.0572 M solution. The solution was injected into an automated HPLC system and the product containing fraction was collected. The solvent was evaporated and the residue dissolved in the appropriate volume of DMSO to give an either 30 mM or 10 mM solution. The product containing solutions were analyzed by LCMS and submitted for screening. Table 2

443.0 AA

AA

BB

444.1 BB

BB

BB

BB

414.1 BB

BB

BB

BB

BB

BB

BB

BB

BB

BB

BB

In the experimentals described above, the term "min" refers to minutes; the term "MS" refers to mass spectroscopy; the term m/z refers the mass/charge ratio; the term "HPLC" refers to high performance liquid chromatography; the term "Ki" refers to activity against 11βHSD1 as measured by the assay as described above; and N/A refers to not tested.

Various embodiments of the present invention have been described above but a person skilled in the art realizes further minor alterations that would fall into the scope of the present invention. The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

Claims

We Claim:

1. A compound of formula (I):

I or a pharmaceutically acceptable salt or solvate thereof, wherein; R¹ is pyridine substituted with 1 to 3 R⁷ groups; or R¹ is

wherein W is C or N, and R¹ is substituted with 0 to 3 R⁷ groups;

R² and R³ are optionally each independently selected from hydrogen, hydroxyl, (C₁-C₆)BIkOXyI, (Ci-C_fOalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (CR⁵R⁶)_n(C₃-C₁₀)cycloalkyl, (C=O)O(C₁-C₆)alkyl and SO₂(Ci-C₆)aikyl, and R² and R³ are each independently substituted with 0 to 4 R⁷ groups; or

R² and R³ form a 5, 6 or 7-membered saturated ring containing 1 or 2 heteroatoms each independently selected from N, O or S, and the 5, 6 or 7 membered saturated ring is substituted with 0 to 4 R⁷ groups; R⁴ is selected from hydrogen, hydroxyl, halogen, (Ci-Cβ)alkoxy and (Ci-C₆)alkyl, and R⁴ is optionally substituted with 0 to 4 R⁷ groups;

R⁵ and R⁶ are each independently selected from hydrogen and (Ci-CβJalkyI; each R⁷ is independently selected from hydroxyl, halogen, cyano, amino, azido, nitro, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, (CrC₆)alkoxy, (C^C^alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C=O)R⁸, (C=O)OR⁸, 0(C=O)R⁸, NR⁸(C=O)R⁹, (C=O)NR⁸R⁹, NR⁸R⁹, NR⁸OR⁹,

S(O)_jNR⁸R⁹, S(O)_i(C₁-C₆)alkyl, OSO₂R⁸, NR⁸S(O)_jR⁹, (CR⁸R⁹)_k(C₆-C₁₀aryl), (CR⁸R⁹)_k(5-10)-membered heterocyclyl, (CR⁸R⁹)_k(C=O)(CR⁸R⁹)_m(C₆-C_1Q)aryl, (CR⁸R⁹)_k(C=O)(CR⁸R⁹)_m(5-10)-membered heterocyclyl,

(CR⁸R⁹)_kO(CR⁸R⁹)_m(C₆-Cio)aryl, (CR⁸R⁹)_kO(CR⁸R⁹)_m(5-10)-membered heterocyclyl,

(CR⁸R⁹)_kS(O)_j(CR⁸R⁹)_m(C₆-C₁₀)aryl and (CR⁸R⁹)_kS(O)_j(CR⁸R⁹)_m(5-10)-membered heterocyclyl; and each R⁷ is substituted with O to 4 R¹⁰ groups; each j, k and m are independently O, 1 , 2 or 3; and each R⁸ and R⁹ are independently selected from hydrogen, (C_rC₆)alkyl, (CR⁵R^β)_p(C₆-C₁₀)aryl or (CR⁵R⁶)_P(5-10)-membered heterocyclyl; each R¹⁰ is independently selected from hydroxyl, halogen, cyano, amino, azido, nitro, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, (C₁-C₆)BIkOXy, (C₁-C₆)BlKyI, (C₂-C₆)alkenyl,

(C₂-C₆)alkynyl, (C=O)R⁸, (C=O)OR⁸, 0(C=O)R⁸, NR⁸(C=O)R⁸, (C=O)NR⁸R⁹, NR⁸R⁹, NR⁸OR⁹,

S(O)_jNR⁸R⁹, S(O)j(CrC₆)alkyl, OSO₂R⁸, NR⁸S(O)_jR⁹, (CR⁸R⁹)_k(C₆-C₁₀aryl), (CR⁸R⁹)_k(5-10)-membered heterocyclyl, (CR⁸R⁹)_k(C=O)(CR⁸R⁹)_m(C₆-C₁₀)aryl, (CR⁸R⁹)_k(C=O)(CR⁸R⁹)_m(5-10)-membered heterocyclyl, (CR⁸R⁹)_kO(CR⁸R⁹)_m(C₆-C₁₀)aryl, (CR⁸R⁹)_kO(CR⁸R⁹)_m(5-10)-membered heterocyclyl,

(CR⁸R⁹)_kS(O)_j(CR⁸R⁹)_m(C₆-C₁₀)aryl and (CR⁸R⁹)_kS(O)_j(CR⁸R⁹)_m(5-10)-membered heterocyclyl.

