ZA200600316B - 1,1,1-Trifluoro-4-Phenyl-4-methyl-2-(1H-Pyrrolo - Google Patents

Description

1,1, 1-TRIFLUORO-4-PHENYL-4-M ETHYL-2- (1H-PYRROLO'2, 2-C1 PYRIDIN —2-YLMETHYL) PENTAN- 5.0L DERIVATIVES AND RELATED COMPOUNDS AS GLUCOCORTICOID LIGANDS FOR THE TREATME

NT OF INFLAMMATORY DISEASES AND DIABETES

Field of the Invention

The present invention relate=s to glucocorticoid mimetics or ligands, methods of making such compounds, their use in wharmaceutical compositions, and their use in modulating the glucocorticoid receptor function, treating disease-states or conditions mediated by the - glucocorticoid receptor func=tion in a patient in need of such treatment, amd other uses. oo 10

Background of the Inventiion

Glucocorticoids, a class of -corticosteroids, are endogenous hormones with profound effects on the immune system and pultiple organ systems. They suppress a variety of immune and

Co inflammatory functions by inhibition of inflammatory cytokines such as IL-1, IL-2, 1-6, and

TNF, inhibition of arachiclonic acid metabolites including prostaglaradins and leukotrienes, depletion of T-lymphocytes, and reduction of the expression of adhesion molecules on endothelial cells (P.J. Barmes, Clin. Sci., 1998, 94, pp. 557-572; PJ. Barnes et al., Trends

Pharmacol. Sci., 1993, 14, pp. 436-441). In addition to these effects, gRucocorticoids stimulate glucose production in the Eiver and catabolism of proteins, play a role Xn electrolyte and water balance, reduce calcium ab sorption, and inhibit osteoblast function. } The anti-inflammatory anc® immune suppressive activities of endogenous glucocorticoids have stimulated the developmert of synthetic glucocorticoid derivatives including dexamethasone, prednisone, and prednisol<one (L. Parente, Glucocorticoids, N.J. Goulding and R.J. Flowers (eds.), Boston: Birkhauser , 2001, pp. 35-54). These have found wide use in the treatment of inflammatory, immune, an_d allergic disorders including rheumatic diseases such as rheumatoid arthritis, juvenile arthritis, and ankylosing spondylitis, dermatological diseases including " psoriasis and pemphigus, allergic disorders including allergic rhinitis, atopic dermatitis, and contact dermatitis, pulmorary conditions including asthma and chronic obstructive pulmonary disease (COPD), and othier immune and inflammatory diseases in cluding Crohn disease, ulcerative colitis, systemic lupus erythematosus, autoimmune chronic active hepatitis, osteoarthritis, tendonitis, and bursitis (J. Toogood, Glucocorticoids, N.J. Goulding and R.J.

Flowers (eds.), Boston: Birkhauser, 2001, pp. 161-174). They have also been used to help prevent rejection in organ transplantation.

Unfortunately, in. addition to the desired therapeutic effects of glucocorticoids, their use is associated with = number of adverse side effects, s ome of which can be severe= and life- threatening. Thesse include alterations in fluid and electrolyte balance, edema, weight gain, hypertension, muscle weakness, development or =aggravation of diabetes meMlitus, and osteoporosis. Therefore, a compound that exhibite=d a reduced side effect profile while maintaining the potent anti-inflammatory effects would be particularly desirable especially when treating a chronic disease.

The effects of glucocorticoids are mediated at the ceh lular level by the glucocorticoid receptor (R.H. Oakley and J. Cidlowski, Glucocorticoids, N.J. sGoulding and R.J. Flowers (ed_s), Boston:

Birkhauser, 2001, pp. 55-80). The glucocorticoid receptor is a member of a class of structurally related intracellwalar receptors that when coupled with a ligand can function as a transcription factor that affects gene expression (R.M. Evans, Science, 1988, 240, pp. 889-8 95). Other members of th e family of steroid receptors incliade the mineralocorticoid, pmrogesterone, estrogen, and androgen receptors. In addition to the effects mentioned above for glucocorticoids, hormones that act on this receptor £amily have a profound influexrce on body homeostasis, rmineral metabolism, the stress response, and development of sexual characteristics. Glucocorticoids, N.J. Goulding and R.J. Flowers (eds.), Boston: Birkhauser, 2001, is hereby incorporated by reference in its entire=ty to better describe the state c>fthe art.

A molecular mechanism which accounts for the beneficial anti-inflammatory effects and the undesired side effects has been proposed (e.g. S. Fleck ef al., EMBO J, 1994, 1 7, pp. 4087- 4095; H.M. Resichardt et al., Cell, 1998, 93, pp. 5 31-541; F. Tronche et al, Cream. Opin. in

Genetics and IDev., 1998, 8, pp. 532-538). Many of the metabolic and cardiovascular side : effects are thovaght to be the result of a process called transactivation. In transactivation, the translocation of the ligand-bound glucocorticoid receptor to the nucleus is followe-d by binding to glucocorticoid response elements (GREs) in the promoter region of side effe-ct-associated genes, for exammple, phosphoenolpyruvate carboxy kinase (PEPCK), in the case of increased glucose production. The result is an increased toranscription rate of these gernes which is believed to ressult, ultimately, in the observed side effects. The anti-inflammatomcy effects are thought to be Jue to a process called transrepressiosn. In general, transrepressiorm is a process independent of DNA binding that results from inhibition of NF-K2B and AP-1-mediated pathways, leading to down regulation of many inflammatory aned immune mediators.

Additionally, it is believed that a number of the observed side effects yay be due to the cross- reactivity of the currently available g=lucocorticoids with other steroid re=ceptors, particularly the mineralocorticoid and progesterone receptors.

Thus, it may be possible to discover ligands for the glucocorticoid receptor that are highly selective and, upon binding, can dissociate the transactivation and treansrepression pathways, providing therapeutic agents with ea reduced side effect profile. Assamy systems to determine effects on transactivation and transmrepression have been described (e.£=., CM. Bamberger and

HM. Schulte, Eur. J. Clin. Inve st, 2000, 30 (suppl. 3), pp. 6-3). Selectivity for the glucocorticoid receptor may be deteermined by comparing the binding affinity for this receptor with that of other steroid family receptors including those mentioned abwove.

Glucocorticoids also stimulate thes production of glucose in the liver by a process called gluconeogenesis and it is believed that this process is mediated b=y transactivation events.

Increased glucose production can exacerbate type II diabetes, themrefore a compound that selectivity inhibited glucocorticoid mediated glucose production may ave therapeutic utility in this indication (J.E. Freidman et al. , I. Biol. Chem., 1997, 272, pp. 31475-31481).

