GB2429975A - 1,5-substituted-1H-tetrazole 11beta-hydroxysteroid dehydrogenase type 1 inhibitors - Google Patents

Abstract

A 1,5-substituted-1H-tetrazole compound of formula: <EMI ID=1.1 HE=22 WI=24 LX=945 LY=627 TI=CF> <PC>wherein one of W<1> and W<5> is a group -J-L-Q; and the other is a group Z; wherein Z is hydrogen or R<Q>; J is S, S(O), S(O)2, O, NR<NJ> or CH2, with the proviso that if W<1> is -J-L-Q, then J is S, S(O)2, CH2 or additionally C(O); L is optionally substituted C1-6alkylene; Q is -C(O)R<A1>, C(O)OR<E1>, optionally substituted tetrahydropyran-2-yl, NR<N1>C(O)R<A2>, C(O)NR<N2>R<N3>, NR<N4>C(O) NR<N5>R<N6>, NR<N7>C(O)OR<E2>, a cyclic group or hydrogen; R<Q> is optionally substituted alkyl, alkenyl, alkynyl, cyclyl, R<N7> (hetero)arylalkyl or heterocyclylalkyl; R<NJ>, R<A1>, R<E1>, R<E2>, R<N1>, R<A2>, R<N2>, R<N3>, R<N4>, R<N5>, R<N6> are all substituents; pharmaceutically acceptable salts, solvates, amides, esters, ethers, N-oxides, chemically protected forms and prodrugs thereof may be useful as 11beta-hydroxysteroid dehydrogenase type-1 (11-beta-HSD1) inhibitors. These compounds may be useful for the treatment of the metabolic syndrome which induces conditions such as type 2 diabetes and obesity; as well as insulin dependence, hypertension, lipid disorders and cardiovascular disorders; and the treatment of CNS conditions including dementia and Alzheimer's Disease. Preferred compounds feature W<5> as -J-L-Q where J is S, S(O) or S(O)2.

Description

WJW/LP6326342

THERAPEUTIC COMPOUNDS

TECHNICAL FIELD

The present invention pertains generally to the field of therapeutic compounds.

More specifically the present invention pertains to certain 1,5substituted-i H-tetrazole compounds that, inter a/ia, inhibit ii 3hydroxysteroid dehydrogenase type 1 (Ii 13-HSD1).

The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit 11 3-hydroxysteroid dehydrogenase type 1; to treat conditions that are ameliorated by the inhibition of ii 13-hydroxysteroid dehydrogenase type 1; to treat the metabolic syndrome, which includes conditions such as type 2 diabetes and obesity, and associated disorders including insulin resistance, hypertension, lipid disorders and cardiovascular disorders such as ischaemic (coronary) heart disease; to treat CNS conditions such as mild cognitive impairment and early dementia, including Alzheimer's disease; etc.

BACKGROUND

A number of patents and publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

Throughout this specification, including the claims which follow, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and "comprising," will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.

WJW/LP6326342 Ranges are often expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent "about," it will be understood that the particular value forms another embodiment.

Glucocorticojds (cortisol in man, corticosterone in rodents) are hormones that regulate a range of pathways involved in stress and metabolic signalling. They are antagonists of insulin action and impair insulindependent glucose uptake, increase lipolysis, and enhance hepatic gluconeogenesis. These effects are evident in Gushing's syndrome, which is caused by elevated circulating levels of glucocorticoids. The features of Cushing's syndrome are diverse and reflect the tissue distribution of glucocorticoid receptors in the body. They include a cluster of metabolic (central/visceral obesity, insulin resistance, hyperglycaemia, dyslipidaemia) and cardiovascular (hypertension) abnormalities which, when observed in patients without Gushing's syndrome, constitute the metabolic syndrome. These abnormalities confer a substantial risk of cardiovascular disease. In addition, Cushing's syndrome is associated with neuropsychiatric manifestations including depression and cognitive impairment. The features of Gushing's syndrome are reversible upon removal of the cause of glucocorticoid excess.

It is recognised that glucocorticoid activity is controlled at the tissue level by the intracellular conversion of active cortisol and inactive cortisone by 11 3-hydroxysteroid dehydrogenases (see, e.g., Secki et al., 2001). These enzymes exist in two distinct isoforms. 11 3-HSD1, which catalyses the reaction that activates cortisone, is expressed in liver, adipose tissue, brain, skeletal muscle, vascular smooth muscle and other organs, while, 1113-HSD2, which inactivates cortisol, is predominantly expressed in the kidney.

Pharmacological inhibition of 11 -HSD1 in rat and man with carbenoxolone (see, e.g., Walker et al., 1995), and transgenic knockout in mice (see, e. g., Kotelevtsev et al., 1997), results in enhanced hepatic insulin sensitivity and reduced gluconeogenesis and glycogenolysis, suggesting that I I 13-HSDI inhibition will be a useful treatment in type 2 diabetes and other insulin resistance syndromes. Furthermore, mice lacking 11 13HSD1 possess low triglycerides, increased HDL cholesterol, and increased apo-lipoprotein Al levels (see, e.g., Morton et al., 2001), suggesting that inhibitors of 1113-HSDI may be of utility in the treatment of atherosclerosis.

WJW/LP6326342 The link between 11 3-HSD1 and the metabolic syndrome has been strengthened by studies in transgenic mice and man. 11 3-HSD1 knockout mice on two different genetic backgrounds are protected from dietary obesity (see, e.g., Morton et al., 2004), while administration of carbenoxolone to patients with type 2 diabetes enhances insulin sensitivity (see, e.g., Andrews et al., 2003). However, it has become apparent that the key tissue in which 11 13-HSDI exerts the greatest influence upon metabolic disease is the adipose tissue rather than the liver. Mice with transgenic overexpression of 11 -HSD1 in adipose tissue (see, e.g. Masuzaki et aL, 2001) have a more profound metabolic syndrome and obesity than mice with overexpression in liver (see, e.g., Paterson et al., 2004). In obese humans, 1113-HSD1 activity is increased in adipose tissue, but enzyme activity is decreased in the liver (see, e.g., Rask et al., 2001).

In the CNS, 11 13-HSD1 is highly expressed in regions important for cognition such as hippocampus, frontal cortex, and cerebellum (see, e.g., Moison et al., 1990). Elevated cortisol is associated with cognitive dysfunction, and glucocorticoids have a range of neurotoxic effects. I 13HSD1 knockout mice are protected against age-related cognitive dysfunction (see, e.g., Yau et al., 2001), while administration of the 1113-HSD inhibitor carbenoxolone has been shown to enhance cognitive function in elderly men and type 2 diabetics who have a selective impairment in verbal memory (see, e.g., Sandeep et al., 2004). Thus, 11 13-HSD1 inhibitors are of potential therapeutic utility in the treatment of diseases such as Alzheimer's Disease, which are characterised by cognitive impairment.

The isozymes of 113-HSD are also expressed in the blood vessel wall (see, e.g., Walker et al., 1991; Christy et al., 2003). 1113-HSDI is expressed in vascular smooth muscle, while I 113-HSD2 is expressed in endothelial cells where it modulates endothelial- dependent vasodilation (see, e.g., Hadoke et al., 2001). 113-HSD1 knockout mice have normal vascular function, but they exhibit enhanced angiogenesis in response to inflammation or ischaemia (see, e.g., Small et al., 2005). This offers therapeutic potential in the treatment of myocardial infarction, since inhibition of 11 3-HSD1 may enhance revascularisation of ischaemic tissues.

Studies have shown that 113-HSD1 affects intraocular pressure in man (see, e.g., Rauz et al., 2001). Inhibition of 1113-HSDI may be useful in reducing intraocular pressure in the treatment of glaucoma.

WJW/LP6326342 Glucocorticoicis are involved in the regulation of bone formation and skeletal development. Treatment of healthy volunteers with carbenoxolone led to a decrease in bone resorption markers suggesting that 11 -HSDi plays a role in bone resorption (see, e.g., Cooper et al., 2000). 1 113-HSD1 inhibitors could be used as protective agents in the treatment of osteoporosis.

The inventors have discovered compounds that inhibit 11 3-hydroxysteroid dehydrogenase type 1 (11 13-HSD1) that are useful in the treatment, control, and/or prevention of disorders, diseases, or conditions that are responsive to the inhibiton of 1113-HSD1.

There is a recognized need for more and better treatments for such conditions that offer, for example, one or more the following benefits: (a) improved potency; (b) improved efficacy; (C) improved specificity; (d) reduced toxicity (e.g., cytotoxicity); (e) complement the activity of other treatments (e.g., chemotherapeutic agents); (f) reduced intensity of undesired side-effects; (g) fewer undesired side-effects; (h) simpler methods of administration (e.g., route, timing, compliance); (i) reduction in required dosage amounts; (j) reduction in required frequency of administration; (k) increased ease of synthesis, purification, handling, storage, etc.; (I) reduced cost of synthesis, purification, handling, storage, etc. Thus, one aim of the present invention is the provision of active compounds that offer one or more of the above benefits.

BRIEF DESCRIPTION OF THE DRAWINGS

Figures 1 to 29 show examples of 1,5-substituted-i H-tetrazoles of the present invention.

WJW/Lp6326342

SUMMARY OF THE INVENTION

One aspect of the invention pertains to active compounds, specifically, certain 1,5-substituted-1H-tetrazole compounds, as described herein.

Another aspect of the invention pertains to a composition comprising an active compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.

Another aspect of the present invention pertains to a method of inhibiting 113-hydroxysteroid dehydrogenase type 1 (1fl3-HSD1) in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of an active compound, as described herein.

Another aspect of the present invention pertains to a method for the treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of an active compound, as described herein, preferably in the form of a pharmaceutical composition.

Another aspect of the present invention pertains to an active compound as described herein for use in a method of treatment of the human or animal body by therapy.

Another aspect of the present invention pertains to use of an active compound, as described herein, in the manufacture of a medicament for use in treatment.

In one embodiment, the treatment is treatment of a condition that is ameliorated by the inhibition of I 1-hydroxysteroid dehydrogenase type 1 (1 113-HSD1).

In one embodiment, the treatment is treatment of the metabolic syndrome, which includes conditions such as type 2 diabetes and obesity, and associated disorders including insulin resistance, hypertension, lipid disorders and cardiovascular disorders such as ischaemic (coronary) heart disease.

In one embodiment, the treatment is treatment of CNS conditions such as mild cognitive impairment and early dementia, including Alzheimer's disease.

WJW/LP6326342 Another aspect of the present invention pertains to a kit comprising (a) an active compound, as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the active compound.

Another aspect of the present invention pertains to compounds obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.

Another aspect of the present invention pertains to compounds obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.

Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.

Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein.

As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspect of the invention.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention pertains to compounds that may be described as 1,5-substituted-I H-tetrazoles, and their surprising and unexpected ability to inhibit 11 3-hydroxysteroid dehydrogenase type I (11 13-HSD1).

Compounds One aspect of the present invention pertains to compounds of the following formula: w5 3 F" 2 1"\ 1 w WJW/LP6326342 wherein: one of W1 and W5 is a group -J-L-Q; and the other of W1 and W5 is a group Z; wherein: Z is independently -H or R ; J is independently: -S-, -S(=O)-, - S(=O)2-, O., -NR-, or -Cl-I2-; with proviso that if: W1 is -J-L-Q, then: J is -S-, -S(=O)2-, -CH2-, or -C(0)-; wherein: RNJ is independently -H or RN; and if J is -CH2-, it is independently unsubstituted or substituted; L is independently C16alkylene; and is independently unsubstituted or substituted; Q is independently selected from: C(=O)RAI; -C(O)OR; R6 P4 NRNlC(O)R2; C(O)NRN2R3; NRN4C(O)NRN5RN6; NRN7C(O)QRE2; C614carboaryl, and is independently unsubstituted or substituted; WJW/LP6326342 C514heteroaryl, and is independently unsubstituted or substituted; C312cycloalkyl, and is independently unsubstituted or substituted; C312cycloalkenyl, and is independently unsubstituted or substituted; C312heterocyclic, and is independently unsubstituted or substituted; -H; wherein: each of R3, R4, R5, and R6 is independently -H or a monovalent additionally, R3 and R4, or R4 and R5, or R5 and R6, taken together with the carbon atoms to which they are attached, optionally form a benzene ring fused to the tetrahydropyran-2-yl ring; each of RAI, RA2, R, and RE2 is independently R; each of RNI, RN2, RN3, RN4, RN5, RNS, and RN7 is -H or RN; additionally, RN2 and RN3, taken together with the nitrogen atom to which they are attached, optionally form a ring having from 3 to 7 ring atoms, which may itself be fused to another ring; additionally, RNS and RNS, taken together with the nitrogen atom to which they are attached, optionally form a ring having from 3 to 7 ring atoms, which may itself be fused to another ring; additionally, RN1 and RA2, taken together with the >N-C(=O)- group to which they are attached, optionally form a ring having from 5 to 7 ring atoms, which may itself be fused to another ring; WJW/LP6326342 additionally, RN4 and RN5, taken together with the >N-C(=O)N< group to which they are attached, optionally form a ring having from 5 to 7 ring atoms, which may itself be fused to another ring: additionally, RN7 and RE2, taken together with the >N-C(=O)-O- group to which they are attached, optionally form a ring having from 5 to 7 ring atoms, which may itself be fused to another ring; each RN is independently selected from: R and -C(O)R; each R is independently selected from: C17alkyl; C27alkenyl; C27alkynyl; C312cycloalkyl; C312cycloalkenyl; C614carboaryl; C514heteroaryl; C312heterocyclic; C614carboaryl-C17alkyl; C514heteroarylC17alkyl; C312heterocyclic-C17alkyl; and is independently unsubstituted or substituted; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, N-oxides, chemically protected forms, and prodrugs thereof.

Note that it is j intended that L be linked to the tetrazole ring except via the group J. Simillarly, it is not intended that Q be linked to J except via the group L. Simillarly, it is t intended that W1 and W2 are linked except via the tetrazole ring.

Note that is is not intended that W1 and W2 are linked so as to form a ring fused to the tetrazole ring.

WJW/LP6326342 The Groups W1 and W5 In one embodiment, W5 is a group -J-LQ, and W1 is a group Z:

J-L-Q 3,NyZ 2\

In one embodiment, W1 is a group -J-L-Q, and W5 is a group Z: 21\

J-L--Q

The Group J The group J is independently: -S-, -S(=O)-, -S(=O)2-, -NR-, or -CH2-; with proviso that if: W1 is -J-L-Q, then: J is -S-, -S(=O)2-, CH2-, or -C(0)-; wherein: RNJ is independently -H or RN; and if J is -CH2, it is independently unsubstituted or substituted.

In one embodiment, W5 is -J-L-Q and J is independently: -S-, -S(=O)-, -S(=O)2-, -0-, or NRN.

In one embodiment, W5 is -J-L-Q and J is independently: -S-, -S(=0)-, S(=0)2-, or -0-.

In one embodiment, W5 is -J-L-Q and J is independently: -S-, -S(=0)-, or S(=O)2-.

In one embodiment, W5 is -J-L-Q and J is independently: -S- or -0-.

In one embodiment, W1 is -J-L-Q and J is independently: -S(=0)2- or -CH2-.

In one embodiment, W1 is -J-L-Q and J is independently: -S(0)2-.

In one embodiment, W1 is -J-L-Q and J is independently: -CH2-.

In each case, if J is -CH2-, it is independently unsubstituted or substituted (see below).

In one embodiment, RNJ is independently -H or -Me.

In one embodiment, RNJ is independently -H.

WJW/LP6326342 If J is -CH2-, it is independently unsubstituted or substituted.

In one embodiment, if J is -CH2-, it is independently unsubstituted.

In one embodiment, if J is -CH2-, it is independently substituted.

In one embodiment, if J is -CH2-, it is independently unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, etc.) substituents.

In one embodiment, substituents on J as -CH2-, if present, are selected from the substituents described under the heading "The Group R : Substituents Thereon" below.