2. The compound of claim 1 , wherein R¹ is pyridine.

3. The compound of claim 1 , wherein R¹ is benzo[b]thiophene.

4. The compound of claim 1 , wherein R² and R³ are optionally each independently selected from hydrogen, (Ci-C₆)alkyl, (C=O)O(C₁-C₆)BlKyI and SO₂(Ci-C₆)alkyl; or

R² and R³ form a 5 or 6-membered saturated ring containing 1 or 2 heteroatoms each independently selected from N or O.

5. The compound of claim 1 , wherein R² and R³ form a pyrrolidine, piperidine or morpholine ring.

6. The compound of claim 1 , selected from the group comprising:

7. The compound of claim 1 , selected from the group comprising:

8. The compound of claim 1 , selected from the group comprising:

9. A compound of formula (II):

Il or a pharmaceutically acceptable salt or solvate thereof, wherein;

R¹ is naphthyl or is

^R? wherein Q and Z are each independently C or N, but are not both N, and wherein R¹ is substituted with O to 4 R¹⁰ groups; R² and R³ are optionally each independently selected from hydrogen, hydroxyl, (C₁-C₆)BIkOXyI,

(Ci-Cejalkyl, (C₂-C₆)alkenyi, (C₂-C₆)alkynyl, (CR⁵R⁶)_n(C₃-C₁₀)cycloalkyl, (C=O)O(C₁-C₆)alkyl and SO₂(C₁-C₆)SIkYl, and R² and R³ are each independently substituted with O to 4 R¹⁰ groups; or

R² and R³ form a 5, 6 or 7-membered saturated ring containing 1 or 2 heteroatoms each independently selected from N, O or S, and the 5, 6 or 7 membered saturated ring is substituted with O to 4 R¹⁰ groups;

R⁴ is selected from hydrogen, hydroxyl, halogen, (C₁-C^aIkOXy and (Ci-C₆)alkyl, and R⁴ is optionally substituted with O to 4 R¹⁰ groups;

R⁵ and R⁶ are each independently selected from hydrogen and (Ci-C₆)alkyl; R⁷ is selected from (C₆-C₁₀)aryl or (5-10)-membered heteroaryl, and is substituted with 1 to 4 R¹⁰ groups; each R⁸ and R⁹ are independently selected from hydrogen, (CrC₆)alkyl, (CR⁵R^e)_p(C₆-Cio)aryI or (CR⁵R⁶)p(5-10)-membered heterocyclyl; each R¹⁰ is independently selected from hydroxyl, halogen, cyano, amino, azido, nitro, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, (C₁-C₆JaIkOXy, (Ci-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C=O)R⁸, (C=O)OR⁸, 0(C=O)R⁸, NR⁸(C=O)R⁹, (C=O)NR⁸R⁹, NR⁸R⁹, NR⁸OR⁹, S(O)₁NR⁸R⁹, S(O)_|(C_rC_β)alkyl, OSO₂R⁸, NR⁸S(O)₁R⁹, (CR⁸R⁹)_k(C₆-C₁₀aryl), (CR⁸R⁹)_k(5-10)-membered heterocyclyl, (CR⁸R⁹)_k(C=O)(CR⁸R⁹)_m(C₆-C₁₀)aryl, (CR⁸R⁹)_k(C=O)(CR⁸R⁹)_m(5-10)-membered heterocyclyl, (CR⁸R⁹)_kO(CR⁸R⁹)_m(C₆-C₁₀)aryl, (CR⁸R⁹)_kO(CR⁸R⁹)_m(5-10)-membered heterocyclyl,

(CR⁸R⁹)_kS(O)_l(CR⁸R⁹)_m(C₆-C₁₀)aryl and (CR⁸R⁹)_kS(O)_j(CR⁸R⁹)_m(5-10)-membered heterocyclyl; and each j, k and m are independently 0, 1 , 2 or 3.

10. The compound according to claim 9, wherein R¹ is

^R?

11. The compound according to claim 10, wherein R⁷ is benzyl.

12. The compound according to claim 10, wherein R⁷ is pyridine.

13. The compound according to claim 10, wherein Q is C and Z is N.

14. The compound according to claim 10, wherein Q is N and Z is C.

15. The compound according to claim 9, wherein R¹ is naphthyl substituted with 1 to 4 R¹⁰ groups.

,

16. A pharmaceutical composition comprising an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

17. A method of treating a condition that is mediated by the modulation of 11 βHSD1 , the method comprising administering to a mammal an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

18. A method of treating diabetes, metabolic syndrome, insulin resistance syndrome, obesity, ophthalmic diseases, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, atherosclerosis, dementia, depression, virus diseases, inflammatory disorders, or diseases in which the liver is a target organ, the method comprising administering to a mammal an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

19. A method of treating glaucoma according to claim 11 , comprising administering to a mammal an effective amount of a compound of claim 1 or claim 2, in combination with a prostanoid receptor agonist, wherein said agonist is latanoprost.