Novel ligands for the glucocortico id receptor have been described in the scientific and patent literature. For example, PCT International Publication No. WWO 99/33786 discloses triphenylpropanamide compounds with potential use in treating inflammatory diseases. PCT

International Publication No. WO 00/66522 describes non-steroidal compounds as selective modulators of the glucocorticoiad receptor potentially useful in treating metabolic and inflammatory diseases. PCT Inter national Publication No. WO 99/4 256 describes tetracyclic modulators of the glucocorticoid receptor potentially useful in treatirg immune, autoimmune, and inflammatory diseases. U.S. Patent No. 5,688,810 describ-es various non-steroidal compounds as modulators of glusocorticoid and other steroid receptors. PCT International

Publication No. WO 99/63976 describes a non-steroidal, liver—-selective glucocorticoid antagonist potentially useful in thie treatment of diabetes. PCT International Publication No.

WO 00/32584 discloses non-stexoidal compounds baving anti-infSlammatory activity with dissociation between anti-iriflammatory and metabolic effec=ts. PCT International Publication

No. WO 98/54159 describes non-steroidal cyclically substituted acylanilides with mixe=d gestagen and androgen activity. U.S. Patent No. 4,880,8339 describes acylanilides haviomg progestational activity and EP 253503 discloses acylanilid es with antiandrogenic propertie=s. ’ 5 PCT International Publication No. WO 97/27852 descritoes amides that are inhibitors ef farnesyl-protein transferase.

A compound that is found to interact with the glucocorticoid receptor in a binding assay comld be an agonist or an antagonist. The agonist properties of tine compound could be evaluated in 10 the transactivation or trans Tepression assays described abovee. Given the efficacy demonstrat=ed by available glucocorticoic] drugs in inflammatory and immune diseases and their adverse si_de effects, there remains a need for novel glucocorticoid recesptor agonists with selectivity ower other members of the stesroid receptor family and a diss ociation of the transactivation amnd transrepression activities. Alternatively, the compound may be found to have antagoruist 15 activity. As mentioned above, glucocorticoids stimulatee glucose production in the liver.

Increased glucose production induced by glucocorticoid excess can exacerbate existing diabetes, or trigger latent clisbetes. Thus a ligand for the ght acocorticoid receptor that is found to be an antagonist may be useful, inter alia, for treating or pre=venting diabetes. 20 Prior applications U.S. Serial No. 60/367,798, filed M™March 26, 2002, U.S. Serial No. 60/431,817, filed December 12, 2002, U.S. Serial No. 60/=442,404, filed January 24, 2003, sand

U.S. Patent Application Pub. No. 2004/0023999, are caclh incorporated by reference in tieir entireties. 25 Summary of the Invention

The instant invention is directed to compounds of Formula (IA) 3

R H

1

R CF, (A) wherein:

WOB 2005/030213 PCT/TUS2004/031009

R! isan aryl or heteroaryl group, each optionally independently substitutecs with one to three substituent groups, wherein each substituent group of R'is independently C1-C; alkyl, C-Cs alkenyl, C-Cs alkynyl, Cs-Cs cycloalkyl, heterocyclyl, aryl, heteroaryl, C-Cs alkoxy, Ci-Cs alkenyloxy, C,-Cs alkynyloxy, aryloxy, acyl, C,-Cs alkoxycarbonyl, CZ,-C;s alkanoyloxy,

C;-Cs alkanoyl, aroyl, aminocarbomyl, alkylaminocarbonyl, diaBikylaminocarbonyl, aminocarbonyloxy, Ci1-Cs alkylaminocarbonyloxy, C,-Cs dialkylamizxocarbonyloxy, Ci-

Cs alkanoylamino, Ci-Cs alkoxycarbonylamino, Cy-Cs amlkyisulfonylamino, aminosulfonyl, Ci-Cs alkylaminosulfonyl, C,-Cs dialkylaminossulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, or= amino wherein the nitrogen atom is optionally independently mono- or di-substituted_ by C;-Cs alkyl or aryl; or ureido wherein either nitrogen atom. is optionally independertly substituted with . C,-Cs alkyl; or C;-Cs alkylthio wherein the sulfur atom is optiommally oxidized to a sulfoxide or sulfone, wherein each substituent group of R! is optionally independently substituted with one to three substituent groups selected from methyl, methoxy halogen, hydroxy, oxo, cyano, heteroaryl, heterocyclyl, or amino wherein thes nitrogen atom is . 20 optionally independently mono- or di-substituted by Cy-Cs alkyws1 or aryl; or ureido wherein either nitrogen atom is optiomally independently sub-stituted with C;-Cs alkyl;

So R® and R® are each independently hydrogem or C;-Cs alkyl, or R? and FR? together with the carbon atom they are commonly attached to form a C3-Cg spiro cycloalkyl ring;

R* is C,-Cs alkyl, C,-Cs alkenyl, or C,-Cs alkynyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R* is independently C:-C; alkyl, hydroxy, halogen, amino, or oxo; and

R® is a heteroaryl group optionally inadependently substituted with one to three substituent groups, wherein each substituent group oft R® is independently C1-Cs alkyl, C,-Cs alkenyl, C2-Cs alkynyl, C3-Cs cycloalkyl, heterocyclyl, aryl, heteroaryl, C-Cs alkoxy, C»-Cs alkenyloxy, C,-Cs alkynyloxy, ar=yloxy, acyl, Ci-Cs alkoxycarbonyl, C;—Cs alkanoyloxy, heterocyclyicarbonyl, aro}, aminocarbonyl, alky/laminocarbonyl, dialkylaminocarbonyl, aminocaurbonyloxy, Ci-Cs alkylaminocarbeonyloxy, C,-Cs dialkylaminocarbonyloxy, Ci-Cs alkanoylamino, Ci-Cs alkoxycarbonylamino, Ci-Cs alkylsulfonylamino, aminostalfonyl, C-Cs alkylaminosul fonyl, Ci-Cs dialkylaminosulfonyl, halogerm, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethy thio, nitro, or amino wherein the mitrogen atom is optionally independently mono— or di-substituted by C;-Cs alkyl; ox ureido wherein either nitrogen atom is optionall y independently substituted with C;-C; alkyl; or Ci-Cs alkylthio wherein the sulfur ato is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of R’ is optionally independently” substituted with one to three substituent groups selected from C,-C; alkyl, C;-C3 alkoxy, acyl, Ci-Cs silanyloxy, Ci-Cs alkoxycarbonyl, carboxy, halogen, hydroxy, «xo, cyano, aryl, heteroaryl, heterocyclyl, or" amino wherein the nitrogen atom is optionally independently mono- or di-ssubstituted by C;-Cs alkyl or aryl; or ureido wherein either nitrogen atom is optionally independently substituted witth C;-Cs alkyl, or trifluoromethyl, ora tautomer, prodmg, solvate, or salt thereof.