In one embodiment, substituents on J as -CH2-, if present, are independently selected from: methyl, ethyl, n-propyl, i-propyl, t-butyl; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; phenyl, benzyl; nitrile, methyl nitrile; hydroxy, hydroxymethyl, hydroxyethyl.

The GrouD L The group L is independently C1.6alkylene, and is independently unsubstituted or Examples of linear C1aIkyIene groups include -(CH2)-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, and -(CH2)6-.

Examples of branched C16aIkylene groups include: -CH2CH(CH3)-, -CH(CH3)CH2-; -CH2CH(CH2CH3)-, -CH(CH2CH3)CH2-; -CH2CH2CH(CH3)-, -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-; -CH2CH2C(CH3)2-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-; -CH2CH2CH(CH2CH3)-, -CH(CH2CH3)CH2CH2-, -CH2CH(CH2CH3)CH2-; WJW/LP6326342 -CH(CH3)CH2CH2CH2-, -CH2CH(CH3)CH2CH2-, -CH2CH2CH(CH3)CH2-, -CH2CH2CH2CH(CH3)-.

In one embodiment, L is independently C14alkylene, and is independently unsubstituted In one embodiment, L additionally has a carbon backbone length of 4 or less.

In one embodiment, L additionally has a carbon backbone length of 3 or less.

In one embodiment, L is independently -(CH2)k-, where k is independently 1, 2, 3, or 4 (i.e., -(CH2)-, -(Cl-I2)2-, -(CH2)3-, or -(CH2)4-), wherein each -CH2- unit is independently In one embodiment, k is 1, 2, or 3.

In one embodiment, k is 1 or 2.

In one embodiment, k is 1.

In one embodiment, L is independently -(CH2)-, -(CH2)2-, -(CH2)3-, or (CH2)4-, wherein each -CH2- unit is independently unsubstituted or substituted.

In one embodiment, L is independently -(CH2)-, -(CH2)2-, -(CH2)3-, or (CH2)4-.

In one embodiment, L is independently -(CH2)-, -(CH2)2-, or -(CH2)3-, wherein each -CH2- unit is independently unsubstituted or substituted.

In one embodiment, L is independently -(CH2)-, -(CH2)2-, or -(CH2)3-.

In one embodiment, L is independently -(CH2)3-.

In one embodiment, L is independently -(CH2)2-.

In one embodiment, L is independently -(CH2)-.

The Group L is independently unsubstituted or substituted.

In one embodiment, L is independently unsubstituted.

WJW/LP6326342 - 13- In one embodiment, L is independently substituted.

In one embodiment, L is independently unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, etc.) substituents.

In one embodiment, the substituents on L, if present, are selected from the substituents described under the heading "The Group R : Substituents Thereon" below.

In one embodiment, the substituents on L, if present, are selected from: C17a1ky1; phenyl, unsubsituted or substituted with 1, 2, or 3 C1..7aIkyI groups; (e.g., tolyl, xylyl, mesitylyl, cymenyl) benzyl, unsubsituted or substituted with 1, 2, or 3 C17a1ky1 groups; (e.g., tolyl-methyl; xylyl-methyl; mesitylyl-methyl; cymenyl-methyl) C514heteroaryl, unsubsituted or substituted with 1, 2, or 3 C1.7akyl groups; (e.g., furanyl, thiophenyl, I H-pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, or thiadiazole, each unsubsituted or substituted with 1, 2, or 3 C17a1ky1 groups).

The Group Q: Acyl Groups: -C(=O)R In one embodiment, Q is C(=O)RAl, wherein R' is independently R. WJW1LP6326342 Examples of suitable (unsubstitued) groups include:

NH ACb

Substituents on R'8'1, if present, may be selected from the substituents described below under the heading "The Group R : Substituents Thereon." Additional examples of R' include those described below under the headings "The Group R ," "The Group R : Subsitutents Thereof," and "The Group R : Some Preferred Embodiments." The Group Q: Ester Groups: C(=O)OREl In one embodiment, Q is -C(O)OR, wherein RE1 is independently R .

WJW/LP6326342 Examples of suitable (unsubstitued and substituted) groups include: Substituents on RE1, if present, may be selected from the substituents described below under the heading "The Group R: Substituents Thereon." Additional examples of RE1 include those described below under the headings "The Group R ," "The Group R : Subsitutents Thereof," and "The Group R : Some Preferred Embodiments." The Group Q: Tetrahydropyran-2-yl Groups In one embodiment, Q is: R6 P4 wherein: each of R3, R4, R5, and R6 is independently -H or a monovalent monodentate additionally, R3 and R4, or R4 and R5, or R5 and R6, taken together with the carbon atoms to which they are attached, optionally form a benzene ring fused to the tetrahydropyran-2-yl ring, which benzene ring itself is independently unsubstituted or In one embodiment: each of R3, R4, R5, and R6 is independently -H; and additionally, R3 and R4, or R4 and R5, or R5 and R6, taken together with the carbon atoms to which they are attached, optionally form a benzene ring fused to the WJW/LP6326342 - 16 tetrahydropyran-2-yI ring, which benzene ring itself is independently unsubstituted or In one embodiment, exactly one of R3, R4, R5, and R6 is a monovalent monodentate In one embodiment, exactly one of R3, R4, R5, and R6 is a monovalent monodentate substituent, and the tetrahydropyran-2- yl ring is not fused to any other ring.

In one embodiment, exactly two of R3, R4, R5, and R6 are monovalent monodentate In one embodiment, exactly two of R3, R4, R5, and R6 are monovalent monodentate substituents, and the tetrahydropyran-2-yl ring is not fused to any other ring.

In one embodiment, Q is independently: In one embodiment, Q is independently selected from: In one embodiment, the or each monovalent monodentate substituent is independently selected from the monovalent monodentate substituents described below under the heading "The Group R : Substituents Thereon." In one embodiment, the or each substituent, if present, on the fused benzene ring, if present, is independently selected from the substituents (for example, the monovalent monodentate substituents) described below under the heading "The Group R: For example, in one embodiment, Q is independently selected from the following: WJW/LP6326342 (R1)X (RPB)X wherein each x is independently 0, 1, 2, 3, or 4; and each RPB, if present, is independently a substituent, for example, a substituent selected from the substituents (for example, the monovalent monodentate substituents) described below under the heading "The Group In one embodiment, each R8 is independently selected from: (3) aminoacyl or aminothioacyl; (5) halo; (9) ether; (15) acylamino or thioacylamino; (21) C520carboaryl-C17alkyl or C5..20heteroaryl-C1.7aIkyl; (22) C520carboaryl or C520heteroaryl.

In one embodiment, each RPB is independently selected from: -F, -Cl, -Br; -OMe, -OEt, -Ph, -Ph-F; -Me, -Et; -C(0)NMe2, -(C=O)morpholino; -NMe(C=O)Ph, pyridyl, furanyl.

The Group Q: Acyl Amino Groups: NRwlC(=O)RP2 In one embodiment, Q is NRC(=O)R, wherein: RN1 is independently -H or RN; RA2 is independently R ; and additionally, RN1 and R, taken together with the >N-C(=O)- group to which they are attached, optionally form a ring having from 5 to 7 ring atoms (e.g., pyrrolidino, WJW/LP6326342 - 18- piperidino, piperazino, morpholino), which may itself be fused to another ring (e.g., a benzene ring, a pyridine ring).

Examples of suitable (unsubstitued) groups include: rThcj XII

HYJCUN

Examples of suitable (unsubstitued) groups (wherein RN1 and RA2, taken together with the >N-C(=O)- group to which they are attached, form a ring having from 5 to 7 ring atoms (e.g., pyrrolidino, piperidino, piperazino, morpholino), which may itself be fused to another ring (e.g., a benzene ring, a pyridine ring)) include: m N0 Substituents on R' and RA2, if present, may be selected from the substituents described below under the heading "The Group R : Substituents Thereon." Additional examples of RA2 include those described below under the headings "The Group R ," "The Group R : Subsitutents Thereof," and "The Group R : Some Preferred Embodiments." The Group Q: Amino Acyl Groups: C(=O)NRN2RN3 In one embodiment, Q is C(O)NRN2RNa, wherein: each of RN2 and RN3 is independently -H or RN; and WJW1LP6326342 - 19- additionally, RN2 and RN3, taken together with the nitrogen atom to which they are attached, optionally form a ring having from 3 to 7 ring atoms (e.g., azetidino, pyrrolidino, piperidino, piperazino, morpholino), which may itself be fused to another ring (e.g., a benzene ring, a pyridine ring).

Examples of suitable (unsubstituted) groups include: )LN

NH

Substituents on RN2 and RN3, if present, may be selected from the substituents described below under the heading "The Group R : Substituents Thereon." The Group Q: Urea Groups: In one embodiment, Q is NRN4C(=O)NRNSRN6, wherein: each of RN4, RN5, and RN6 is -H or RN; additionally, RN5 and RN6, taken together with the nitrogen atom to which they are attached, optionally form a ring having from 3 to 7 ring atoms (e.g., azetidino, pyrrolidino, piperidino, piperazino, morpholino), which may itself be fused to another ring (e.g., a berizene ring, a pyridine ring); and additionally, RN4 and RNS, taken together with the >N-C(=O)-N< group to which they are attached, optionally form a ring having from 5 to 7 ring atoms (e.g., pyrrolidino, piperidino, piperazino, morpholino), which may itself be fused to another ring (e.g., a benzene ring, a pyridine ring).

Examples of suitable (unsubstituted) groups include: WJW/LP6326342 Substituents on RN4, RN5, and RNS, if present, may be selected from the substituents described below under the heading "The Group R: Substituents Thereon." The Group Q: Carbamate Groups: NRN7C(=O)ORE2 In one embodiment, Q is NRN7C(=O)ORE2, wherein: RN7 is -H or RN; RE2 is independently R; and additionally, RN7 and RE2, taken together with the >N-C(=O)-O- group to which they are attached, optionally form a ring having from 5 to 7 ring atoms (e.g., pyrrolidino, piperidino, piperazino, morpholino), which may itself be fused to another ring (e.g., a benzene ring, a pyridine ring).

Examples of suitable (unsubstituted) groups include:

TO

Substituents on RN7 and RE2, if present, if present, may be selected from the substituents described below under the heading "The Group R : Substituents Thereon." Additional examples of RE2 include those described below under the headings "The Group R ," "The Group R: Subsitutents Thereof," and "The Group R : Some Preferred Embodiments." The Group Q: C4Carboarvl and C4HeteroaryI Groups In one embodiment, Q is selected from: C614carboaryi, and is independently unsubstituted or substituted; C514heteroaryl, and is independently unsubstituted or substituted.

WJW/LP6326342 - 21 - In one embodiment, Q is C614carboaryl, and is independently unsubstituted or substituted.

In one embodiment, Q is C610carboaryl, and is independently unsubstituted or substituted.

In one embodiment, Q is C514heteroaryl, and is independently unsubstituted or In one embodiment, Q is C512heteroaryl, and is independentlyunsubstituted or In one embodiment, Q is C510heteroaryl, and is independently unsubstituted or In one embodiment, Q is C56heteroaryl, and is independently unsubstituted or substituted.

Examples of suitable (unsubstituted) C614carboaryl groups include: Examples of suitable (unsubstituted and substituted) C5..14heteroaryl groups include: L-ç/ WJW/LP6326342 - 22 - Substituents on C614carboaryl and C14heteroaryI, if present, if present, may be selected from the substituents described below under the heading "The Group R : Substituents Thereon." The Group Q: CQycloalkyl, CCycloaJkenyl, and CHeterocyclic Groups In one embodiment, Q is selected from: C12cycloalkyl, and is independently unsubstituted or substituted; C12cycloalkenyI, and is independently unsubstituted or substituted; and C31 2heterocyclic, and is independently unsubstituted or substituted.

In one embodiment, Q is selected from: C312cycloalkyl, and is independently unsubstituted or substituted; and C312cycloalkenyl, and is independently unsubstituted or substituted.

In one embodiment, Q is selected from: C7cycIoaIkyI, and is independently unsubstituted or substituted; and C7cycloaIkenyl, and is independently unsubstituted or substituted.

In one embodiment, Q is: C312heterocyclic, and is independently unsubstituted or substituted.

In one embodiment, Q is: C37heterocyclic, and is independently unsubstituted or substituted.

Examples of suitable (unsubstituted) C312cycIoalkyI groups include: WJW/LP6326342 - 23 - Examples of suitable (unsubstituted) C12heterocycIic groups include: _ I" -N) -N NH -N o \I \/

NQ -N

For example, in one embodiment, Q is independent'y: (RPB)X wherein x is independently 0, 1, 2, 3, or 4, and each RPB is independently a substituent, for example, a substituent selected from the substituents (for example, the monovalent monodentate substituents) described below under the heading "The Group R : The Group Q: -H In one embodiment, Q is independently -H.

Some Preferred Groups -J-L-Q In one embodiment: J is-S-; L is -CH2-, (CH2)2-, or -(CH2)3-, and is independently unsubstituted or substituted; and Q is C(=O)RM, wherein RA is independently R .

In one embodiment: J is -S-; L is -CH2-, and is independently unsubstituted or substituted; and Q is C(=O)RAl, wherein R is independently R .

WJW/LP6326342 - 24- In one embodiment: J is -8-; L is -CH2-; and Q is.c(Q)M, wherein is independently R .

In one embodiment, J, L, and Q are as defined above, and W5 is -J-L-Q.

Each group RN is independently selected from: R and -C(0)R .

In one embodiment, any particular group RN is independently R .

In one embodiment, any particular group RN is independently -C(0)R .

In one embodiment, any particular group RN is independently -Me or -C(0) Me.

In one embodiment, any particular group RN is independently -Me.

The Group Z The group Z is independently -H or R. In one embodiment, Z is independently -H.

In one embodiment, Z is independently -R .

Examples of suitable (unsubstitued) groups include: i-Me Substituents on R , if present, may be selected from the substituents described below under the heading "The Group R : Substituents Thereon." WJW/LP6326342 - Additional examples of R include those described below under the headings "The Group R ," "The Group R: Subsitutents Thereof," and "The Group R : Some Preferred Embodiments." The Group R Each group R is independently selected from: C1..7 a Iky I; C27alkenyl; C2.7alkynyl; C312cycloalkyl; C3. .1 2cycloalkenyl; C614carboaryl; C514heteroaryl; C3..12heterocyclic; C614carboaryl-C17alkyl; C514heteroaryl-C17alkyl; C312heterocyclic- C17alkyl; and is independently unsubstituted or substituted.

In one embodiment, any particular R, or each R , is independently selected from: Ci.7alkyl; C3..12cycloalkyl; C614carboaryl; C514heteroaryl; C12heterocyclic; C6.14carboaryl-C17alkyl; C514heteroaryl-C17a1ky1; C3. 12heterocyclic-C17alkyl; and is independently unsubstituted or substituted.

In one embodiment, any particular R, or each R , is independently selected from: C1.7alkyl; C3.12cycloalkyl; C614carboaryl; C5.14heteroaryl; WJW1LP6326342 - 26 - C6.14carboaryl-C17alky1; C514heteroaryl-C17alky1; and is independently unsubstituted or substituted.

In one embodiment, any particular R , or each R, is independently selected from: C17a1ky1; C3.12cycloalkyl; C614carboaryl; C514heteroaryl; and is independently unsubstituted or substituted.

In one embodiment, any particular R, or each R , is independently selected from: C312cycloalkyl; C614carboaryl; C514heteroaryl; and is independently unsubstituted or substituted.

In one embodiment, any particular R , or each R, is independently selected from: C614carboaryl; C514heteroaryl; and is independently unsubstituted or substituted.

In one embodiment, any particular R , or each R, is independently selected from: C,.7alkyl; and is independently unsubstituted or substituted.

In one embodiment, any particular R , or each R , is independently selected from: C614carboaryl; C514carboaryl-C1.7alkyl; and is independently unsubstituted or substituted.

In one embodiment, any particular, or each, C17a1ky1 is C1alkyl.

In one embodiment, any particular, or each, C614carboaryl is C610carboaryl.

In one embodiment, any particular, or each, C6.14carboaryl is C6carboaryl.

WJW1LP6326342 - 27 - In one embodiment, any particular, or each, C5.14heteroaryl is C512heteroaryl.

In one embodiment, any particular, or each, C5..14heteroaryl is C510heteroaryl.

In one embodiment, any particular, or each, C514heteroaryl is C56heteroaryl.

In one embodiment, any particular, or each, C312heterocyclic is C310heterocyclic.

In one embodiment, any particular, or each, C312heterocyclic is C37heterocyclic.

In one embodiment, any particular, or each, C312heterocyclic is C36heterocyclic.

In one embodiment, any particular, or each, C12heterocycIic is C510heterocyclic.

In one embodiment, any particular, or each, C312heterocyclic is C57heterocyclic.

In one embodiment, any particular, or each, C12heterocyclic is C56heterocyclic.

Some preferred examples of (unsubstituted) C17a1ky1 groups include: -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu.

Some preferred examples of (unsubstituted) C312cycIoaIkyl groups include: cylcopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (C6), adamantyl (C10).

Some preferred examples of (unsubstituted) C614carboaryl groups include: phenyl; naphthyl, e.g., naphth-1-yl, naphth-2-yI.

Some preferred examples of (unsubstituted) C514heteroaryl groups include: furanyl, e.g., furan-2-yl, furan-3-yl; thiophenyl, e.g., thiophen-2-yl, thiophen-3-yl; IH-pyrrolyl, e.g., 1H-pyrrol-2-yI, 1H-pyrrol-3-yI; pyridinyl, e.g., pyridine-2-yl, pyridine-3-yl, pyridine-4-yl; pyrazinyl, pyrimidinyl, pyridazinyl; imidazolyl, pyrazolyl, oxazolyl, thiazolyl, thiadiazole; benzo[1,3]dioxolyl, e.g., benzo[1,3]dioxol-5-yl; 2,3-dihydro-benzo[1,4]dioxinyl, e.g., 2,3-dihydro-benzo[1,4]dioxin-6-yl; 2,3-dihydro-benzofuranyl, e.g, 2,3-dihydro-benzofuran-2-yI; 4H-benzo[1,4]oxazin-3-one-yI, e.g., 4H-benzo[1,4]oxazin-3-one-6-yl.

WJW/LP6326342 - 28 - Some preferred examples of (unsubstituted) C312heterocyclic groups include: pyrrolidinyl, imidazolidinyl, pyrazolidinyl; piperidinyl, piperazinyl; tetrahydrofuranyl, tetrahydrothiophenyl; tetrahydropyranyl, morpholinyl; azepinyl; azabicyclo[3,2, 1 Joctane; azabicyclo[3,2,2]nonane.

Some preferred examples of (unsubstituted) C6.14carboaryl-C17alkyl groups include: benzyl; phenyl-ethyl.

Some preferred examples of (unsubstituted) C5.14heteroaryl-C17aIkyl groups include: pyridyl-methyl; pyridyl-ethyl.

In one embodiment, each R is independently selected from those (core groups) exemplified under the heading "Some Preferred Embodiments" and is independently unsubstituted or substituted, for example, with one or more substituents as defined under the heading "The Substituents, R : Substituents Thereon" below, or with one or more substituents independently selected from those substituents exemplified under the heading "Some Preferred Embodiments." Any particular R , or each R , is independently unsubstituted or substituted.

In one embodiment, any particular R , or each R , is independently unsubstituted.

In one embodiment, any particular R, or each R, is independently substituted.

In one embodiment, any particular R , or each R, is independently unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, etc.) substituents.

WJW/LP6326342 - 29 - In one embodiment, the substituents are independently selected from the following: (1) carboxylic acid; (2) ester; (3) aminoacyl or aminothioacyl; (4) acyl; (5) halo; (6) cyano; (7) nitro; (8) hydroxy; (9) ether; (10) thiol; (II) thioether; (12) acyloxy; (13) carbamate; (14) amino; (15) acylamino orthioacylamino; (16) aminoacylamino or aminothioacylamino; (17) sulfonamino; (18) sulfonyl; (19) sulfonate; (20) sulfonamido; (21) C520carboaryl-C17a1ky1 or C520heteroaryl-C17alkyl; (22) C520carboaryl or C520heteroaryl; (23) C20heterocyclyl; (24) C17alkyl; C27alkenyl; C27alkynyl; C312cycloalkyl; C312cycloalkenyl; (25) oxo; (26) imino; (27) hydroxyimino.

(Obviously, if a particular group (e.g., R) is alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl, then it is not substituted with a moiety of group (24).) In one embodiment, the substituents are independently selected from the following: (1) -C(0)OH; (2) -C(=O)0R1, wherein R1 is independently as defined in (21), (22), (23) or (24); (3) -C(=O)NR2R3 or -C(=S)NR2R3, wherein each of R2 and R3 is independently -H; or as defined in (21), (22), (23) or (24); or R2 and R3 taken together with the nitrogen atom to which they are attached form a ring having from 3 to 7 ring atoms; (4) -C(0)R4, wherein R4 is independently -H, or as defined in (21), (22), (23) or (24); (5) -F, -Cl, -Br, -I; (6) -CN; (7) -NO2; (8) -OH; (9) -OR5, wherein R5 is independently as defined in (21), (22), (23) or (24); (10) -SH; (11) -SR6, wherein R6 is independently as defined in (21), (22), (23) or (24); (12) -OC(=O)R7, wherein R7 is independently as defined in (21), (22), (23) or (24); (13) -OC(=O)NR8R9, wherein each of R8 and R9 is independently -H; or as defined in (21), (22), (23) or (24); or R8 and R9 taken together with the nitrogen atom to which they are attached form a ring having from 3 to 7 ring atoms; (14) -NR10R11, wherein each of R1 and R11 is independently -H; or as defined in (21), (22), (23) or (24); or R1 and R11 taken together with the nitrogen atom to which they are attached form a ring having from 3 to 7 ring atoms; WJW/Lp6326342 - 30- (15) -NR12C(=O)R13 or -NR12C(=S)R13, wherein R12 is independently -H; or as defined in (21), (22), (23) or (24); and R13 is independently -H, or as defined in (21), (22), (23) or (24); (16) -NR14C(=Q)NR15R16 or -NR14C(=S)NR15R16, wherein R14 is independently -H; or as defined in (21), (22), (23) or (24); and each of R15 and R16 is independently -H; or as defined in (21), (22), (23) or (24); or R15 and R16 taken together with the nitrogen atom to which they are attached form a ring having from 3 to 7 ring atoms; (17) -NR17S02R18, wherein R17 is independently -H; or as defined in (21), (22), (23) or (24); and R18 is independently -H, or as defined in (21), (22), (23) or (24); (18) -S02R19, wherein R19 is independently as defined in (21), (22), (23) or (24); (19) -0S02R2 and wherein R2 is independently as defined in (21), (22), (23) or (24); (20) -S02NR21R22, wherein each of R21 and R22 is independently -H; or as defined in (21), (22), (23) or (24); or R21 and R22 taken together with the nitrogen atom to which they are attached form a ring having from 3 to 7 ring atoms; (21) C5.20carboaryl-C17alkyI or C520heteroaryl-C1.7alkyl; unsubstituted or substituted, e.g., with one or more groups as defined in (1) to (27); (22) C520carboaryl or C520heteroaryl; unsubstituted or substituted, e.g., with one or more groups as defined in (1) to (27); (23) C20heterocyclyl; unsubstituted or substituted, e.g., with one or more groups as defined in (1) to (27); (24) C1.7alkyl; C27alkenyl; C27alkynyl; C312cycloalkyl; C312cycloalkenyl; unsubstituted or substituted, e.g., with one or more groups as defined in (1) to (23) and (25) to (27); e.g., halo-C17alkyl; e.g., amino-C17alkyl (e.g., -(CH2)-amino, w is 1, 2, 3, or 4); e.g., carboxy-C17alkyl (e.g., - (CH2)-COOH, w is 1, 2, 3, or 4); e.g., acyl-C1..7alkyl (e.g., -(CH2)-C(=O) R4, w is 1, 2, 3, or 4); e.g., hydroxy-C1.7alkyl (e.g., -(CH2)-OH, w is 1, 2, 3, or 4); e.g., C17alkoxy-C17alkyl (e.g., -(CH2)-O-C1.7alkyl, w is 1, 2, 3, or 4); (25) =0; (26) NR23, wherein R23 is independently -H; or as defined in (21), (22), (23) or (24); (27) =NOH.

In one embodiment, the substituents are independently selected from the following: (1) -C(0)OH; WJW/LP6326342 - 31 - (2) -C(0)OMe, -C(=O)OEt, -C(=O)Q(ipr), -C(=O)O(tBu); -C(=O)0(cPr); -C(=0)OCH2CH2OH, -C(=O)OCH2CH2OMe, -C(0)OCH2CH2OEt; -C(0)OPh, -C(0)OCH2Ph; (3) -(C=O)NH2, -(C0)NMe2, -(C=O)NEt2, -(C0)N(iPr)2, -(C=O)N(CH2CH2OH)2; -(C0)-morpholino, -(C=O)NHPh, -(C=O)NHCH2Ph; (4) -C(=O)H, -(C=O)Me, -(C=O)Et, -(C=O)(tBu), -(C=O)-cHex, -(C=0)Ph; -(C0) CH2Ph; (5) -F, -CI, -Br, -I; (6) -CN; (7) -No2; (8)-OH; (9) -OMe, -OEt, -O(iPr), -O(tBu), -OPh, -OCH2Ph; -OCF3, -OCH2CF3; -OCH2CH2OH, -OCH2CH2OMe, -OCH2CH2OEt; -OCH2CH2NH2, -OCH2CH2NMe2, -OCH2CH2N(iPr)2; -OPh-Me, -OPh-OH, -OPh-OMe, -OPh-F, -OPh-CI, -OPh-Br, -OPh-I; (10) -SH; (11) -SMe, -SEt, -SPh, -SCH2Ph; (12) -OC(0)Me, -OC(=O)Et, -OC(=O)(iPr), -OC(O)(tBu); -OC(=O)(cPr); -OC(=O)CH2CH2OH, -OC(=O)CH2CH2OMe, -OC(O)CH2CH2QEt; -OC(=O)Ph, -OC(0)CH2Ph; (13) -OC(=O)NH2, -OC(=O) NHMe, -OC(0)NMe2, -OC(=O) NHEt, -OC(=O)NEt2, -OC(=O)NHPh, -OC(0)NCH2Ph; (14) -NH2, -NHMe, -NHEt, -NH(iPr), -NMe2, -NEt2, -N(iPr)2, -N(CH2CH2OH)2; -NHPh, -NHCH2Ph; piperidino, piperazino, morpholino; (15) -NH(C0)Me, -NH(C=O)Et, -NH(C0)nPr, -NH(C=O)Ph, -NHC(0)CH2Ph; -NMe(C=O)Me, -NMe(C=O)Et, -NMe(C=O)Ph, -NMeC(=O)CH2Ph; (16) -NH(C=O)NH2, -NH(C0)NHMe, -NH(C=O)NHEt, -NH(C=O)NPh, -NH(C0)NHCH2Ph; -NH(C=S)NH2, -NH(C=S)NHMe, -NH(C=S)NHEt, -NH(C=S)NPh, -NH(CS)NHCH2Ph; (17) -NHSO2Me, -NHSO2Et, -NHSO2Ph, -NHSO2PhMe, -NHSO2CH2Ph; -NMeSO2Me, -NMeSO2Et, -NMeSO2Ph, -NMeSO2PhMe, -NMeSO2CH2Ph; (18) -SO2Me, -SO2CF3, -SO2Et, -SO2Ph, -SO2PhMe, -SO2CH2Ph; (19) -OSO2Me, -OSO2CF3, -OSO2Et, -OSO2Ph, -OSO2PhMe, -OSO2CH2Ph; (20) -SO2NH2, -SO2NHMe, -SO2NHEt, -SO2NMe2, -SO2NEt2, -S02-morpholino, -SO2NHPh, -SO2NHCH2Ph; (21) -CH2Ph, -CH2Ph-Me, -CH2Ph-OH, -CH2Ph-F, -CH2Ph-CI; WJW/LP6326342 - 32 - (22) -Ph, -Ph-Me, -Ph-OH, -Ph-OMe, -Ph-NH2, -Ph-F, -Ph-Cl, -Ph-Br, -Ph-I; pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl; furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, thiadiazolyl; (23) pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, azetidinyl; (24) -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, -nPe; -cPr, -cHex; -CH=CH2, -CH2-CH=CH2; -CF3, -CHF2, -CH2F, -Cd3, -CBr3, -CH2CH2F, -CH2CHF2, and -CH2CF3; -CH2OH, -CH2OMe, -CH2OEt, -CH2NH2, -CH2NMe2; -CH2CH2OH, -CH2CH2OMe, -CH2CH2OEt, -CH2CH2CH2NH2, -CH2CH2NMe2; (25) =0; (26) =NH, =NMe; =NEt; (27) =NOH.

In one embodiment, the substituents are independently selected from those defined above in groups: (5), (9), (22), (23), (24), (3), (21), (17), (6), (15).

In one embodiment, the substituents are independently selected from C17a1ky1, e.g., -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu; C14haloalkyl, e.g., -CF3, -CH2F, -CHF2, -CH2CF3; C17alkoxy, e.g., -OMe, OEt, -0-nPr, -O-iPr, -0-nBu, -0-iBu, -O-sBu, -O-tBu; C14haloalkoxy, e.g., -OCF3, -OCH2F, -OCHF2, -OCH2CF3; C17alkyl-acyl, e.g., -C(0)Me, -C(=0)Et; halo, i.e., -F, -Cl, -Br, -I; -NO2; -CN; phenyl, unsubstituted or substituted; and C56heteroaryl, unsubstituted or substituted In one embodiment, the substituents are independently selected from those substituents exemplified under the heading "Some Preferred Embodiments." WJW1LP6326342 - 33 - The Group R : Some Preferred Embodiments In one embodiment, R is independently selected from: t-butyl, cylcopropyl, cyclohexyl, cycloheptyl, cyclohex-1 -enyl, inden-2-yI, 3-methylinden-2-yl, bicyclo[2. 2.1]hept-2-yI, adamantyl, phenyl, tolyl, mesitylyl, xylyl, cymenyl, 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluoroyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2-chiorophenyl, 4-chiorophenyl, 2,4-dichlorophenyl, 3,4-dichiorophenyl, 4-cyanophenyl, 4-hydroxyphenyl, 4-hydroxymethyiphenyl, 4-(2-hydroxyethyl)phenyl, 4-trifluoromethyiphenyl, 4-trifluoromethoxyphenyl, napthalen-2-yl, napthalen-1 -yl, benzo[1,3]dioxol-5-yI, 2,4-dihydro-benzo[1,4]dioxin-2-yI, I,2,3,4-tetrahydro-napthalen-1-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yI, 4H-benzo[1,4loxazin-3-one, thiophen-2-yI, 3-chlorothiophen-2-yI, 3-bromothiophen-2-yI, 3-fluorothiophen-2-yl, thiophen-3-yI, 2-chlorothiophen-3-yI, 2-bromothiophen-3-yI, 2-fluorothiophen-3-yI, furan2-yI, 3-chlorofuran-2-yI, 3-bromofuran-2-yl, 3-fluorofuran-2-yI, furan-3-yl, 2-chlorofuran-3-yI, 2-bromofuran-3-yI, 2-fluorofuran-3-yI, WJW/LP6326342 - 34 - oxazolyl, oxazol-2-yI, isoxazolyl, isoxazol-3-yI, benzoxazolyl, benzoxazol-2-yI, benzisoxazolyl, benzisoxazol-3-yI, benzofuranyl, benzofuran-2-yI, pyridine-2-yI, pyridine-3-yI, pyridine-4-yI, quinolin-2- yI cyclohexyl-methyl, benzyl (i.e., phenyl-methyl), tolyl-methyl, mesitylyl-methyl, xylyl-methyl, cymenyl-methyl, fluorophenyl-methyl 2- fluorophenyl-methyl, 4-fluorophenyl-methyl, 2,4-difluorophenyl-methyl, 3,4-difluorophenyl-methyl, chiorophenyl-methyl, 2-chiorophenyl-methyl, 4-chiorophenyl-methyl, 2,4-dichlorophenyl-methyl, 3,4-dichiorophenyl-methyl, methoxyphenyl- methyl, 2-methoxyphenyl-methyl, 4-methoxyphenyl-methyl, 2,4-dimethoxyphenyt-methyl, 3,4-dimethoxyphenyl-methyl, cyanophenyl- methyl, 2-cyanophenyl-methyl, 4-cyanophenyl-methyl, hydroxyphenyl-methyl, 4-hydroxyphenyl-methyl, 4-hydroxymethyiphenyl-methyl 4-(2-hydroxyethyl)phenyl-methyl, 4-trifluoromethyiphenyl-methyl, 4-trifluoromethoxyphenyl-methyl, thiophen-2-yI-methyl 3-fluorothiophen-2-yI-methyl, 3-chlorothiophen-2-yI-methyl, 3- bromothiophen-2-yI-methyl, thiophen-3-yl-methyl, 2-fluorothiophen-3-yI-methyl, 2-chlorothiophen-3-yI-methyl, 2- bromothiophen-3-yI-methyl, W.JW/LP6326342 - 35 - furan-2-yI-methyl, 3-fluorofuran-2-yl-methyl, 3-chlorofuran-2-yI-methyl, 3-bromofuran-2-yI- methyl, furan-3-yI-methyl, 2-fluorofuran-3-yI-methyl, 2-chlorofuran-3-yI-methyl, 2-bromofuran-3-yImethyl, pyridine-2-yI-methyl, pyridine-3-yI-methyl, pyridine-4-yl-methyl, quinolin-2-yl-methyl.