AArother aspect of the invention includes compounds of Formula (XA), whereim:

FR! is thienyl, phenyl, naphthyl, dihydrobenzofuranyl, benzofuranyl, chromanyl, dibydroindolyl, indolyl, dilydrobenzothienyl, benzothienyl, benzodioxolanyl, dihydrobenzoxazolyl, benzoxazeolyl, benzisoxazolyl, benzpyrazolyl, benzimidazolyl,

thienyl, quinolinyl, pyridinyl, pyrimidiny~1, or pyrazinyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R! is Sndependently C1-C; alkyl, C2—Cj alkenyl, C2-Cs alkynyl, C1-C; alkoxy, C-Cs alkenylox=y, C;-C alkanoyl, C,-C3 alko—xycarbonyl, Ci-Cs alkanoyloxy, halogen, hydroxy, carboxy, cyano, heterocyclyl. trifluoromethyl, triflucromethoxy, nitro, amino whereirm the nitrogen atom is optionally independently mono- or di-substituted by C;-Cs alkyl Or aryl; or ureido wherein eitheer nitrogen atom is optionally independently substituted with C,-Cs alkyl, or C1-C3 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of RR! is optionally independently~ substituted with a substituent group selected from methyl, methoxy, halogen, hydroxy, oxo, cyano, Of : amino;

R? znd R® are each independently hydrogen or Ci-C; alkyl, or R? and R= together with the carbon atom they are commonly attache to form a Cs-Cs spiro cycloalkyl ring;

R* as CHy; and

R® is an imidazolyl, pyridyl, indolyl, inclazolyl, azaindolyl, diazaind oly], benzofuranyl, furanopyridinyl, furanopyrimidinyl, imidazolopyrimidinyl, inmidazolopyridazinyl, imidazolopyrazinyl, benzothienyl, thien_opyridinyl, thienopyrimidinyl , thienopyridazinyl, benzoxazolyl, oxazolopyridinyl, ben=zothiazolyl, thiazolopyridiny=l, benzimidazolyl, imidazolopyridinyl, quinolinyl, or isocguinolinyl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of I’ is independently C;-C; al kyl, C;-Cs alkenyl, phenyl, C,-C; alkoxy, methoxycarboenyl, aminocarbonyl, C;-Cs aalkylaminocarbonyl,

C,-C; dialkylaminocarbonyl, hetero -cyclylcarbonyl, hydroxy, oo, fluoro, chloro, bromo, cyano, trifluoromethyl, am3no wherein the nitrogen =atom is optionally independently mono- or di-substitutecd by Ci-Cs alkyl or aryl; or umreido wherein either nitrogen atom is optionally independentRy substituted with C,-Cs alkyl, or C-Cs alkylthio wherein the sulfur atom is optionaally oxidized to a sulfoxide or sulfone, wherein each substituent group of R® iss optionally independently substituted with. a substituent group selected from methyl, methoxy, fluoro, chloro, bromo, Oxo, Of trifluoromethyl, hydroxy, cyano, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted By C;-Cs alkyl or aryl, or a tzautomer, prodrug, solvate, or salt thereof.

Yet another aspect of the invention includes compmounds of Formula (IA), wherein:

R'is thienyl, phenyl, naphthyl, pyridyl, chromany~], dihydrobenzofuranyl, or benzofuran_yl, each optionally independently substituted with omne or two substituent groups, wherein each substituent group of R! is i ndependently methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, hydroxy, triffuomromethyl, trifluoromethoxy, cyano, c»1 Ci-Cs alkylthio wherein the sulfur atom is optiomnally oxidized to a sulfoxide or sulfone;

R® and R are each independently methyl or ethyl, or R? and R® together with the carbon atom they are commonly attached to form a spiro cyclopropyl ring;

R* iss CH; and

RS is a pyridyl, indolyl, azaindolyl, dBiszaindolyl, benzofuranyl, furanops yridinyl, thienopyridinyl, benzoxazolyl, benzimida=zolyl, quinolinyl, or isoquinolinyl grosup, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R’ is independently methyl, phenyl, methoxy”, ethoxy, 1SOpIOPOXY, methoxycarbonyl, aminocarbonyl, methylaminoecarbon yl, dimethylaminocarbonyl, morpholin-ylcarbonyl, morpholinyl, piperidinyl, trifluoromethyl, fluoro, chloro, bromo, knydroxy, cyano, or amino wherein the nitrogen i. .

atom is optionally independently” mono- or di-substituted by C;-C=s alkyl or aryl or trifluoromethyl, oT a tautomer, prodrug, solvate, or salt thesreof. wet another aspect of the invention inclucles compounds of Formula (TA), wherein:

R' is phenyl, dihydrobenzofuranyl, or benzofuranyl, each optionamlly independently substituted with one to three substi tuent groups, wherein each substituent group oof R! is independently C;-C; alkyl, C2-Cs alkenyl, C;-Cs alkynyl, C;-C; alkoxy, C2-Cs allcenyloxy, C,-C; alkanoyl, Ci-Cs alkeoxycarbonyl, Ci-Cs alkanoyloxy, halogen, hydroxys, carboxy, cyano, trifluoromethyl, nitro, or Ci-Cs alkylthio wherein the sulfur atonra is optionally oxidized to a sulfoxide or sulfone; and “R? and R® are each independently hydrogen or C,-Cs alkyl, or a tautomer, prodrug, solvate, or salt thereof.

Yet another aspect of the invention incliades compounds of Formula (TA), w_herein:

R° is a pyridyl, indolyl, azaindolyl, diazaindolyl, benzofurany-1, furanopyridinyl, thienopyridinyl, benzoxazolyl, benzimidazolyl, quinolinyl, or isoquiinolinyl group, each optionally independently substituted with one to three substituent growups, . or a tautomer, prodrug, solvate, or salt thereof. } Another aspect of the invention include s compounds of Formula (IA), wher—ein:

R! is thienyl, phenyl, naphthyl, dihydrobenzofuranyl, benzofiaranyl, chromanyl, dihydroindolyl, indolyl, diihydrobenzothienyl, benzothienyw], benzodioxolyl, dihydrobenzoxazolyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzimidazolyl,

thienywl, quinolinyl, pyridinyl, pyrimidinyl, or pyrazinyl, each optionally immdependently substi—tuted with one to three substituent groups-, whe=rein each substituent group of R! is independently C;-C; alkyl, C,-C; alkenyl, C-Cs alkymyl, Ci-C; alkoxy, C2-Cs alkenyloxy, Ci ~C; alkanoyl, Ci-Cs alkoxycar=bonyl, C-Cs alkzanoyloxy, aryl, heteroaryl, halogen, hydroxy, carboxy, cyano, heterocyclyl, trifMuoromethyl, trifluoromethoxy, nitro, amninosulfonyl, dialkylaminosul—fonyl, amino whe=rein the nitrogen atom is optionally independently mono- or di-substit_1ted by Cy-Cs alk=yl or aryl; or ureido wherein either mmitrogen atom is optionally independently submstituted with C,-Cs alkyl, or C,-Cs alky thio wherein the sulfur atom _ is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of R! iss optionally independently sulbstituted with one or two substituent groups selected from methyl, methoxy, halosgen, hydroxy, oxo, cyano, morpholinyl, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted bys C4-Cs alkyl;