Molecular Weight In one embodiment, the compound has a molecular weight of 300 to 1000.

In one embodiment, the bottom of range is 325; 350; 375; 400; 425; 450.

In one embodiment, the top of range is 900; 800; 700; 600; 500.

In one embodiment, the range is 300 to 900.

In one embodiment, the range is 300 to 800.

In one embodiment, the range is 300 to 700.

In one embodiment, the range is 300 to 600.

In one embodiment, the range is 300 to 500.

Some Preferred Sub-Classes of Compounds All plausible and compatible combinations of the embodiments described above are explicitly disclosed herein. Each of these combinations is disclosed herein to the same extent as if each individual combination was specifically and individually recited.

Some preferred sub-classes of compounds includes the following: ,NJNyRA2 N_N\RQ WJW1LP6326342 - 36 - J_(RPB)x R \N_N\RQ N'T'_ N'(1 Some Preferred Embodiments Examples of some preferred compounds include those shown in Figures 1 to 29.

Chemical Terms The term "carbo," "carbyl," "hydrocarbo," and "hydrocarbyl, " as used herein, pertain to compounds and/or groups that have only carbon and hydrogen atoms (but see "carbocyclic" and "carboaromatic" below).

The term "hetero," as used herein, pertains to compounds and/or groups which have at least one heteroatom, for example, multivalent heteroatoms (which are also suitable as ring heteroatoms) such as boron, silicon, nitrogen, phosphorus, oxygen, sulfur, and selenium (more commonly nitrogen, oxygen, and sulfur) and monovalent heteroatoms, such as fluorine, chlorine, bromine, and iodine.

The term "saturated," as used herein, pertains to compounds and/or groups that do not have any carbon-carbon double bonds or carbon-carbon triple bonds.

The term "unsaturated," as used herein, pertains to compounds and/or groups that have at least one carbon-carbon double bond or carbon-carbon triple bond. Compounds and/or groups may be partially unsaturated or fully unsaturated.

The term "aliphatic," as used herein, pertains to compounds and/or groups that are linear or branched, but not cyclic (also known as "acyclic" or "open-chain" groups).

WJW/LP6326342 - 37 - The term "ring," as used herein, pertains to a closed ring of from 3 to 10 covalently linked ring atoms, more preferably 3 to 8 covalently linked ring atoms, yet more preferably 5 to 6 covalently linked ring atoms. A ring may be an alicyclic ring or an aromatic ring. The term "alicyclic ring," as used herein, pertains to a ring that is not an aromatic ring.

The term "carbocyclic ring," as used herein, pertains to a non-aromatic ring wherein all of the ring atoms are carbon atoms. Typically, the carbocyclic ring has from 3 to 7 ring atoms.

The term "heterocyclic ring," as used herein, pertains to a non-aromatic ring wherein at least one of the ring atoms is a multivalent ring heteroatom, for example, nitrogen, phosphorus, silicon, oxygen, or sulfur, though more commonly nitrogen, oxygen, or sulfur.

Typically, the heterocyclic ring has from 3 to 7, and more commonly from 5 to 7, ring atoms. Typically, the heterocyclic ring has from 1 to 4 ring heteroatoms.

The term "carboaromatic ring," as used herein, pertains to an aromatic ring wherein all of the ring atoms are carbon atoms. Typically, the carboaromatic ring has 6 ring atoms.

The term "heteroaromatic ring," as used herein, pertains to an aromatic ring wherein at least one of the ring atoms is a multivalent ring heteroatom, for example, nitrogen, phosphorus, silicon, oxygen, or sulfur, though more commonly nitrogen, oxygen, or sulfur.

Typically, the heteroaromatic ring has from 3 to 7, and more commonly from 5 to 7, ring atoms. Typically, the heteroaromatic ring has from I to 4 ring heteroatoms.

The term "cyclic compound," as used herein, pertains to a compound that has at least one ring.

Where a cyclic compound has two or more rings, they may be fused (e.g., as in naphthalene, decalin, etc.), bridged (e.g., as in norbornane, adamantane, etc.), Spiro (e.g., as in spiro[3.3]heptane), or a combination thereof. Cyclic compounds with one ring may be referred to as "monocyclic" or "mononuclear," whereas cyclic compounds with two or more rings may be referred to as "polycyclic" or "polynuclear." The term "carbocyclic compound," as used herein, pertains to a cyclic compound that has only carbocyclic ring(s) (and no other rings), and is not an aromatic compound.

WJW/LP6326342 - 38 - The term "heterocyclic compound," as used herein, pertains to a non- aromatic cyclic compound that has at least one heterocyclic ring, and is not an aromatic compound.

The term "aromatic compound," as used herein, pertains to a cyclic compound that has at least one aromatic ring.

The term "carboaromatic compound," as used herein, pertains to a cyclic compound that has only carboaromatic ring(s) (and not other rings).

The term "heteroaromatic compound," as used herein, pertains to a cyclic compound that has at least one heteroaromatic ring; or at least one aromatic ring and at least one heterocyclic ring (typically fused together).

The phrase "optionally substituted," as used herein, pertains to a parent group which may be unsubstituted or which may be substituted.

Unless otherwise specified, the term "substituted," as used herein, pertains to a parent group that bears one or more substitutents. The term "substituent" is used herein in the conventional sense and refers to a chemical moiety that is covalently attached to, or if appropriate, fused to, a parent group. A wide variety of substituents are well known, and methods for their formation and introduction into a variety of parent groups are also well known.

Alkyl: The term "alkyl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of an aliphatic saturated hydrocarbon compound having from I to 20 carbon atoms (unless otherwise specified). Examples of groups of alkyl groups include C1alkyl, C17alkyl, and C220a1ky1.

The prefixes (e.g., C1.4, C1.7, C1.20, C2.7, C3.7, etc.) denote the number of carbon atoms, or range of number of carbon atoms. For example, the term "C1alkyl," as used herein, pertains to an alkyl group having from 1 to 4 carbon atoms.

Examples of (unsubstituted) alkyl groups include: methyl (C1), ethyl (C2), propyl (C3), butyl (C4, pentyl (C5), hexyl (06), heptyl (C7), octyl (C8), nonyl (C9), decyl (C10), undecyl (C11), dodecyl (C12), tridecyl (C13), tetradecyl (C14), pentadecyl (C15), and eicodecyl (C20).

WJW/LP6326342 - 39 - Examples of (unsubstituted) linear alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), n-butyl (C4), n-pentyl (amyl) (C5), n-hexyl (C6), and n-heptyl (C7).

Examples of (unsubstituted) branched alkyl groups include: iso-propyl (C3) , iso-butyl (C4), sec-butyl (C4), tert-butyl (C4), iso-pentyl (C5), and neo-pentyl (C5).

Alkylene: The term "alkylene," as used herein, pertains to a bidentate moiety obtained by removing two hydrogen atoms, either both from the same carbon atom, or one from each of two different carbon atoms, of an aliphatic saturated hydrocarbon compound having from I to 20 carbon atoms (unless otherwise specified). Examples of groups of alkylene groups include C1alkylene ("lower alkylene"), C17alkylene, and C120alkylene.

Examples of (unsubsituted) linear alkylene groups include: -(CH2)- where n is an integer from Ito 7, for example, -CH2- (methylene), -CH2CH2(ethylene), - CH2CH2CH2- (propylene), and -CH2CH2CH2CH2- (butylene).

Examples of (unsubsituted) branched alkylene groups include: -CH(CH3)-, CH(CH3)CH2-, -CH(CH3)CH2CH2-, -CH(CH3)CH2CI-12CH2-, -CH2CH(CH3)CH2-, -CH2CH(CH3)CH2CH2- , -CH(CH2CH3)-, -CH(CH2CH3)CH2-, and -CH2CH(CH2CH3)CH2-.

Alkenyl: The term "alkenyl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of an aliphatic hydrocarbon compound having from 2 to 20 carbon atoms (unless otherwise specified), and one or more carbon- carbon double bonds. Examples of groups of alkenyl groups include C24alkenyl, C2.7alkenyl, and C2.20alkenyl.

Examples of (unsubstituted) alkenyl groups include: ethenyl (vinyl, CHCH2), 1-propenyl (-CH=CH-CH3), 2-propenyl (allyl, -CH-CH=CH2), isopropenyl (1 -methylvinyl, -C(CH3)=CH2), butenyl (C4), pentenyl (C5), and hexenyl (C6).

Alkynyl: The term "alkynyl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of an aliphatic hydrocarbon compound having from 2 to 20 carbon atoms (unless otherwise specified), and one or more carbon- carbon triple bonds. Examples of groups of alkynyl groups include C2alkynyl, C2.7alkynyl, and C220alkynyl.

WJW/LP6326342 -40 - Examples of (unsubstituted) alkynyl groups include: ethynyl (ethinyl, - CCH) and 2-propynyl (propargyl, -CH2-CCH).

Cycloalkyl: The term "cycloalkyl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom (usually a ring carbon atom) of a cyclic saturated hydrocarbon compound having from 3 to 20 carbon atoms (unless otherwise specified), and one or more carbocyclic rings. Examples of groups of cycloalkyl groups include C36cycloalkyl, C3.7cycloalkyl, C310cycloalkyl, C312cycloalkyl, and C320cycloalkyl.

Examples of cycloalkyl groups include those derived from: cyclopropane (C3), cyclobutane (C4), cyclopentane (C5), cyclohexane (C6), cycloheptane (C7), methylcyclopropane (C4), dimethylcyclopropane (C5), methylcyclobutane (C5), dimethylcyclobutane (C6), methylcyclopentane (C6),dimethylcyclopentane (C7), methylcyclohexane (C7), dimethylcyclohexane (C8), menthane (C10), thujane (C10), carane (C10), pinane (C10), bornane (C10), norcarane (C7), norpinane (C7), norbornane (C7), adamantane (C10), decalin (decahydronaphthalene) (C10).

Cycloalkenyl: The term "cycloalkenyl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom (usually a ring carbon atom) of a cyclic hydrocarbon compound having from 3 to 20 carbon atoms (unless otherwise specified), one or more carbocyclic rings, and one or more carbon-carbon double bonds.

Examples of groups of cycloalkenyl groups include C6cycloalkenyl, C37cycloalkenyl, C310cycloalkenyl, C312cycloalkenyl, and C320cycloalkenyl.

Examples of cycloalkenyl groups include those derived from: cyclopropene (C3), cyclobutene (C4), cyclopentene (C5), cyclohexene (C6), methylcyclopropene (C4), dimethylcyclopropene (C5), methylcyclobutene (C5) , dimethylcyclobutene (C6), methylcyclopentene (C6), dimethylcyclopentene (C7), methylcyclohexene (C7), dimethylcyclohexene (C8), camphene (C10), limonene (C10), pinene (C10).

Aryl: The term "aryl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom (usually an aromatic ring atom) of an aromatic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified). Typically, each ring has from 5 to 7 ring atoms.

WJW/LP6326342 Carboaryl: The term "carboaryl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom (usually an aromatic ring atom) of a carboaromatic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified). Typically, each ring has from 5 to 7 ring atoms. Examples of groups of carboaryl groups include C620carboaryl, C614carboaryl, C612carboaryl, and C610carboaryl.

Examples of carboaryl groups include those derived from benzene (i.e., phenyl) (C6), naphthalene (C10), azulene (C10), anthracene (C14, phenanthrene (C14), naphthacene (C18), and pyrene (C16).

Examples of carboaryl groups include those derived from the following (which comprise fused rings, at least one of which is an aromatic ring): indane (e.g., 2, 3-dihydro-IH- indene) (C9), indene (C9), isoindene (C9), tetraline (1,2,3,4- tetrahydronaphthalene (C10), acenaphthene (C12), fluorene (C13), phenalene (C13), acephenanthrene (C15), and aceanthrene (C16), cholanthrene (C20).

Heteroaryl: The term "heteroaryl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom (usually an aromatic ring atom) atom of a heteroaromatic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified). Typically, each ring has from 5 to 7 ring atoms. Typically, each heteroaromatic or heterocyclic ring has from I to 4 ring heteroatoms. Examples of groups of heteroaryl groups include C5..20heteroaryl, C14heteroaryl, C5.12heteroaryl, C5.10heteroaryl, and C5..6heteroaryl.

Note that the prefixes (e.g., C320, C57, C56, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term "C6heteroaryl," as used herein, pertains to an aryl group having 5 or 6 ring atoms, at least one of which is a heteroatom. Similarly, "C37heterocyclic," as used herein, pertains to a heterocyclic group having from 3 to 7 ring atoms, at least one of which is a heteroatom.

Examples of (unsubstituted) monocyclic heteroaryl groups include those derived from: N1: pyrrole (azole) (C5), pyridine (azine) (C6); O: furan (oxole) (C5); WJW/LP6326342 -42 - S1: thiophene (thiole) (C5); N101: oxazole (C5), isoxazole (C5), isoxazine (C6); N201: oxadiazole (furazan) (C5); N301: oxatriazole (C5); N1S: thiazole (C5), isothiazole (C5); N2: imidazole (1,3-diazole) (C5), pyrazole (1,2-diazole) (C5), pyridazine (1,2-diazine) (C6), pyrimidine (1, 3-diazine) (C6) (e.g., cytosine, thymine, uracil), pyrazine (1,4-diazine) (C6); N3: triazole (C5), triazine (C6); and, N4: tetrazole (C5).

Heterocyclyl: The term "heterocyclyl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified). Typically, each ring has from 3 to 7 ring atoms. Typically, each heterocyclic ring has from I to 4 ring heteroatoms. Examples of groups of heterocyclyl groups include C20heterocycIyI, C520heterocyclyl, 03.1 5heterocyclyl, C51 5heterocyclyl, C31 2heterocyclyl, C51 2heterocyclyl, C310heterocyclyl, 0heterocyclyl, C3. 7heterocyclyl, C57heterocyclyl, and C5.6heterocyclyl.

Examples of (unsubstituted) monocyclic heterocyclyl groups include those derived from: N1: aziridine (C3), azetidine (04), pyrrolidine (tetrahydropyrrole) (Ce), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C5), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (Ce), piperidine (06), dihydropyridine (C6), tetrahydropyridine (06), azepine (C7); O: oxirane (C3), oxetane (04), oxolane (tetrahydrofuran) (05), oxole (dihydrofuran) (05), oxane (tetrahydropyran) (06), dihydropyran (C6), pyran (C6), oxepin (07); S1: thiirane (03), thietane (04), thiolane (tetrahydrothiophene) (C5), thiane (tetrahydrothiopyran) (06), thiepane (07); 02: dioxolane (C5), dioxane (06), and dioxepane (C7); 03: trioxane (06); N2: imidazolidine (C5), pyrazolidine (diazolidine) (Ce) , imidazoline (05), pyrazoline (dihydropyrazole) (05), piperazine (C6); WJW/LP6326342 - 43 - N1 01: tetrahydrooxazole I dihydrooxazole (C5), tetrahyd roisoxazole (C5), dihydroisoxazole (C5), morpholine (C6), tetrahydrooxazine (C6), dihydrooxazine (C6), oxazine (C6); N1S1: thiazoline (C5), thiazolidine (C5), thiomorpholine (C5); N201: oxadiazine (C6); 01S1: oxathiole (C5) and oxathiane (thioxane) (C6); and, N101S1: oxathiazine (C6).

Examples of substituted monocyclic heterocyclyl groups include those derived from: saccharides, in cyclic form, for example, furanoses (C5), such as arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse, and pyranoses (C6), such as allopyranose, altropyranose, glucopyranose, mannopyranose, gulopyranose, idopyranose, galactopyranose, and talopyranose.

Examples of (unsubstituted) heteroaryl groups and (unsubstituted) heterocyclic groups, that comprise fused rings, include those derived from: C9 groups (with 2 fused rings): benzofuran (01), isobenzofuran (0), indole (N1), isoindole (N1), indolizine (N1), indoline (N1), isoindoline (N1), purine (N4) (e.g., adenine, guanine), benzimidazole (N2), indazole (N2), benzoxazole (N101), benzisoxazole (N101), benzodioxole (02), benzofurazan (N201), benzotriazole (N3), benzothiofuran (S1), benzothiazole (N1 S1), benzothiadiazole (N2S); C10 groups (with 2 fused rings): chromene (0), isochromene (O), chroman (O), isochroman (0), benzodioxan (02), quinoline (N1), isoquinoline (N1), quinolizine (N1), benzoxazine (N101), benzodiazine (N2), pyridopyridine (N2), quinoxaline (N2), quinazoline (N2), cinnoline (N2), phthalazine (N2), naphthyridine (N2), pteridine (N4) ; C11 groups (with 2 fused rings): benzodiazepine (N2); WJW/LP6326342 -44 - C13heterocyclic groups (with 3 fused rings): carbazole (N1), dibenzofuran (0), dibenzothiophene (S1), carboline (N2), perimidine (N2), pyridoindole (N2); C14heterocyclic groups (with 3 fused rings): acridine (N1), xanthene (0), thioxanthene (S1), oxanthrene (02), phenoxathiin (01S1), phenazine (N2), phenoxazine (N101), phenothiazine (N1 S1), thianthrene (S2), phenanthridine (N1), phenanthroline (N2), phenazine (N2).

Heteroaryl groups and heterocyclic groups that have a nitrogen ring atom in the form of an -NH- group may be N-substituted, that is, as -NR-. For example, pyrrole may be N-methyl substituted, to give N-methylpyrrole. Examples of N-substitutents include, but are not limited to C17alkyl, C620carboaryl, C520heteroaryl, C320heterocyclyl, C620carboaryl- C17a1ky1, C520heteroaryl-C17a1ky1, C20heterocyclyl-C1.7alkyl, and acyl groups Heteroaryl groups and heterocyclic groups that have a nitrogen ring atom in the form of an -N= group may be substituted in the form of an N-oxide, that is, as -N(--+0) (also denoted -N(--*0)=). For example, quinoline may be substituted to give quinoline N-oxide; pyridine to give pyridine N-oxide; benzofurazan to give benzofurazan N-oxide (also known as benzofuroxan).

Cyclic groups (e.g., cylcoalkyl, cycloalkenyl, carboaryl, heteroaryl, heterocyclyl) may additionally bear one or more oxo (=0) groups on ring carbon atoms.

Monocyclic examples of such groups include those derived from: C5: cyclopentanone, cyclopentenone, cyclopentadienone; C6: cyclohexanone, cyclohexenone, cyclohexadienone; 0: furanone (C5), pyrone (C6); N1: pyrrolidone (pyrrolidinone) (C5), piperidinone (piperidone) (C6), piperidinedione (C6); N2: imidazolidone (imidazolidinone) (C5), pyrazolone (pyrazolinone) (C5), piperazinone (C6), piperazinedione (C6), pyridazinone (C6), pyrimidinone (C6) (e.g., cytosine), pyrimidinedione (C6) (e.g., thymine, uracil), barbituric acid (C6); N1S1: thiazolone (C5), isothiazolone (C5); N101: oxazolinone (C5).

Polycyclic examples of such groups include those derived from: C9: indenedione; WJW/LP6326342 -45 - C10: tetralone, decalone; C14: anthrone, phenanthrone; N1: oxindole (C9); 0: benzopyrone (e.g., coumarin, isocoumarin, chromone) (C10); N01: benzoxazolinone (C9), benzoxazolinone (C10); N2: quinazolinedione (C10); benzodiazepinone (C11); benzodiazepined lone (C1); N4: purinone (C9) (e.g. , guanine).

Still more examples of cyclic groups which bear one or more oxo (=0) groups on ring carbon atoms include those derived from: cyclic anhydrides (-C(=0)-O-C(=0)- in a ring), including but not limited to maleic anhydride (C5), succinic anhydride (C5), and glutaric anhydride (C6); cyclic carbonates (-0-C(=0)-0- in a ring), such as ethylene carbonate (C5) and 1,2-propylene carbonate (C5); imides (-C(=0)-NR-C(=0)- in a ring), including but not limited to, succinimide (C5), maleimide (C5), phthalimide, and glutarimide (C6); lactones (cyclic esters, -0-C(=0)- in a ring), including, but not limited to, 3-propiolactone, y-butyrolactone, O-valerolactone (2-piperidone), and c- caprolactone; lactams (cyclic amides, -NR-C(=0)- in a ring), including, but not limited to, 3-propiolactam (C4), y-butyrolactam (2-pyrrolidone) (C5), O-valerolactam (C6), and c-caprolactam (C7); cyclic carbamates (-0-C(=0)-NR- in a ring), such as 2-oxazolidone (C5); cyclic ureas (-NR-C(=0)-NR- in a ring), such as 2-imidazolidone (C5) and pyrimidine-2,4-dione (e.g., thymine, uracil) (C6).

Includes Other Forms Unless otherwise specified, a reference to a particular group also includes the well known ionic, salt, solvate, and protected forms thereof. For example, a reference to carboxylic acid (COOH) also includes the anionic (carboxylate) form (-COO), a salt or solvate thereof, as well as conventional protected forms. Similarly, a reference to an amino group includes the protonated form (-NHR1R2), a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group.

Similarly, a reference to a hydroxyl group also includes the anionic form (-0), a salt or solvate thereof, as well as conventional protected forms.

WJW/LP6326342 Isomers Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and I-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; aand 13-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").

Note that, except as discussed below for tautomeric forms, specifically excluded from the term "isomers," as used herein, are structural (or constitutional) isomers (i.e., isomers which differ in the connections between atoms rather than merely by the position of atoms in space). For example, a reference to a methoxy group, -OCH3, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C17alkyl includes n-propyl and isopropyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

The above exclusion does not pertain to tautomeric forms, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.

Iii ___,OH H -c-c c=c c=c I / H / \ keto enol enolate Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H (D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; 0 may be in any isotopic form, including 16Q and 18Q; and the like.

WJW/LP6326342 - 47 - Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof.

Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner. Salts

It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the active compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge eta!., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19.

For example, if the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO-), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na4 and K4, alkaline earth cations such as Ca24 and Mg2, and other cations such as Al43.

Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH44) and substituted ammonium ions (e.g., NH3R4, NH2R24, NHR34, NR44). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4.

If the compound is cationic, or has a functional group which may be cationic (e.g., -NH2 may be -NH3'), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.

Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, WJW1LP6326342 -48 - isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

Unless otherwise specified, a reference to a particular compound also includes salt forms thereof.

Solvates It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the active compound. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tn-hydrate, etc. Unless otherwise specified, a reference to a particular compound also includes solvate forms thereof.

Chemically Protected Forms It may be convenient or desirable to prepare, purify, and/or handle the active compound in a chemically protected form. The term "chemically protected form" is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like). In practice, well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

W.JW/LP6326342 - 49 - Unless otherwise specified, a reference to a particular compound also includes chemically protected forms thereof.

A wide variety of such "protecting," "blocking," or "masking" methods are widely used and well known in organic synthesis. For example, a compound which has two nonequivalent reactive functional groups, both of which would be reactive under specified conditions, may be derivatized to render one of the functional groups "protected," and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group may be "deprotected" to return it to its original functionality.

For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(=O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH3, -OAc).

For example, an aldehyde or ketone group may be protected as an acetal (RCH(OR)2) or ketal (R2C(OR)2), respectively, in which the carbonyl group (> C=O) is converted to a diether (>C(OR)2), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.

For example, an amine group may be protected, for example, as an amide (NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCOCH3); a benzyloxy amide (-NHCO-OCH2C6H5, -NH-Cbz); as a t-butoxy amide (NHCO-OC(CH3)3, -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc), as a 9- fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH- Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-Alloc), as a 2(phenylsulphonyl)ethyloxy amide (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>N-O.).

For example, a carboxylic acid group may be protected as an ester for example, as: an C7alkyl ester (e.g., a methyl ester; a t-butyl ester); a C17haloalkyl ester (e.g., a WJW1LP6326342 - 50 - C17trihaloalkyl ester); a triC17alkylsilyl-C1.7alkyl ester; or a C5. 20aryl-C1.7alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.

For example, a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC(=O) CH3).

Prodrugs It may be convenient or desirable to prepare, purify, and/or handle the active compound in the form of a prodrug. The term "prodrug," as used herein, pertains to a compound which, when metabolised (e.g., in vivo), yields the desired active compound. Typically, the prodrug is inactive, or less active than the active compound, but may provide advantageous handling, administration, or metabolic properties.

Unless otherwise specified, a reference to a particular compound also includes prodrugs thereof.

For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(0)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid groups (-C(=O)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.

Also, some prodrugs are activated enzymatically to yield the active compound, or a compound that, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.

Chemical Synthesis Several methods for the chemical synthesis of 1,5substituted-I H-tetrazole compounds are described herein. These and/or other well known methods may be modified and/or adapted in known ways in order to facilitate the synthesis of additional 1,5-substituted-I Htetrazole compounds and other compounds described herein, in accordance with WJW1LP6326342 - 51 - standard techniques, from readily available starting materials, and using appropriate reagents and reaction conditions.

In one approach, 1,5-substituted-I H-tetrazoles are synthesised from a substituted azide and an appropriate substituted nitrite. An example of such a method is illustrated in the following scheme.

Scheme 1 RN3 + RXCEN (X=O,S,N) In another approach, 5-substituted-I Htetrazoles are synthesised from sodium azide and an appropriate substituted nitrile in the presence of zinc ions. An example of such a method is illustrated in the following scheme.

Scheme 2

N-N

NaN3, ZnBr2 // \\ R-CEN N., H20, reflux N The resulting 5-substituted-i Htetrazoles may be further functionalised at the 1-position, for example, using an appropriate halide. An example of such a method is illustrated in the following scheme.

Scheme 3 R2 N-N Br N-N N,,, + R1 K2C03, DMF, EtOH N'R + N 95 C, hv R' R1 In another approach, 5-sulfanyl-iH-tetrazoles may be synthesised from approrpriately substituted isothiocyanates and sodium azide. An example of such a method is illustrated in the following scheme.

WJW/LP6326342 - 52 - Scheme 4 NaN3 N-N R1-N=CS R1 Additionally, 5-sulfanyl-l H-tetrazoles may be functionalised by nucleophillic substitution with a suitable halide (e. g., haloalkane). An example of such a method is illustrated in the following scheme.

Scheme 5

N-N N-N

N'SH + R2 Et3N, MeCN Additionally, 1-substituted-5-amino-1H-tetrazoles may be functionalised by nucleophillic substitution with a suitable halide (e.g., haloalkane). An example of such a method is illustrated in the following scheme.

Scheme 6 + L.R2 K2C03, MeCN, 6N HCI reflux, 10% pyridine/water Uses The 1,5- substituted-I H-tetrazole compounds, described herein, are useful, for example, in the treatment of conditions that are ameliorated by the inhibition of 11 3-hydroxysteroid dehydrogenase type I (1113-HSDI), as described herein.

Use in Methods of Inhibiting Ii 13-Hydroxysteroid Dehydrogenase Type I (11 13-HSDI) One aspect of the present invention pertains to a method of inhibiting 1 13-hydroxysteroid dehydrogenase type I in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a compound, as described herein.

WJW/LP6326342 - 53 - Suitable assays for determining 11 -hydroxysteroid dehydrogenase type 1 inhibition are described herein and/or are known in the art.

In one embodiment, the method is performed in vitro.

In one embodiment, the method is performed in vivo.

In one embodiment, the compound is provided in the form of a pharmaceutically acceptable composition.

Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g., bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.

One of ordinary skill in the art is readily able to determine whether or not a candidate compound inhibits 11 3-hydroxysteroid dehydrogenase type 1. For example, suitable assays are described herein.

For example, a sample of cells may be grown in vitro and a compound brought into contact with said cells, and the effect of the compound on those cells observed. As an example of "effect," the morphological status of the cells (e.g., alive or dead, etc.) may be determined. Where the compound is found to exert an influence on the cells, this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a patient carrying cells of the same cellular type.

Use in Methods of TheraDy Another aspect of the present invention pertains to a compound as described herein for use in a method of treatment of the human or animal body by therapy.

Use in the Manufacture of Medicaments Another aspect of the present invention pertains to use of a compound, as described herein, in the manufacture of a medicament for use in treatment.

WJW/LP6326342 - 54 - Methods of Treatment Another aspect of the present invention pertains to a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of a compound as described herein, preferably in the form of a pharmaceutical composition.

Conditions Treated - Conditions Ameliorated by the Inhibition of 1113Hydroxysteroid Dehydrogenase Type I In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment or prevention of a condition that is ameliorated by the inhibition of 11 3-hydroxysteroid dehydrogenase type 1.

Conditions Treated - Conditions characterised by Up-Regulation of 11 13HSDI etc. In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment or prevention of a condition that is characterised by one or more of: up-regulation of 11 13-HSDI; up-regulation of glucocorticoid receptor mediated pathways; elevated PEPCK levels; other biochemical markers pertaining to glucocorticoid excess and insulin resistance.

Conditions Treated In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment or prevention of one or more of the following: (1) Cushing's syndrome; (2) type 2 diabetes; (3) insulin resistance syndromes such as myotonic dystrophy, Prader Willi, etc; (4) obesity; (5) lipid disorders; (6) atherosclerosis and its sequelae, including myocardial infarction and peripheral vascular disease; (7) Metabolic Syndrome; (8) steatohepatitis/fatty liver; WJW/LP6326342 - 55 - (9) cognitive impairmentin type 2 diabetes, glucose intolerance and ageing, and in psychotic disorders and pre-schizophrenia; (10) dementias such as Alheimer's disease, multi-infarct dementia, dementia with Lewy bodies, fronto-temporal dementia (including Pick's disease), progressive supranuclear palsy, Korsakoffs syndrome, Binswanger's disease, HIV-associated dementia, Creutzfeldt-Jakob disease (CJD), multiple sclerosis, motor neurone disease, Parkinson's disease, Huntington's disease, Niemann-Pick disease type C, normal pressure hydrocephalus, and Down's syndrome; (11) mild cognitive impairment (cognitive impairment, no dementia); (12) 13-cell dysfunction in pancreatic disease; (13) glaucoma; (14) anxiety; (15) depression and other affective disorders; typical (melancholic) and atypical depression; dysthymia; post-partum depression; bipolar affective disorder; drug-induced affective disorders; anxiety; posttraumatic stress disorder; panic; phobias; (16) inflammatory disease; (17) osteoporosis; (18) myocardial infarction, for example, to prevent left ventricular dysfunction after myocardial infarction; and (19) stroke, for example, to limit ischaemic neuronal loss after cardiovascular accident.