R? and R®™ arc each independently hydrogen or C:1-Cs alkyl, or R? and R® togeether with the carbeon atom they are commonly attached to form a Cs-Cs spiro cycloalkyl ring;

R* is CHpz: and

RS is aan imidazolyl, pyridyl, indolyl, indazoRkyl, azaindolyl, diazaindolyl, benzofuranyl, fura_nopyridinyl, furanopyrimidiny}, imiidazolopyrimidinyl, ~imidazcolopyridazinyl, imiciazolopyrazinyl, benzothienyl, thienopyr=dinyl, thienopyrimidinyl, thie=nopyridazinyl, ben=zoxazolyl, oxazolopyridinyl, benzothiazolyl, thiazolopyridinyl, b enzimidazolyi, imicdazolopyridinyl, quinolinyl, or isoquinowlinyl group, each optionally independently : subsstituted with one to three substituent grourps, : 30 whherein each substituent group of R® is independently C;-C; alkyl, C»C, alkenyl, phaenyl, heteroaryl, heterocyclyl, acy-l, dialkylaminosulfonyl, CCi-C; alkoxy, m_ethoxycarbonyl, aminocarbonyl, Ci-Cs alkylaminocarbo-myl, Ci-Cs dialkylaminocarbonyl, heterocyclylcarbonyl, hydroxy, oxo, fluoro, chloro, bromo, cyano, trifluoromethyl, amino wherein the nitrogen atom is optionally independently mono- or di-substituted. by C,-Cs alkyl or aryl; or ureido wherein either nitrogen atom is optionally independently substituted with C,-Cs alkyl; or C,-Cs alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of R® is optionally indepenclently substituted with one or two substituent groups selected from methyl, methoxy, fluoro, chloro, bromo, oxo, trifluoromethy~], hydroxy, cyano, morpholinyl, pyrrolidimyl, or amino wherein the nitrogen atom iss optionally independently mono- or di-substituted by Ci-Cs alkyl or aryl, or a tautomer, prodrug, solvate, or salt thereof.

Yet another aspect of the invemtion includes compounds of Formula (IA), wherein:

R! is thienyl, phenyl, naphthyl, pyridyl, chromanyl, benzodioxolyl, dihydrobenzofuranyl, or benzofuranyl, each optionally independently substituted with ©ne or two substituent groups, wherein each substitment group of R! is independently methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo», hydroxy, trifluoromethyl, triflucrometho xy, morpholinylmethyl, dimethylaminomethyll, aminosulfonyl, dimethylaminosulfonyk, phenyl, pyrimidinyl, pyridinyl, thienyl, naaphthalenyl, morpholinyl, piperidinyl, cyano, or C,-C; alkylthio wherein the sulfur atoem is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of R' is optionally indepexidently substituted with one or two groups selected from cyano, chloro, bromo, or fluoro;

R2 and R® are each independ ently methyl or ethyl, or R? and R® togeth er with the carbon atom they are commonly attached to form a spiro cyclopropyl ring;

: R* is CI; and

R® is a pyridyl, indolyl, azaindolyl, di=zaindolyl, benzofuranyl, thiesnopyridazinyl,

Furanopyridinyl, thienopyridinyl, benz=zoxazolyl, benzimidazolyl, qjuinolinyl, or 3 i soquinolinyl group, each optionally irdependently substituted with one to three ssubstituent groups, wherein cach substituent group of RS is imdependently methyl, phenyl, meethoxy, ethoxy, isopropoxy, methoxycarbonyl, aminocarbonyl, methyl=aminocarbonyl, dimethylaminocarbonyl, morpholinylczrbonyl, morpbolinyl, piperid3nyl, phenoxy, pyrrolidinyl, acetyl, pivaloyl, ethylcarboonyl, isopropylcarbonyl, pyridin_yl, pyrimidinyl, trifluoromethyl, fluoro, chloro, bromo, Taydroxy, cyano, or amino wherein the nitrogen atom is optionally independently moneo- or di-substituted by C;-Cs alkyl or aryl or trifluoromethyl, 15 . wherein each substituent group of IR’ is optionally independently =substituted with one or two substituent groups selectexd from cyano, halogen, methyl, dimethylamino, morpholinyl, pyrrolidinyl, or piperid dnyl, or a tautomer, prodrug, solvate, or salt thereof. : Yet a_mother aspect of the invention includes compounds of Formula (IA), wheresin:

R! is phenyl, dihydrobenzofuranyl, or benzofuranyl, each optionally independently substituted with one to three substituent groups, x wherein each substituent group of R! iss independently C;-C; alkyl, C;-CTs alkenyl, C,-Cs alkynyl, Ci-C; alkoxy, C-C; alkenylozxy, C;-C; alkanoyl, C1-C; alkoxycarbonyl, C;-Cs alkanoyloxy, halogen, hydroxy, carboz<y, cyano, trifluoromethyl, nitro, aryl, heteroaryl, heterocyclyl, or C;-C; alkylthio wher-ein the sulfur atom is optionally oxidized to a sulfoxide or sulfone; and

R? and R® are each independently hydrogen or C;-C; alkyl, or a tautomer, prodrug, solvate, or salt thereof.

Yet another aspect of the invention includes compounds of Formula (IA), vevherein:

R® is a pyridyl, indolyl, azaindolyl, diazaindolyl, benzofurany1, thienopyridazinyl furanopyridinyl, thienopyridinyl, benzoxazolyl, benzimidazolyl, quinofinyl, or isoquinolinyl group, each optionally independently substituted with one to three substituent groups, or a tautomer, prodrug, solvate, or salt thereof.

Representative compounds of Formula (IA) according to the invention amre appended hereto as

Table IA, where column A is the compound name according to stand=ard nomenclature and column B is the corresponding chemical structure.