In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment or prevention of one or more of the following: (1) hyperglycaemia; (2) glucose intolerance and impaired glucose tolerance; (3) insulin resistance; (4) hyperlipidaemia; (5) hypertriglyceridaemia; (6) hypercholesterolaemia; (7) low HDL levels; (8) high LDL levels; (9) vascular restenosis; (10) abdominal obesity; (11) neurodegenerative disease; (12) retinopathy; WJW/LP6326342 - 56- (13) neuropathy; (14) hypertension; and (15) other diseases where insulin resistance is a component.

In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment or prevention of the adverse effects of glucocorticoids used to treat inflammatory diseases, such as asthma, chronic obstructive pulmonary disease, skin diseases, rheumatoid arthritis, and other arthropathies, inflammatory bowel disease, and giant cell arthritis/polymyalgia rheumatica.

In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment or prevention of the metabolic syndrome, which includes conditions such as type 2 diabetes and obesity, and associated disorders including insulin resistance, hypertension, lipid disorders and cardiovascular disorders such as ischaemic (coronary) heart disease.

In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment or prevention of CNS conditions such as mild cognitive impairment and early dementia, including Alzheimer's disease.

Treatment The term "treatment," as used herein in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviatiation of symptoms of the condition, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e., prophylaxis, e.g., prevention) is also included. For example, use with patients who have not yet developed the condition, but who are at risk of developing the condition, is encompassed by the term "treatment." For example, treatment of metabolic syndrome includes the prophylaxis of metabolic syndrome, reducing the incidence of metabolic syndrome, alleviating the symptoms of metabolic syndrome, etc. WJW/LP6326342 - 57 - The term "therapeutically-effective amount," as used herein, pertains to that amount of an active compound, or a material, composition or dosage form comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.

Combination Therapies The term "treatment" includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously.

For example, the compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents, for example, cytotoxic agents, anticancer agents, etc. Examples of treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g., drugs, antibodies (e.g., as in immunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiation therapy; photodynamic therapy; gene therapy; and controlled diets.

For example, it may be beneficial to combine treatment with a compound as described herein with one or more (e.g., 1, 2, 3, 4, etc.) other agents or therapies.

The particular combination would be at the discretion of the physician who would select dosages using his or her common general knowledge and dosing regimens known to a skilled practitioner.

The agents (i.e., the compound described here, plus one or more other agents) may be administered simultaneously or sequentially; may be administered separately or together in a single formulation (e.g., in a single tablet or in separate tablets); and may be administered in individually varying dose schedules and via different routes. For example, when administered sequentially, the agents can be administered at closely spaced intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1, 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).

WJW/LP6326342 - 58 - The agents (i.e., the compound described here, plus one or more other agents) may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use, as described below.

Examples of additional agents/therapies that may be coadministered/combined with treatment with the 1,5-substituted-I Htetrazole compounds described herein include the following: (1) insulin and insulin analogues; (2) insulin sensitising agents, for example: PPAR-y-agonists; PPAR-a agonists; PPAR-ci/y dual agonists; biguanides; (3) incretin and incretin mimetics; (4) sulfonylureas and other insulin secretogogues; (5) a-glucosidase inhibitors; (6) glucagon receptor antagonists; (7) GLP-1, GLP-I analogues, and GLP-receptor agonists; (8) GIP, GIP mimetics, and GIP receptor agonists; (9) PACAP, PACAP mimetics, and PACAP receptor 3 agonists; (10) agents that suppress hepatic glucose output, such as metformin; (11) agents designed to reduce the absorption of glucose from the intestine, such as acarbose; (12) phosphotyrosine phosphatase lB inhibitors; (13) glucose 6-phosphatase inhibitors; (14) gluokinase activators; (15) g lycogen phosphorylase inhibitors; (16) fructose 1,6-biphosphatase inhibitors; (17) glutamine:fructose-6-phosphate amidotransferase inhibitors; (18) anti-obesity agents, including: orilistat, sibutramine, fenfluramine, phentermine, dexfenfluramine, cannabinoid CB1 receptor antagonists or inverse agonists, ghrelin antagonists, neuropeptide Yl or Y5 antagonists, melanocortin receptor agonists, and melanin-concentrating hormone receptor antagonists; (19) anti-dyslipidaemia agents, including: HMG-CoA reductase inhibitors, PPAR-a agonists, PPAR-a/y dual agonists, bile acid sequestrants, ileal bile acid absorption inhibitors, acyl CoA:cholesterol acyltransferase inhibitors, cholesterol absorption WJW/LP6326342 - 59 - inhibitors, cholesterol ester transfer protein inhibitors, nicotinyl alcohol and its analogues, and anti-oxidants; (20) anti-inflammatory agents, including: non-steroidal anti-inflammatory drugs such as aspirin; and steroidal anti-inflammatory agents such as hydrocortisone and dexamethasone; (21) anti-hypertensive agents, including: 13-blockers such as atenolol and inderal; calcium antagonists such as nifedipine; ACE inhibitors such as lisinopril, aptopril and captopril; angiotensin receptor antagonists such as candesartan, losartan and cilexetil; diuretic agents such as furosemide and benzthiazide; and a-antagonists.

Other Uses The compounds described herein may also be used as cell culture additives to inhibit 11 3-hydroxysteroid dehydrogenase type 1 (11 13-HSD1), etc. The compounds described herein may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.

The compounds described herein may also be used as a standard, for example, in an assay, in order to identify other active compounds, other 11 3-hydroxysteroid dehydrogenase type 1 (1113-HSD1) inhibitors, etc. Kits One aspect of the invention pertains to a kit comprising (a) an active compound as described herein, or a composition comprising an active compound as described herein, e.g., preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the active compound or composition.

The written instructions may also include a list of indications for which the active ingredient is a suitable treatment.

WJW/LP6326342 - 60 - Routes of Administration The active compound or pharmaceutical composition comprising the active compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).

Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

The Subiect/Patient The subject/patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a monotreme (e.g., duckbilled platypus), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g. , a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human.

Furthermore, the subject/patient may be any of its forms of development, for example, a foetus.

In one preferred embodiment, the subject/patient is a human.

Formulations While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) WJW/LP6326342 61 - comprising at least one active compound, as defined above, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents. The formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.

Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one active compound, as defined above, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the active compound.

The term "pharmaceutically acceptable" as used herein pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 2nd edition, 1994.

The formulations may be prepared by any methods well known in the art of pharmacy.

Such methods include the step of bringing into association the active compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with carriers (e. g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.

WJW/LP6326342 - 62 - The formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof.

Formulations may suitably be in the form of liquids, solutions (e.g., aqueous, non- aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil- in-water, water- in-oil), elixirs, syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, losenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols.

Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like which is impregnated with one or more active compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in the form of a depot or reservoir.

The active compound may be dissolved in, suspended in, or admixed with one or more other pharmaceutically acceptable ingredients. The active compound may be presented in a liposome or other microparticulate that is designed to target the active compound, for example, to blood components or one or more organs.

Formulations suitable for oral administration (e.g., by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.

Formulations suitable for buccal administration include mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Losenges typically comprise the active compound in a flavored basis, usually sucrose and acacia or tragacanth. Pastilles typically comprise the active compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia. Mouthwashes typically comprise the active compound in a suitable liquid carrier.

Formulations suitable for sublingual administration include tablets, losenges, pastilles, capsules, and pills.

WJW/LP6326342 - 63 - Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil- in-water, water-in-oil), mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.

Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.

Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.

Tablets may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl phydroxybenzoate, sorbic acid); flavours, flavour enhancing agents, and sweeteners. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach.

Ointments are typically prepared from the active compound and a paraffinic or a water- miscible ointment base.

WJW/LP6326342 - 64 - Creams are typically prepared from the active compound and an oil-in- water cream base.

If desired, the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-I,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. The topical formulations may desirably include a compound that enhances absorption or penetration of the active compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.

Emulsions are typically prepared from the active compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax, and the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.

Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for intranasal administration, where the carrier is a liquid, include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the active compound.

WJW/LP6326342 - 65- Formulations suitable for intranasal administration, where the carrier is a solid, include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.

Formulations suitable for pulmonary administration (e.g., by inhalation or insufflation therapy) include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichorotetrafluoroethane, carbon dioxide, or other suitable gases.

Formulations suitable for ocular administration include eye drops wherein the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound.

Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active compound, such carriers as are known in the art to be appropriate.

Formulations suitable for parenteral administration (e.g., by injection), include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the active compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate). Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient.

Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.

Typically, the concentration of the active compound in the liquid is from about I ng/ml to about 10 pg/mI, for example from about 10 ng/ml to about I pg/mI. The formulations may WJW/LP6326342 - 66 - be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

Dosage It will be appreciated by one of skill in the art that appropriate dosages of the active compounds, and compositions comprising the active compounds, can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient. The amount of compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action that achieve the desired effect without causing substantial harmful or deleterious side-effects.

Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.

In general, a suitable dose of the active compound is in the range of about 100 pg to about 250 mg (more typically about 100 pg to about 25 mg) per kilogram body weight of the subject per day. Where the active compound is a salt, an ester, an amide, a prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.

WJW/LP6326342 - 67 -

EXAMPLES

The following are examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.

In the following examples, molecules with a single chiral centre, unless otherwise noted, were provided, prepared, or obtained as a racemic mixture of enantimomers. Individual enantiomers/diastereomers may be obtained using well known methods.

Temperatures are quoted in degrees Celcius. Unless otherwise indicated, all evaporations are performed under reduced pressure, preferably between about 15 and mm Hg (-20-133 mbar). The structures of the final products, intermediates, and starting materials are confirmed by standard analytical methods, e.g., microanalysis, melting point, and spectroscopic analysis (e.g., MS, IR, NMR). The abbreviations used are conventional in the art.

Example I

Synthesis of I -phenyl-2-(1 -phenyl-1 H-tetrazol-5-yI-sulfanyl)-ethanone NYL_SH BrJ( MeOH, MeONa 0.045 g (0.0011 mol) of NaOH was dissolved in 5 mL of MeOH. After cooling, 0.178 g (0.001 mol) of 1-phenyl-IH-tetrazole-5-thiol was added to the solution. 0. 2 g (0.001 mol) of phenacylbromide was added to reaction mixture and the reaction mixture heated at 60 C for 4 hours. After cooling, the solution was poured into water, and the white precipitate formed was filtered off, thoroughly washed with water, and recrystallized from EtOH (yield 67%, mp = 150 C). NMR: 5.1 (2H, s, CH2), 7.5 (2H, t, 5+3HR1), 7.55-7.7 (6H, m, 5HR+4-HR1), 8.1 (2H, d, 2+ 6-HR1); mlz: 297 [M+1J. By analogous methods, and using appropriate starting materials, the

following compounds were also prepared: WJW/LP6326342 - 68 - Ex Structure 1H NMR MS[m/z] 1.25(9H,s, 3CH3), [M+1]

NI

4.65(2H,s, CH2), 7.5- 1-1 7.7(5H, m, 5HR) 277 [M+1] 1-2 235 N s,tL,,JZj1 3.8(2H,s,CH2Ph), 4.5(2H,s, [M+1] 1-3 N' CH2), 7.1-7.4(5H, m, Hph), 7.6(5H, s, HcH2ph) 311 (j 3.8(3H,s, OCH3), 5.1(2H,s, N' CH2), 7.1(2H, d, 3+5-HR1), [M+1] 1-4 LL 7.7(5H, m, 5-HR), 8.1(2H, 327 d, 2+6-HR1) 5.1(2H,s, CH2), 7.4(1H, t, N' HR1), 7.5-7.7(6H, m, [M+1] 1-5 -N 5HR+1HR1), 7.75(IH, d, 6329 HR1), 7.9(1H, d, 2-HRI) N(I" 5.1(2H, s, CH2), 7.4(1H, m, [M+1] 1-6 LF HR1), 7.5-7.7(5H, m, 5HR), 7.9-8.1(2H, m, 2HR1) 2.1(3H,s, CH3), 3.8(3H, s, OCH3), 3.85(3H,s,OCH3), N' 5.1(2H,s, CH2), 7. 1(2H, d, [M+1] 1-7 5-HR1), 7.4-7.75(5H, m, 371 4HR+2HR1), 7.75(1 H, d, 6- HR1) WJW/LP6326342 - 69 Ex Structure 1H NMR MS[m/z] 2.4(3H,s, OH3), 3.6(3H, s, OCH3), 3.7(3H, s, 00H3), N' 5.1(2H, s, OH2), 7. 1(2H, d, [M+1] 1-8 2HR1), 7.4(2H, d, HR), 371 7.5(IH, s, H), 7.6(2H, d, HR), 7.7(1H, d, HR1) 2.1(3H,s, CH3), 2.4(3H,s, o CH3), 3.6(3H, s, OCH3), N'1'11T1J 3.7(3H,s, 00H3), 5.1 (2H,s, [M+1] OH2), 7.1(2H, d, 2HR1), 1-9 7.3(3H, d+s, HR1+HR), 7.5(IH, s, HR), 7.7(IH, d, HR1) 3.6(3H, s, 00H3), [M+1] 3NOH3), 4.9(2H,s, OH2), 1-10 NT1J 3.7(3H,s,OCH3), 4.1(3H,s,

- N

7.1(IH, d, 5-HR1), 7.5(IH, s, 2-H), 7.7(1H, d, 6-HR1) 1.65(9H, s, 3OH3), 3.6(3H, 1-11 NTI1I s, 00H3), 3.7(3H,s,00H3), [M+1] 5.2(2H,s, OH2), 7.1(IH, d, 5-HR1), 7.5(IH, s, 2-H), 7.7(1H, d, 6-HR1) 1.5(6H, d, 2OH3), 3.6(3H, 0 s, OOH3), 3.7(3H,s,00H3), 1-12 N'( _NiiiiIh1I; 4.75(1H, m, OH), 5.0 (2H,s, [M+1] CH2), 7.1(IH, d, 5-HR1), 323 7.5(IH, s, 2-HR1), 7.7(1H, d, 6-HR1) WJW!LP6326342 - 70 - Ex Structure 1H NMR MS[m/z] 3.6(3H, s, OCH3), o 3.7(3H,s,OCH3), 5.0 (2H,s, CH2), 5.7 (2H,s, CH2R),

NI

1-13 7.1(IH, d, 5-HR1), 7.3(IH, [M+1] d, HR), 7.4(3H, m, HR), 7.5 (IH, s, HR1), 7.7(1H, d, 6- HR1) 3.6(3H, s, OCH3), 3.7(3H,s,OCH3), 5.0 (2H,s, N'i""Tc( CH2), 5.7 (2H,s, CH2R), [M+1]

- N

7.0(2H, m, HR+5-HR1), 1-14 7.25(1 H, s, 2-HR1), 7.4(1H, m, HR1), 7.6 (IH, s, HR), 7.7(IH, d, 6HRI) 1.05(1H, m, HCH2), 1.49(2H, m, CH2), o 1.6(IH,m, HCH2), 1.75(4H,m, CH2), 2.1(2H, N N( [M+1] m, HCH2), 3.6(3H, s, OCH3), 1-15 3.7(3H,s,OCH3), 4.4(IH, m, CH), 5.0 (2H,s, CH2), 7.1(IH, d, 5HR1), 7.5(IH, s, 2HR1), 7.7(IH, d, 6HR1) By analogous methods, and using appropriate starting materials, the following compounds were also prepared: Ex Structure MS[m/z] Ex Structure MS[m/z] [M+1] N 1-16 1-40 N 305 [M+1] F 361 WJW/LP6326342 Ex Structure MS[m/z] Ex Structure MS[m/z] 1-17 [M+1] NS [M+1] 1-41 NN 319 325 1-18 [M+1] (M+1] 7 - 1-42 215 347 [M+1] N' [M+1] Br 396 375 1-19 N_li s 1-43 1-20 S 1-44 sN02 [M+1] EM+1]+ N