Preferred compounds of Formula (IA) include the following: 4-Cyclohexyl-1,1,1 trifluoro-4—methyl-2-quinolin-4-ylmethylpentan-2-ol; 4-Pyrimidin-5-y1-2-{4,4,4-trifluoro-3 -hydroxy-1,1-dimethyl-3 -(1H-pyrrol=of2,3-clpyridin-2- ylmethyl)butyllphenol;

L11 ~Trifluoro-4-(5-fluoro-2-rmethoxyphenyl)-4-methyl-2-(3 -methyl-1 H—pyrrolo[3,2-c]pyridin- 2-ylmethyl)pentan-2-ol; 1,1,1-Trifluoro-4-(5 -fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-( 1H=pyrrolo[3,2-cJpyridin- 2-ylmethyl)pentan-2-ol;

1,1,1-Trifluoro-4-(5-flucro-2-metiaylphenyl)-4-methyl-2-(3-methyM -LH-pyrrolo[2,3-clpyridin-2- ylmethyl)pentan-2-ol; 2-(4,6-Dimethyl-1 H-pyrrolo[3,2-Clpyridin-2-ylmethyl)-1,1,1-triflu_oro-4-(5-fluoro-2-

methoxyphenyl)-4-methylpentan-22-ol; 2-(5,7-Dimethyl-1H-pyrrolo{2,3 -c)pyridin-2-ylmethyl)-1,1 ,1-trifluworo-4-(5-fluoro-2- methoxyphenyl)-4-methylpentan—2-ol;

2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-triftuorom methylpentyl]-15- pyrrolo[3,2-b]pyridine-5-carbonitrile; 1,1,1-Trifluoro-4-(5 -fluoro-2-me#hoxyphenyl)-4-methyl-2-(6-met_hyl- 1H-pyrrolo[3,2-c]pyridin- 2-ylmethyl)pentan-2-ol;

. 1,1,1-Trifluoro-4-(5-fluoro-2-me -thoxyphenyl)-4-methyl-2-(4-met=hyl- 1H-pyrrolo {3,2-c]pyridin- 2-ylmethyl)pentan-2-ol; 2-[4-(5-Fluoro-2-methoxyphenyR)-2-hydroxy-4-methyl-2-trifluorcmethylpentyl]-4-methyl-1H-

pyrrolo[3,2-c]pyridine-6-carboni trile; 2-{4-(5-Fluoro-2-methoxyphenyX)-2-hydroxy-4-methyl-2-trifluorcomethylpentyl]-14- pyrrolo[2,3-c]pyridine-5-carboni trile;

. 25 2-[4-(5-Fluoro-2-methoxyphenyX)-2-hydroxy-4-methyl-2-trifluoreomethylpentyl]-1H- pyrrolo[3,2-c]pyridine-4-carbontrile; 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(SH-p —yrrolo[3,2-dlpyrimidin-6- ylmethyl)pentan-2-ol;

: 30 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-thienc>|[2,3 -dlpyridazin-2- ylmethylpentan-2-ol;

1,1,1-Trifluoro-4-(5 -fluoro-2-methoxyphenyl)-4-methyl-2-(SH: -pyrrolo[3,2-c]pyridazin-=6- ylmethy~1)pentan-2-ol;

14, 1-Txifluoro-4-(5-fluoro-2-methoxyphenyl)-4-me~thyl-2-(2-methyl-SH-pyrrolo{3,2- d]pyrimyidin-6-ylmethyl)pentan-2-ol;

1,1,1-Txifluoro-4-(5 fluoro-2-methylphenyl)-4-metimyl-2-(1 H-pyrrolo{2,3-d]pyridazin-2_- ylmethw/I)pentan-2-ol;

2-(4,6-WDimethyl-1 H-pyrrolo[3 ,2-cJpyridin-2-ylmetizyl)-1,1,1 ~trifluoro-4-(5-fluoro-2- methylyphenyl)-4-methylpentan-2-ol; 4-(5-Chhloro-2,3-dihydrobenzofiran-7-yl)-2-(4,6-dimmethyl-1H-pyrrolo [3.,2-clpyridin-2-

ylmethyl)-1,1,1 -triffuoro~4-methylpentan-2-ol;

2-[4-(5 -Fluoro-2 -methylphenyl)-2-hydroxy-4-meth~yl-2 -trifluoromethylpentyl]- 1 H-pyrmrolo[3,2- b]pyriciine-5-carbonitrile;

4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1 -trifluoro-4-methyl-2-(3-methyl- 1 H-pymrrolo{2,3-

¢]pyriclin-2-ylmethyl)pentan-2-ol; 1,1,1 “Irifluoro4-(5-fluoro-2-methylphenyl)-4-met=hyl-2-(5 H-pymolo[3,2-c]pyridazin-«6- ylmethyl)pentan-2-ol;

: 4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1 -tri #luoro-4-methyl-2-(SH-pyrrolo[3,2- c]pyriciazin-6-ylmethyl)pentan-2-ol; 4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-1,1, 1-tri afluoro-4-methyl-2-(1H-pyrrolo[2,3- d]pyri dazin-2-ylmethyl)pentan-2-ol;

1,1,1-Trifluoro-4~(5-fluoro-2 -methoexyphenyl)-2-(7-fluoro-1H- _pyrrealo[2,3-clpyridin-2- = yimethyl)-4-methylpentan-2-ol; 1,11 _Trifluoro-4-(5-fluoro-2-methcxyphenyl)-4-methyl-2-(4-methe/l- 1H-pymolo[2,3-c]pyridin- 2-ylmethyl)pentan-2-ol; 2.(5,7-Dichloro-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-1,1,1-trifluo-ro-4-(5-fluoro-2- _- methoxyphenyl)-4-methylpentan-2—ol; oc 10 1,1,1-Trifluoro-4-(5-fluoro-2-meth oxyphenyl)-4-methyl-2-(5-triflu oromethyl-1H-pyrrolo[2,3- : ¢]pyridin-2-ylmethyl)pentan-2-ol; 1,1,1-Trifluoro-4-(5 -fluoro-2-methn oxyphenyl)-2-(5-methoxy-1H-p yrrolo[2,3-c]pyridin-2- ylmethyl)-4-methylpentan-2-ol;

1,1 1-Trifluoro-4-(5-fluoro-2-methmyiphenyl)4-methyl-2-(4-methyM-1 H-pyrrolo[2,3-c]pyridin-2- ylmethyl)pentan-2-ol; 1,1,1-Trifluoro-4-(5 —fluoro-2-metlaylphenyl)-2-(5-isopropoxy-1H-gpyrrolo [2,3-clpyridin-2-

ylmethyl)-4-methylpentan-2-ol; 1,1,1-Trifluoro-4-(5 -fluoro-2-metinaylphenyl)-2-(5-methoxy-1H- -py—xrolo[2,3-clpyridin-2- ylmethyl)-4-methylpentan-2-ol;

4-(5-Chloro-2,3-dihydrobenzofurean-7-yl)-1,1,1-trifluoro-2-(5-met=hoxy-1 H-pyrrolo[2,3- clpyridin-2-ylmethyl)-4-methylpemntan-2-ol; 1,1,1-Trifluoro-4-(5-fluoro-2-metkylphenyl)-2-(7-fluoro-14-pyrro lo[2,3-c]pyridin-2-ylmethyl)- 4-methylpentan-2-ol;

4-(5-Chloro-2,3-dihydrobenzofuraan-7-yl)-1,1, 1-trifluoro-4-methyM-2-(5-trifluoromethyl-1H- pyrrolo[2,3-c]pyridin-2-ylmethyl) pentan-2-ol;