NN

Br 396 N'q [M+1] 1-45 [M+1] CI 352 NN 1-21 327 1-46 NN 7 0> 1-22 [M+1] [M+1] 369 341 1-23 [M+1] 1-47 [M+1] 371 396 + N_S 1-24 [M+1] - N' [M+1] 1 48 -N N0 357 382 [M+1] 1-49 [M+1] 1-25 -N 7 371 \N) 396 WJW/LP6326342 - 72 - Ex Structure MS[m/z] Ex Structure MS[m/zl

F

[M+1] [M+1] 1-26 1-50 NN CN 329 366 o- N'C [M+1] 1-51 N' [M+1] 1-27 329 CI 332 [M+1] [M+1] 1-28 -N F 1-52 315 N\ N02 356 1-29 N_NF [M+1] 1-53 N' [M+1] F 347 371 [M+1] [M+1] 1-54 1-30 374 N'11 [M+1] 1-55 [M+1] 1-31 390 N [M+1] N [M+1] 1-32 k-N 1-56 249 249 1-33 [M+1] 1-57 N( [M+1]

-N

287 303 NSN\ - [M+1] [M+1] 1-34 N\ 370 1-58 342 WJW/LP6326342 - 73 - Ex Structure MS[m/z] Ex Structure MS[m/z] 1-59 [M+l] 1-35 [M+1] (M+l] ,N S(O [M+1]

N N(

1-36 -N F 1-60 NS11 [M+1J [M+1] 1-37 -u 1-61 367 416

F

1-38 [M+1] [M+1] 1-62 N 387 NN _-tr FIF [M+ I] 1 63 / [M+1] 1-39 N\\ N-N 365 - NN -

Example 2

Synthesis of 1 -(4-fluoro-phenyl)-4-(1 -m-tolyl-1 H-tetrazol-5-ylsulfanyl)-butan-1 -one

N-N

N-N

NSH + MeONa N N 0 0.045 g (0.0011 mol) of NaOH was dissolved in 5 mL of MeOH. After cooling, 0.178 g (0.001 niol) of 1-m-tolyl-IH-tetrazole-5-thiol was added to the solution. 0.2 g (0.001 mol) of 4-chloro-1-(4-fluoro-phenyl)-butan-1-one was added to reaction mixture. The reaction mixture was heated at 60 C for 6 hours. After cooling, the mixture was poured into water, and the white precipitate filtered off, thoroughly washed with water, and recrystallized from i-PrOH (yield 51%, m.p. 134 C). mlz: 357 (M+1).

WJW!LP6326342 - 74- By analogous methods, and using appropriate starting materials, the following compounds were also prepared: Ex Structure MS[m/z] Ex Structure MS(m/z] 2..1 [M+1] 2-2 [M+1]

Example 3

Synthesis of I -(dimethyl-phenyl)-5-(tetrahydro-pyran-2-yl-methylsulfanyl)-1 H-tetrazole N'SH BrY ) MeOH, MeONa 0.045 g (0.0011 mol) of NaOH was dissolved in 5 mL of MeOH. 0.206 g of 1-(2,4-dimethylphenyl)-IH-tetrazole-5-thiol was added to the resulting solution and 0.180 g (0.001 mol) of 2-(bromomethyl)tetrahydro-2H-pyran added with caution. The reaction mixture was stirred for 2 hours at 60 C, and then poured into water. The resulting oil was extracted with dichloromethane and extracts washed with Na2CO3 solution and water. After evaporation of solvent in vacuo, the target compound was obtained as a yellow oil (yield 45%). mlz: 305 (M+1).

Example 4

Synthesis of 1 -[1 -(2,4-dimethyl-phenyl)-1 H-tetrazole-5-sulfinyl]-3, 3dimethyl-butan-2-one and 1 -[1 -(2,4-dimethyl-phenyl)-1 H-tetrazole-5sulfonyl]-3,3-dimethyl-butan-2-one KHSO5 ____ aq. MeOH.

To a solution of sulfide (4) (50 mg, 0.16 mmol) in methanol (5 mL) at 0 C was added a solution of oxone (295 mg, 0.48 mmol, 3 eq.) in water (5 mL). The resulting cloudy suspension was stirred for 18 hours at room temperature and then diluted with water and extracted with CHCI3 (3 x 10 mL). The combined organic layers were washed with water, WJW/LP6326342 75 - then brine, and then dried over MgSO4. Concentration in vacuo followed by flash column chromatography (Si02, Hex/Et20 40:60) afforded the desired sulfone (2) (31.7 mg, 59% yield) as a white solid, followed by the sulfoxide (1) (12.8mg, 25% yield) as a colourless oil.

Ex Structure 1H NMR MS[m/z] o o 1.26 (9H s, 3CH3) 2.17 (3H, S, 4 1 CH3), 2.48 (3H, s, CH3), 4.7 (IH, [M-1] - d, CH), 5.3 (IH, d, CH), 7.2-7.4 319 (3H, m, Hph) a 1.29 (9H, 5 3CH3) 2.16 (3H, s, 4 2 CH3), 2.45 (3H, s, CH3), 4.62 [M-1] - (2H, s, CH2), 7.2-7.3 (3H, m, 335 Biological Methods - Enzyme Inhibition Assay Compounds were assessed by a Scintillation Proximity Assay (SPA) performed according to the following protocol: HEK293 cells were stably tansfected with a construct containing full-length human 11 3-HSD1 enzyme to create HEK293/1 I 3-HSD1 cells. Cells were routinely cultured in DMEM containing 10% calf foetal serum, 1% glutamine, and 1% penicillin and streptomycin. Prior to assay, cells were plated at 2 x io cells/well in 96-well poly-D-Lys coated flat-bottomed microplates and incubated in 5% C02, 95% 02 at 37 C for 24 hours.

The media in each well was removed immediately before assay.

Compounds to be tested were dissolved in DMSO at 10 mM and serially diluted into water containing 10% DMSO. Diluted compounds at a volume of 10 pL were added to wells of a 96-well V-bottomed microplate. A solution of DMEM, 1% glutamine, 1% penicillin and streptomycin, and 22 nM tritiated cortisone was prepared and 90 pL added to each well of the assay plate. This solution (100 pL/well) was transferred to the plate containing the cells. The plate was then incubated in 5% C02, 95% 02 at 37 C for 2 hours.

Following this incubation, 50 pL of the assay solution was transferred to each well of a 96-well scintillation microplate. A mixture consisting of anti-mouse YSi SPA beads, WJW1LP6326342 - 76- pre-mixed with anti-cortisol antibody in assay buffer (50 mM Tris.HCI, pH 7.0; 300 mM NaCI; 1 mM EDTA, 5% glycerol) was prepared and 50 pL added to each well of the scintillation microplate. An adhesive strip was applied to the microplate and the plate gently shaken for at least 2 hours at room temperature, and then spun briefly on a low speed centrifuge. The plate was read on a scintillation counter suitable for 96-well microplates. For the calculation of percentage inhibition, a series of wells were added to the plate that represented the assay maximum and the assay minimum: one set that contained substrate without cells (mimimum) and another set that contained substrate and cells without any compound (maximum).

The calculation of median inhibitory concentration (IC50) values for the compounds was performed using GraphPad Prism software. Dose-response curves for each compound were plotted as fractional inhibition and data fitted to the four parameter logistic equation.

For measurement of inhibition of 11 13-HSD2, CHO cells stably transfected with full-length 11 3-HSD2 were used. Assays were carried out in 96-well microplates containing I x I 0 cells/well. Controls and compounds were plated as above, so that the final DM80 concentration in each well was 1%. To initiate the assay, 90 pL of a solution of HAMS F-12 medium containing 1% glutamine, 1% penicillin and streptomycin, and 22 nM tritiated cortisol was added to each well of the assay plate. The plate was then incubated in 5% C02, 95% 02 at 37 C for 16 hours. Enzyme activity was assessed by SPA as described above. IC50 values for inhibitors were determined as described for Ii 13-HSD1.

Biological Data The 1,5-substituted-i H-tetrazole compounds of the present invention generally have an IC50 of less than about 10 pM, and in many cases less than about 100 nM. Generally, the 1050 ratio for ii 13-HSD2 to ii 13-HSD1 is at least about two or greater, and in many cases about ten or greater. In some cases, the IC50 ratio for ii 3-HSD2 to ii 13-HSD1 is about 100 or greater. For example, the following results were obtained: Example lC50for 1i-HSDi lC for 11f3-HSD2 1-17 i73nM >i00000nM 1-24 93nM >l00000nM 2-i l5OnM >l00000nM !VJW/LP6326342 - 77 - The foregoing has described the principles, preferred embodiments, and modes of operation of the present invention. However, the invention should not be construed as limited to the particular embodiments discussed. Instead, the above-described embodiments should be regarded as illustrative rather than restrictive, and it should be appreciated that variations may be made in those embodiments by workers skilled in the art without departing from the scope of the present invention.

Andrews, R.C., et al., 2003, "Effects of the Ilbeta-hydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with type 2 diabetes," J. Clin. Endocrinol. Metab., Vol. 88, pp. 285-291.

Christy, C., et at., 2003, "Glucocorticoid action in mouse aorta; localisation of 11 13-hydroxysteroid dehydrogenase type 2 and effects on responses to glucocorticoids in vitro," Hypertension, Vol. 42, pp. 580-587.

Cooper, M.S., et al., 2000, "Expression and functional consequences of 11 3-hydroxysteroid dehydrogenase activity in human bone," Bone, Vol. 27, pp. 375-381.

Hadoke, P.W.F., et at., 2001, "Endothelial cell dysfunction in mice after transgenic knockout of type 2, but not type 1, 11 3-hydroxysteroid dehydrogenase," Circulation, Vol. 104, pp. 2832-2837.

Kotelevtsev, Y.V., et al., 1997, "113-Hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid inducible responses and resist hyperglycaemia on obesity and stress," Proc. Nati. Acad. Sci., Vol. 94, pp. 14924-14929 Masuzaki, H., et al., 2001, "A Transgenic Model of Visceral Obesity and the Metabolic Syndrome," Science, Vol. 294, pp. 21662170.

Moisan, M. P., et al., 1990, "11 beta-hydroxysteroid dehydrogenase bioactivity and messenger RNA expression in rat forebrain: localization in hypothalamus, hippocampus, and cortex," Endocrinology, Vol. 127, pp. 1450-1455.

Morton, N.M., et al., 2001, "Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11 3-hydroxysteroid dehydrogenase type 1 null mice," J. Biol. Chem., Vol. 276, pp. 41 29341300.

Morton, N.M., et al., 2004, "Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11 3-hydroxysteroid dehydrogenase type 1 deficient mice," Diabetes, Vol. 53, pp. 931-938.

WJW1LP6326342 - 78 - Paterson, J.M., et al., 2004, "Metabolic syndrome without obesity: hepatic overexpression of 11 3-hydroxysteroid dehydrogenase type I in transgenic mice," Proc. NatI. Acad. Sci., Vol. 101, pp. 7088-7093).

Rask, E., et al., 2001, "Tissue-specific dysregulation of cortisol metabolism in human obesity," J. Clin. Endocrinol. Metab., Vol. 86, pp. 141 8-1421.

Rauz, S., et al., 2001, "Expression and putative role of 11 betahydroxysteroid dehydrogenase isozymes within the human eye," Investigative Opthalmology & Visual Science, Vol. 42, pp. 2037-2042.

Sandeep, T.C., et al., 2004, "113-hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics," Proc. Nati. Acad. Sd., Vol. 101, pp. 6734-6739.

Seckl, J.R., Walker, B.R., 2001, "113-Hydroxysteroid dehydrogenase type 1 - a tissue- specific amplifier of glucocorticoid action," Endocrinology, Vol. 142, pp. 1371-1 376.

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Claims (67)

WJW1LP6326342 - 79 - CLAIMS

1. A compound of the following formula: w5 3N NN\ 1

W

wherein: one of W1 and W5 is a group -J-L-Q; and the other of W' and W5 is a group Z; wherein: Z is independently -H or R; J is independently: -S- , -S(=O)-, -S(=O)2-, -0-, NRNJ, or -CH2-; with proviso that if: W1 is -JL-Q, then: J is -S-, -S(0)2-, -CH2-, or -C(=0)-; wherein: RNJ is independently -H or RN; and if J is -CH2-, it is independently unsubstituted or substituted; L is independently C16alkylene; and is independently unsubstituted or substituted; Q is independently selected from: -C(0)OR; R6 P4 WJW1LP6326342 - 80 - NRC(=O)RA2; C(=O)NRN2RN3; NRN4C(O)NRN5R6; NRN7C(O)ORE2; C614carboaryl, and is independently unsubstituted or substituted; C514heteroaryl, and is independently unsubstituted or substituted; C12cycIoalkyl, and is independently unsubstituted or substituted; C12cycloalkenyl, and is independently unsubstituted or substituted; C312heterocyclic, and is independently unsubstituted or substituted; -H; wherein: each of R3, R4, R5, and R6 is independently -H or a monovalent additionally, R3 and R4, or R4 and R5, or R5 and R6, taken together with the carbon atoms to which they are attached, optionally form a benzene ring fused to the tetrahydropyran-2-yl ring; each of R', RA2, REI, and RE2 is independently R ; each of RN1, RN2, RN3, RN4, RN5, RN6, and RN7 is -H or RN; additionally, RN2 and RN3, taken together with the nitrogen atom to which they are attached, optionally form a ring having from 3 to 7 ring atoms, which may itself be fused to another ring; WJWIL.P6326342 - 81 - additionally, RN5 and RN6, taken together with the nitrogen atom to which they are attached, optionally form a ring having from 3 to 7 ring atoms, which may itself be fused to another ring; additionally, RN1 and RA2, taken together with the >N-C(=O)group to which they are attached, optionally form a ring having from 5 to 7 ring atoms, which may itself be fused to another ring; additionally, RN7 and RE2, taken together with the >N-C(=O)-O- group to which they are attached, optionally form a ring having from 5 to 7 ring atoms, which may itself be fused to another ring; additionally, RN4 and RNS, taken together with the >N-C(=O)-N< group to which they are attached, optionally form a ring having from 5 to 7 ring atoms, which may itself be fused to another ring; each RN is independently selected from: R and -C(=O)R; each R is independently selected from: C17alkyl; C27alkenyl; C27alkynyl; C12cycloalkyl; C312cycloalkenyl; C614carboaryl; C14heteroaryl; C31 2heterocyclic; C614carboaryl-C17alkyl; C514heteroaryl-C17alkyl; C312heterocyclic- C17alkyl; and is independently unsubstituted or substituted; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, N- oxides, chemically protected forms, and prodrugs thereof.

WJW1LP6326342 - 82 -

2. A compound according to claim 1, wherein W5 is a group -J-L-Q, and W is a groupZ: 2i\

3. A compound according to claim 1, wherein W1 is a group -J-L-Q, and W5 is a group Z: NNN7" 21\

J-L-Q

4. A compound according to claim 1, wherein: W5 is -J-L-Q; and J is independently: -S-, -S(=O)-, -S(=O)2-, -0-, or NRN.

5. A compound according to claim 1, wherein: W5 is -J-L-Q; and J is independently: -S-, -S(=O)-, -S(=0)2-, or -0-.

6. A compound according to claim 1, wherein: W5 is -J-L-Q; and J is independently: -S-, -S(=O)-, or -S(=O)2-.

7. A compound according to claim 1, wherein: W5 is -J-L-Q; and J is independently: -S- or -0-.

8. A compound according to claim 1, wherein: W1 is -J-L-Q; J is independently: -S(=O)2- or -CH2-; and if J is -CH2-, it is independently unsubstituted or substituted.

WJW/LP6326342 - 83 -

9. A compound according to claim 1, wherein: W1 is -J-L-Q; and J is independently: -S(=O)2-.

10. A compound according to claim 1, wherein: W1 is -J-L-Q; and J is independently: -CH2-, and is independently unsubstituted or

11. A compound according to any one of claims 1 to 4, wherein RNJ, if present, is independently -H or -Me.

12. A compound according to any one of claims 1 to 11, wherein if J is CH2-, it is independently unsubstituted or substituted with one or more substituents selected from: methyl, ethyl, n-propyl, i-propyl, t-butyl; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; phenyl, benzyl; nitrile, methyl nitrile; hydroxy, hydroxymethyl, hydroxyethyl.