W =O 2005/030213 PCT /US2004/031009 1,1,1-Trifluoro-4-(5~fiuoro-2 -methylpbe nyl)-4-methyl-2-(5 -trifluoromethyl- 1H-pyrrolo[2,3- clpyridin-2-ylmethyl)pentan-2-ol; 4-(5-Chloro-2,3-dihydrob enzofuran-7-y1)-1,1,1-trifluoro-2-(5-isopropoxy- 1.H-pyrrolof2,3- clp yridin-2-ylmethyl)-4-methylpentan-2-ol;

A-(5-Chloro-2,3 -dihydrobenzofuran-7-y*1)-1,1, 1 -trifluoro-2-(7-fluoro-1H-py-trolo [2,3-c]pyridin- 2-ylmethyl)-4-methylpentan-2-o0l; 4-(5-Chloro-2,3 _dihydrobenzofuran-7-3/1)-25 -dimethylamino-1H-pyrrolo[_23 ~clpyridin-2- ylmethyl)-1,1,1-trifluoro-4-methylpentzan-2-ol; 4-(5-Chloro-2,3-dihydrob enzofuran-7--yl)-1,1,1-trifluoro -4-methyl-2-(5-piperidin-1-yl- 1H- pyrrolo[2,3-clpyridin-2-ylmethyl)pentzan-2-ol; 4-(5-Chloro-2,3-dihydrob enzofuran-7-"yl)-1,1, 1-trifluoro-4-methyl-2-(5S-mompholin-4-yl-1H- pyrrolo[2,3-c]pyridin-2-ylmethyl)p ent=an-2-0l; 20» 1,1,1-Trifluoro-4-(5 -fluoro-2-methylpiaenyl)-4-methyl-2-(5-pip eridin-1-yl— LH-pyrrolo{2,3- c]pyridin-2-ylmethyl)pentan-2-ol; 4-(5-Chloro-2,3-dihydrobenzofuran-7—yl) -24(5-ethoxy-1H-pyrrolo[2,3-clp yridin-2-ylmethyl)- 1,1,1-trifluoro-4-methylpentan-2-ol; 2-(5-Benzyloxy-1H-pyrrolo[2,3 -c]pyr-idin-2-ylmethyl)-1,1,1 -trifluoro-4-(S-fluoro-2- methylphenyl)-4-methylpentan-2-ol; 2-(5-Benzyloxy-1H-pyrrolo[2,3 -¢]pyr-idin-2-ylmethyl)-4-(5-chloro-2,3 -dilhydrobenzofuran-7- yD-1,1,1-trifluoro-4-methylpentan-2-ol,

1,1,1 “Trifluoro-4-(5-fluoro-2-mnethoxyphenyl) 2-(5-chloro-1H-pyrrolo[ 2,3 -c]pyridin-2- ylmethyl)-4-methylpentan-2-0l; 1,1,1-Trifluoro-4-(5 fluoro-2-mmethoxyphenyl)-4-methyl-2-[5 -(methylarxmino)-1H-pyrrolo[2,3- cpyridin-2-ylmethyl]pentan-2 -ol; 1,1,1-Trifluoro-4-(5-fluoro -2-1methoxyphenyl)-4-methyl-2-(5 -amino-1.a#- -pyrrolo[2,3-clpyridin- 2-ylmethy!)pentan-2-ol; . 10 1,1,1-Trifluoro-4-(5 fluoro-2-amethylphenyl)-4-methyl-2-(6-amino-1 Ff—pyrrolo(2,3 -clpyridin-2- ylmethyl)pentan-2-ol; 4-(5-Chloro-2,3-dihydrob enzofuran-7-yl)-1,1,1-trifluoro-2-(5-amino- WM H-pyrrolo[2,3-c]pyridin- 2-yimethyl)-4-methylpentan-2-ol;

4-(5-Chloro-2,3-dihydrobenzofuran-7 -yD-1,1,1 -trifluoro-4-methyl-2-(_5-methylamino-1H- pyrrolo[2,3-¢]pyridin-2-ylmethylpentan-2-ol; 7-[4-(5 —Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome#ithylpentyl}-14-

pyrrolo[2,3-b]pyridin-7-ium chloride; 6-{4-(5-Fluoro-2 .methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome—thylpentyl]-2-methyl- 1H- pyrrolo[2,3-c]pyridin-6-ium chloride;

4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2- (1H-pyrrolo[2,3-c]pyridin-

2-yimethyl)pentan-2-ol; 1,1,1-Trifluoro-4-methyl-4-( 5.methyl-2,3-dihydrobenzofuran-7- yD)-2=~(1H-pyrrolo[2,3- c]pyridin-2-ylmethyl)pentan—2-ol;

4-(5-Chloro-2,3-dihydroben=ofuran-7-y})-1,1,1 _trifluoro-4-methyl-2 —(1 H-pyrrolo[2,3-c]pyridin- 2-ylmethyl)pentan-2-ol;

1,1,1-Trifluoro-4-(5-fluoro-2 -methoxyphenyl)-4-methyl-2-pyrrolo [2,3-b]pyrmdin-1- ylmethylpentan-2-ol; 1,1,1-Triflnoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(6-0xy-1H-pyrrol. of2,3-clpyridin-2- ylmethyl)pentan-2-ol; 1,1,1-Trifluoro-4-(5-flucro -2-methoxyphenyl)-4-methyl-2-pyrrolo [2,3-c]lpyr=idin-1- ylmethylpentan-2-ol; 2-Benzo[b]thiophen-2-ylmethyl-1,1,1 —trifluoro-4-(5 _fluoro-2-methoxyphen=yl)-4-methylpentan- 2-ol; 1,1,1 Triftuoro—4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-thieno[2,3 -c]pyrddin-2- ylmethylpentan-2-0l; 1,1,1-Trifluoro-4-(5 -fluoro-2-methoxy/phenyl)-2-indazol- 1-ylmethyl-4-metlhylpentan-2-ol; 1,1,1 Trifluoro—4-(5-fluoro-2-methoxsy/phenyl)-4-methyl-2-[4-(Z)propenyl D-3-vinylpyrazol-1- ylmethyl]pentan-2-ol;

L1,1 Trifluoro-4-(5-fluoro-2-methox yphenyl)-4-methyl-2-pyrazolof1 ,5-almpyridin-2- ylmethylpentan-2-ol; 4~(5-Chloro-2,3 ~dihydrobenzofuran-7 -yl)-2,4-dimethyl-1-thieno [2,3-c]pyrmdin-2-ylpentan-2-ol; 4-(5-Fluoro-2-methylphenyl) -2 4-dimethyl-1-thieno{2,3-c]pyridin-2-ylp en—tan-2-0l; 1,1,1-Trifluoro4-(5 -fluoro-2-methox yphenyl)-2-furof2,3 -c]pyridin-2-ylmesthyl-4- methylpentan-2-ol; 4-(5-Chloro-2,3 -dihydrobenzofuran-"7-yl)-1-furo[2,3 -c]pyridin-2-yl-2,4-dimmethylpentan-2-o};