13. A compound according to any one of claims 1 to 12, wherein L is independently C14alkylene, and is independently unsubstituted or substituted.

14. A compound according to any one of claims 1 to 12, wherein L is independently -(CH2)k-, where k is independently 1, 2, 3, or 4, wherein each -CH2- unit is independently unsubstituted or substituted.

15. A compound according to any one of claims ito 12, wherein L is independently -(CH2)k-, where k is independently 1, 2, 3, or 4, wherein each -CH2- unit is independently unsubstituted or substituted with one or more substituents selected from: C17a1ky1; phenyl, unsubsituted or substituted with 1, 2, or 3 C17alkyl groups; (e.g., tolyl, xylyl, mesitylyl, cymenyl) 1fJW/LP6326342 - 84 - benzyl, unsubsituted or substituted with 1, 2, or 3 C17a1ky1 groups; (e.g., tolyl-methyl; xylyl-methyl; mesitylyl-methyl; cymenyl-methyl) C514heteroaryl, unsubsituted or substituted with 1, 2, or 3 C17a1ky1 groups; (e.g., furanyl, thiophenyl, I H-pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, or thiadiazole, each unsubsituted or substituted with 1, 2, or 3 C17a1ky1 groups).

16. A compound according to any one of claims 1 to 12, wherein L is independently -(CH2)-, -(CH2)2-, -(CH2)3-, or -(CH2)4-.

17. A compound according to any one of claims ito 12, wherein L is independently -(CH2)3-.

18. A compound according to any one of claims ito 12, wherein L is independently -(CH2)2-.

19. A compound according to any one of claims I to 12, wherein L is independently -(CH2)-.

20. A compound according to any one of claims Ito 19, wherein: Q is C(O) RAt, wherein: RAI is independently R. WJW/LP6326342 - 85 -

21. A compound according to any one of claims I to 19, wherein Q is independently se'ected from the following, which may be unsubstituted or substituted: Hj

NH

22. A compound according to any one of claims I to I 9, wherein: Q is C(=O)OR, wherein: REI is independently R .

WJW1LP6326342 - 86 -

23. A compound according to any one of claims Ito 19, wherein Q is independently selected from the following, which may be unsubstituted or substituted: jo joc 1jo

24. A compound according to any one of claims I to 19, wherein Q is: R6 i P4 wherein: each of R3, R4, R5, and R6 is independently -H or a monovalent additionally, R1 and R2, or R2 and R3, or R3 and R4, taken together with the carbon atoms to which they are attached, optionally form a benzene ring fused to the tetrahydropyran-2-yl ring, which benzene ring itself is independently

25. A compound according to claim 24, wherein Q is independently selected from the following: (R) wherein: each x is independently 0, 1, 2, 3, or 4; and each RPB, if present, is independently a substituent.

WJW1LP6326342 - 87 -

26. A compound according to claim 25, wherein each RPB is independently selected from: (3) aminoacyl or aminothioacyl; (5) halo; (9) ether; (15) acylamino or thioacylamino; (21) C520carboaryl-C17a1ky1 or C520heteroaryl-C17a1ky1; (22) C520carboaryl or C5.20heteroaryl.

27. A compound according to claim 25, wherein each R8 is independently selected from: -F, -Cl, -Br; -OMe, -OEt, -Ph, -Ph-F; -Me, -Et; -C(0)NMe2, -(CO)morpholino; -NMe(C=O) Ph, pyridyl, furanyl.

28. A compound according to claim 24, wherein Q is independently:

29. A compound according to claim 24, wherein Q is independently:

30. A compound according to any one of claims I to 19, wherein: Q is NRC(=O)RA2, wherein: RNI is independently -H or RN; R is independently R; and WJW1LP6326342 88 - additionally, RNl and RA2, taken together with the >N-C(=O)- group to which they are attached, optionally form a ring having from 5 to 7 ring atoms (e.g., pyrrolidino, piperidino, piperazino, morpholino), which may itself be fused to another ring (e.g., a benzene ring, a pyridine ring).

31. A compound according to any one of claims I to 19, wherein Q is independently selected from the following, which may be unsubstituted or substituted: H1J3 Hx0 LiQ

32. A compound according to any one of claims ito 19, wherein Q is independently selected from the following, which may be unsubstituted or substituted: VNqQ

33. A compound according to any one of claims 1 to 19, wherein: Q is C(=O) NRN2RN3, wherein: each of RN2 and RN3 is independently -H or RN; and additionally, RN2 and RN3, taken together with the nitrogen atom to which they are attached, optionally form a ring having from 3 to 7 ring atoms (e.g., azetidino, pyrrolidino, piperidino, piperazino, morpholino), which may itself be fused to another ring (e.g., a benzene ring, a pyridine ring).

VJW!LP6326342 - 89 -

34. A compound according to any one of claims ito 19, wherein Q is independently selected from the following, which may be unsubstituted or substituted:

NH O

35. A compound according to any one of claims ito 19, wherein: Q is NRN4C(=O)NRNSRtl6, wherein: each of RN4, RN5, and RNS is -H or RN; additionally, RNS and RN6, taken together with the nitrogen atom to which they are attached, optionally form a ring having from 3 to 7 ring atoms (e.g., azetidino, pyrrolidino, piperidino, piperazino, morpholino), which may itself be fused to another ring (e.g., a benzene ring, a pyridine ring); and additionally, RN4 and RNS, taken together with the >N-C(=O)-N< group to which they are attached, optionally form a ring having from 5 to 7 ring atoms (e.g., pyrrolidino, piperidino, piperazino, morpholino), which may itself be fused to another ring (e.g., a benzene ring, a pyridine ring).

36. A compound according to any one of claims ito 19, wherein Q is independently selected from the following, which may be unsubstituted or substituted: 9H

37. A compound according to any one of claims Ito 19, wherein: Q is NRN7C(=O)QRE2, wherein: RN7 is -H or RN; RE2 is independently R ; and WJW/LP6326342 - 90 - additionally, RN7 and RE2, taken together with the >N-C(=O)-O- group to which they are attached, optionally form a ring having from 5 to 7 ring atoms (e.g., pyrrolidino, piperidino, piperazino, morpholino), which may itself be fused to another ring (e.g., a benzene ring, a pyridine ring).

38. A compound according to any one of claims 1 to 19, wherein Q is independently selected from the following, which may be unsubstituted or substituted:

39. A compound according to any one of claims Ito 19, wherein Q is selected from: C614carboaryl, and is independently unsubstituted or substituted; C514heteroaryl, and is independently unsubstituted or substituted.

40. A compound according to any one of claims 1 to 19, wherein Q is independently selected from the following, which may be unsubstituted or substituted:

41. A compound according to any one of claims Ito 19, wherein Q is independently selected from the following, which may be unsubstituted or substituted: H?-c/ WJW/LP6326342

-O

42. A compound according to any one of claims 1 to 19, wherein Q is selected from: C312cycloalkyl, and is independently unsubstituted or substituted; C12cycloalkenyl, and is independently unsubstituted or substituted; and C312heterocyclic, and is independently unsubstituted or substituted.

43. A compound according to any one of claims 1 to 19, wherein Q is independently selected from the following, which may be unsubstituted or substituted:

44. A compound according to any one of claims I to 19, wherein Q is independently selected from the following, which may be unsubstituted or substituted: -N) -N NH -N 0 \I \I \/ WJW1LP6326342 - 92

45. A compound according to any one of claims I to 19, wherein Q is independently: (RPB)X wherein: x is independently 0, 1, 2, 3, or 4; and each RPB is independently a substituent.

46. A compound according to any one of claims 1 to 19, wherein Q is independently - H.

47. A compound according to any one of claims 1 to 46, wherein each RN, if present, is independently selected from: R and -C(0)R .

48. A compound according to any one of claims 1 to 46, wherein each RN, if present, is independently -Me or -C(=O)Me.

49. A compound according to any one of claims 1 to 48, wherein Z is independently - H.

50. A compound according to any one of claims I to 48, wherein Z is independently R.

51. A compound according to any one of claims I to 48, wherein Z is independently selected from: jMe WJW/LP6326342 - 93 -

52. A compound according to any one of claims I to 51, wherein each R' is independently selected from the following, which may be unsubstituted or -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu; cylcopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (C6), adamantly (C10); phenyl; naphthyl, e.g., naphth-1-y, naphth-2-yl; furanyl, e.g., furan-2- yl, furan-3-yI; thiophenyl, e.g., thiophen-2-yI, thiophen-3-yl; I H- pyrrolyl, e.g., 1 H-pyrrol-2-yl, 1 H-pyrrol-3-yI; pyridinyl, e.g., pyridine-2-yl, pyridine-3-yl, pyridine-4-yl; pyrazinyl, pyrimidinyl, pyridazinyl; imidazolyl, pyrazolyl, oxazolyl, thiazolyl, thiadiazole; benzo[1,3jdioxolyl, e.g., benzo[1,3]dioxol-5-yl; 2,3-dihydro-benzo[1,4]dioxinyl, e.g., 2, 3-dihydro-benzo[1,4]dioxin-6-yl; 2, 3-dihydro-benzofuranyl, e.g, 2, 3-dihydro-benzofuran-2-yl; 4H-benzo[1,4]oxazin-3-one-yl, e.g., 4H-benzo[1,4]oxazin-3-one-6-yl; pyrrolidinyl, imidazolidinyl, pyrazolidinyl; piperidinyl, piperazinyl; tetrahydrofuranyl, tetrahydrothiophenyl; tetrahydropyranyl, morpholinyl; azepinyl; azabicyclo[3,2, I]octane; azabicyclo[3,2,2]nonane; WJW1LP6326342 - 94 - benzyl; phenyl-ethyl; pyridyl-methyl; pyridyt-ethyl.

53. A compound according to any one of claims 1 to 52, wherein each R is independently unsubstituted or substituted with one or more substituents selected from: (1) carboxylic acid; (2) ester; (3) aminoacyl or aminothioacyl; (4) acyl; (5) halo; (6) cyano; (7) nitro; (8) hydroxy; (9) ether; (10) thiol; (11) thioether; (12) acyloxy; (13) carbamate; (14) amino; (15) acylamino orthioacylamino; (16) aminoacylamino or aminothioacylamino; (17) sulfonamino; (18) sulfonyl; (19) sulfonate; (20) sulfonamido; (21) C520carboaryl-C17a1ky1 or C520heteroaryl-C17alkyl; (22) C520carboaryl or C520heteroaryl; (23) C320heterocyclyl; (24) C17a1ky1; C27alkenyl; C27alkynyl; C31 2cycloalkyl; C 12cycloalkenyl; (25) oxo; (26) imino; (27) hydroxyimino.

54. A compound according to any one of claims I to 52, wherein each R is independently unsubstituted or substituted with one or more substituents selected from: C17a1ky1, e.g., -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, tBu; C14haloalkyl, e.g., -CF3, -CH2F, -CHF2, -CH2CF3; C17alkoxy, e.g., OMe, -OEt, -0-nPr, -0-iPr, -0-nBu, -0-iBu, -0-sBu, -0-tBu; C14haloalkoxy, e.g., -OCF3, -OCH2F, -OCHF2, -OCH2CF3; C17alky1-acyl, e.g., -C(=0)Me, C(0)Et; halo, i.e., -F, -Cl, -Br, -I; -No2; -CN; phenyl, unsubstituted or substituted; and C56heteroaryl, unsubstituted or substituted.

55. A compound according to any one of claims I to 54, having a molecular weight of 300 to 1000.

56. A compound selected from the compounds shown in Figures 1 to 29, and pharmaceutically acceptable salts, solvates, amides, esters, ethers, Noxides, chemically protected forms, and prodrugs thereof.

WJW/LP6326342 - 95 -

57. A composition comprising a compound according to any one of claims I to 56 and a pharmaceutically acceptable carrier or diluent.

58. A method of inhibiting 113-hydroxysteroid dehydrogenase type 1 in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a compound according to any one of claims I to 56.

59. A compound according to any one of claims 1 to 56 for use in a method of treatment of the human or animal body by therapy.

60. A compound according to any one of claims I to 56 for use in a method of treatment or prevention of a condition of the human or animal body that is ameliorated by the inhibition of 1 l3-hydroxysteroid dehydrogenase type I by therapy.

61. Use of a compound according to any one of claims I to 56 in the manufacture of a medicament for use in the treatment or prevention of a condition of the human or animal body that is ameliorated by the inhibition of 11 3-hydroxysteroid dehydrogenase type 1.

62. A method of treatment or prevention of a condition of the human or animal body that is ameliorated by the inhibition of 11 3-hydroxysteroid dehydrogenase type I comprising administering to a patient in need of treatment a therapeutically effective amount a compound according to any one of claims I to 56.

63. A compound, use, or method according to any one of claims 60, 61, and 62, wherein the treatment or prevention is treatment or prevention of: (1) Cushing's syndrome; (2) type 2 diabetes; (3) insulin resistance syndromes such as myotonic dystrophy, Prader Willi, etc; (4) obesity; (5) lipid disorders; (6) atherosclerosis and its seq uelae, including myocardial infarction and peripheral vascular disease; (7) Metabolic Syndrome; WJW/LP6326342 - 96 - (8) steatohepatitis/fatty liver; (9) cognitive impairment in type 2 diabetes, glucose intolerance and ageing, and in psychotic disorders and pre-schizophrenia; (10) dementias such as Aiheimer's disease, multi-infarct dementia, dementia with Lewy bodies, fronto-temporal dementia (including Pick's disease), progressive supranuclear palsy, Korsakoffs syndrome, Binswanger's disease, HIV-associated dementia, Creutzfeldt-Jakob disease (CJD), multiple sclerosis, motor neurone disease, Parkinson's disease, Huntington's disease, Niemann-Pick disease type C, normal pressure hydrocephalus, and Down's syndrome; (11) mild cognitive impairment (cognitive impairment, no dementia); (12) -celI dysfunction in pancreatic disease; (13) glaucoma; (14) anxiety; (15) depression and other affective disorders; typical (melancholic) and atypical depression; dysthymia; post-partum depression; bipolar affective disorder; drug- induced affective disorders; anxiety; posttraumatic stress disorder; panic; phobias; (16) inflammatory disease; (17) osteoporosis; (18) myocardial infarction, for example, to prevent left ventricular dysfunction after myocardial infarction; and (19) stroke, for example, to limit ischaemic neuronal loss after cardiovascular accident.

64. A compound, use, or method according to any one of claims 60, 61, and 62, wherein the treatment or prevention is treatment or prevention of: (1) hyperglycaemia; (2) glucose intolerance and impaired glucose tolerance; (3) insulin resistance; (4) hyperlipidaemia; (5) hypertriglyceridaemia; (6) hypercholesterolaemia; (7) low HDL levels; (8) high LDL levels; (9) vascular restenosis; (10) abdominal obesity; (11) neurodegenerative disease; WJW1LP6326342 - 97 - (12) retinopathy; (13) neuropathy; (14) hypertension; and (15) other diseases where insulin resistance is a component.

65. A compound, use, or method according to any one of claims 60, 61, and 62, wherein the treatment or prevention is treatment or prevention of the adverse effects of glucocorticoids used to treat inflammatory diseases, such as asthma, chronic obstructive pulmonary disease, skin diseases, rheumatoid arthritis, and other arthropathies, inflammatory bowel disease, and giant cell arthritis/polymyalgia rheumatica.

66. A compound, use, or method according to any one of claims 60, 61, and 62, wherein the treatment or prevention is treatment or prevention of the metabolic syndrome, which includes conditions such as type 2 diabetes and obesity, and associated disorders including insulin resistance, hypertension, lipid disorders and cardiovascular disorders such as ischaemic (coronary) heart disease.

67. A compound, use, or method according to any one of claims 60, 61, and 62, wherein the treatment or prevention is treatment or prevention of CNS conditions such as mild cognitive impairment and early dementia, including Alzheimer's disease.