W/O 2005/030213 WCT/US2004/031009 4-(5-Fluoro-2-methylpheny)-1-furo[ 2,3-clpyridin-2-y1-2,4-dimethyipen~tan-2-ok 1,1, 1-Trifluoro-4-(5-Auoro-2-methyl phenyl)-4-methyl-2-(1 H-pyrrolo [3,22-c]pyridin-2- ylmethyl)pentan-2-ol; 11,1 Triffuoro-4-methyl-4-(5-meths/1-2,3-dihydrobenzofuran-7-y1)-2-( 1L_H-pyrrolo[3,2- ¢]pyridin-2-ylmethyl)pentan-2-ol; 100 4-(5-Chloro-2,3-dihydrobenzofuran -7-yD)-1,1,1 trifluoro-4-methyl-2-(1_H-pyrrolo[3,2-c]pyridin- 2-ylmethyi)pentan-2-ol, 4-(5-Bromo-2,3 -dihydrobenzofuran -7-y1)-1,1,1 -trifluoro-4-methyl-2-(1 H-pyrrolo[3,2-c}pyridin- 2-ylmethyl)pentan-2-ol; 1s 2-(3-Dimethylaminomethyl- 1H-pyr-rolo[3,2-c]pyridin-2-ylmethyl)-1,1, 1-trifluoro-4-(5-fluoro- 2-methoxyphenyl)-4-methylpentan—2-ol; 1,1 1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-pyrrolo[3,2—c]pyridin-1- 2€ ylmethylpentan-2-ol; 11 1-Trifluoro-4-(5-fluoro-2-methoxyphenyt)-4-methyl-2-pyrrolo [3,2—blpyridin-1- ylmethylpentan-2-ol; 25 L111 Trifluoro-4-(5-fluoro-2-meth oxyphenyl)-2-furo[3,2-c]pyridin-2-"ylmethyl-4- methylpentan-2-ol; 4-(5-Chloro-2,3-dihydrobenzofuram-7-yi)-1,1, 1-trifluoro-4-methyl-2-yrrolo[3,2-blpyridin-1- ylmethylpentan-2-ol; x0 1,1-Diflucro-4-(5-fluoro-2-methoxcyphenyl)-4-methyl-2-(14-pyrrolo[=3 ,2-c]pyridin-2- ylmethyl)pentan-2-ol;

1,1,1-Trifluoro-4-C 5-fluoro -2-methoxyphenyl)-4-methyl-2—thieno [3,2-c]pyridin-2- yimethylpentan-2—ol; 4-(5-Chloro-2,3-d_ihydrobenzofuran-7-y})- 1,11 _trifluoroE--methyl-2-thieno[3,2-c}pyridin—2- ylmethylpentan-2—o}; 1,11 Trifluoro-4—(5-fluorc-2-methylphenyl) -4-methyl-2-poyrrolo[3 ,2-blpyridin-1- ylmethylpentan-2.—ol;

1,1,1-Trifluoro-4 —(5-fluoro-2-methylphenyl)-4-methyl-2-sthieno[3,2-c]pyridin-2- ylmethylpentan-2-o0}; 4-Fluoro-2-(4,4,43-trifluoro-3-hydroxy-1,1 -dimethyl-3-thi~eno[3,2-¢]pyridin-2- ylmethylbutyl)plenol; 4-Fluoro-2-(4,4,=4-trifluoro-3-furo[3 ,2-¢c]pyridin-2-ylmettayl-3-hydroxy-1,1- dimethylbutyl)piaenof; 4-Fluoro-2-(4,4,-4-trifluoro-3-hydroxy-1,1 -dimethyl-3-pyrrolo[3,2-b]pyridin-1- ylmethylbutyl)p¥aenol; 2-[4-(5-Fluoro-2-hydroxyphenyl)-2 -hydroxy-4-methyl-2~ -trifluoromethyipentyl]-1 H-indeole-6- carboxylic acid;

2-[4-(5-Fluoro-=2-hydroxyphenyl)-2 -hydroxy-4-methyl-2= -trifluoromethylpentyl]-1H-ind_ole-6- carboxylic acid dimethylamide; {2-[4-(5-Fluoro -2-hydroxyphenyl)-2-hydroxy-4-methyl—2-trifluoromethylpentyl]- 1 Hina dol-6- yl}morpholin-4 ~ylmethanone;

2.[4-(5-Fluoro-2-methoxypheny)-2-hydrcoxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-6- carboxylic acid dimethylamide; 2-[4<(5-Fluoro-2-methoxyphenyl)-2-hydreony-4-methyi-2-triffuoromethyl gpentyl]-Li-indole-6- carboxylic acid dimethylamide; {2-4-(5-Fluoro-2-methoxyphenyl)-2-hyciroxy-4-methy1-2-trifluorometh ylpentyl]-1 H-indol-6- yl} morpholin-4-ylmethanone; 2.[4-(2,3-Dihydrobenzofuran-7-y})-2-hyeiroxy-4-methy1-2-trifluorometh=ylpentyl]-4-methyl-1H- : indole-6-carbonitrile; 2.[4-(5-Fluoro-2-hydroxyphenyl)-2-hydaoxy-4-methyl-2-trifluoromethyMpentyl]-14-indole-6- carboxylic acid amide; 2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydiroxy-4-methyl-2-trifluoromethy=lpentyl]-1 H-indole-6- carboxylic acid amide; 4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1 ,1-dimethyl-3-(5-nitro-1H-indol -2- ’ ylmethyl)butyl pheno}; . 2-[4-(5-Fluoro-2-methoxyphenyl)-2-hyciroxy-4-methyl-2-trifluorometh yipentyl]-11-indole-6- carbonitrile; 2-[4-(5-Fluoro-2-hydroxypheny)-2-hyAroxy-4-methyl-2-trifluoromeths./Ipentyl]-1 H-indole-6- carbonitrile;

N- {2-[4-(5-Fluoro-2-methoxyphenyl)-2 -hydroxy-4-methyl-2-trifluoronrethylpentyl]-14-indol- 5-yl}acetamide, 1.1, 1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-2-(7-fluoro-4-methyl- 1 J-indol-2-ylmethyl)-4- methylpentan-2-ol;

5—Fluoro-2-[4,4,4-trifluoro-3-(7 -fluoro-4-methyl-1 _H-indol-2-ylmethyl)-3-hydroxy- n.l- d#methylbutyl]phenol;

2 [4-(3-{1,3]Dioxolan-2-ylphenyl)-2-hydroxy-4-miethyl-2-trifluoromethylpentyl}-1 F-indole-3-

. c arbonitrile; 2. {4-(5 Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl}- 1aH-indole-5- carboxylic acid-2-trimethylsilanylethy) ester;

> {4-(5-Fluoro-2-methoxypheny)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1_H-indole-3- carboxylic acid; ~2.[4-(4-Fluoro-2-hydroxyphenyl) -2-hydroxy-4 -methyl-2-triflucromethylpentyl}-4- -methyl-1H-

indole-6-carbonitrile;

{2-[4-(5-Fluoro-2-methoxyphenyl)-2-bydroxy-4 —methyl-2-trifluoromethylpentyl] ~1H-indol-5- yl} piperidin- 1-ylmethanone;

2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]- 1H-indole-5- carboxylic acid methylamide; {2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl_}-1F-indol-5- yl} pyrrolidin-1-ylmethanone;

{- {2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydrox y4-methyl-2-trifluoromethylpent=yl]-11-indole- 5-carbonyl}piperidin-4-one; 2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4—methyl-2-trifluoromethylpentyl]—1H-indole-3 -

carboxylic acid (2-hydroxyethyl)amide;

: (2-4-(5-Fluoro-2-methoxyphesnyl)-2-hydroxy-4-methyl-2-rifluororethylpentyl}-14/-indol-5- : y1}(4-hydroxypiperidin-1-yl)onethanone; : (2-74-(5-Fluoro-2-methoxyph enyl)-2-hydroxy-4-methyl-2-triftuor oxxethylpentyl]- 1 7-indol -5-

y1}(3-hydroxypyrrolidin-1-yI»methanone;

2-[4-(5 Fluoro-2-methoxyphesnyl)-2-hydroxy-4-methyl-2-trifluoro rrethylpentyl]-1 H-indole-5- carboxylic acid cyanomethylaamide;

2-[4-(5-Fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoro methylpentyl]-1H-indole-5- carboxylic acid (2-dimethylaxminoethyl)amide; {2-{4~(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorcamethylpentyl]-1H-indol-5- y1}(4-methylpiperazin-1-yl)mnethanone;

({2-[4-(5-Fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluox—omethylpentyl}-1H- -indole- 5-carbonyl}amino)acetic aci<l methyl ester; 2-[4-(5-Fluoro-2-methoxyph. enyl)-2-hydroxy-4-methyl-2-trifluoro x-nethylpentyl]-14-indole-5-

carboxylic acid carbamoylmeethylamide; 4-({2-[4-(5-Fluoro-2-methoz<yphenyl)-2-hydroxy-4-methyl-2-triflisoromethylpentyl]-1H- indole-5-carbonyl}amino)butyric acid methyl ester;

({2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluomromethylpentyl]-14-indole- 5-carbonyl}amino)acetic aci d; 4-({2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-triflt_zoromethylpentyl]-1H- indole-5-carbonyl}amino)buatyric acid;

2-[4-(3-Dimethylaminomettaylphenyl)-2-hydroxy-4-methyl-2-trifl mioromethylpentyl]-1 H- indole-5-carbonitrile;

4-Fluoro-2-[4,4,4-trifluoro-3-hydreoxy-1 ,1-dimethyl-3-(5 -trifluoromethyB-1 H-indo}-2~ yimethyl)butyllphenol;

2-[4-(5-Bromo-2,3-dibydrobenzofFuran-T-yl)-2-hydroxy-4-methyl-2-triffuoromethyipentyl]-4-

} methyl-1H-indole-6-carbonitrile; } 2-[2-Hydroxy-4-(5-methanesulfomyl-2,3-dihydrobenzofuran-7-yl)-4-mesthyl-2- triftuoromethylpentyl]-4-methyl- 1H. -indole-6-carbonitrile;

2-[4-(5 Bromo-2,3-dihydrobenzosfuran-7-yl)-2-hydroxy-4-methyl-2-triSfluoromethylpentyl}-1LH -

indole-5-carboxylic acid;

2-[4-(5-Bromo-2,3-dihydrobenzofuran-7 -yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- indole-5-carboxylic acid amide;

2-[4-(5-Bromo-2,3 dihydrobenzeofuran-7-yl)-2-hydroxy-4-methyl-2-tri_fluoromethyipentyl]-1H-

indole-5-carboxylic acid dimethylamide;

2-[4~(5-Bromo-2,3-dihydrobenz «ofuran-7-yl)-2-hydroxy-4-methyl-2-tri fluoromethylpentyl]-1H-

indole-5-carboxylic acid cyanonaethylamide;

{2-[4-(5 -Bromo-2,3-dihydrobenyzofuran-7-yl)-2-hydroxy-4-methyl-2-@riftuoromethylpentyl}-

1 H-indol-5-y1} pyrrolidin-1-ylmeethanone;

{2-[4-(5 -Bromo-2,3-dihydrobermzofuran-7-yl)-2-hydroxy-4-methyl-2-~trifluoromethylpentyl]-

1H-indol-5-yl}morpholin-4-ylmethanone;

2-[4-(5 -Fluoro-2-methoxyphensy1)-2-hydroxy-4-methyl-2-trifluoromesthylpentyl]-1H-indole-5- carboxylic acid amide;

(2-[4-(5-Fluoro--2-methoxyphenyl)-2-hydroxy-4-methyR-2-trffuoromethyl pentyl]-1 H-inecol->- yl}morpholin-4- ylmethanone; 2-(4-Benzo[1,3]-dioxo 1-4-yl-2-hydroxy-4-methyl -2-trifl~uoromethylpentyl)- 4-methyl-1H-inclole-6-carbonitrile; 1,1, )-Trifluoro—4-methyl-4-phenyl-2-quinolin-4-ylmetinylhexan-2-ol; 2-[2-Hydroxy-4--methyl-4-(5-methylsulfany!-2,3-dihydkrobenzofuran-7-y1)- :

Lo 10 2-trifluorometh—yipentyl}-1H-indole-3-carbonitrile; 7-(4,4,4-Triflucoro-3-hydroxy-1, 1-dimethyl-3-quinolin—4-ylmethylbutyl)- 2,3-dihydroben_zofuran-5-carbonitrile; 2-[2-Hydroxy-=4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-y1)- 4-methyl-2-trif Tuoromethylpentyl}-1H-indole-3-carbomnitrile; 2-[2-Hydroxy-=4-(2-hydroxy-5-methylphenyl)-4-methsy-2-trifuoromethylpentyl]- 4-methyl-1H-imadole-6-carbonitrile; 1,1,1-Trifluorom-4-(5-fluoro-2, 3-dihydrobenzofuran-7-"yi)-4- methyl-2-(5-m_ethylsulfanyl-1H-indol-2-ylmethyD)pem tan-2-ol;

R 2-[2-Hydroxy—4-(2-methoxy-5-methylsul fanylphenyl D-4-methyl-2-triftuoromethylpent=yl]-1H- indole-3-carbomnitrile; : 2-[2-Hydroxy—45-methanesulfonyl-2-methoxyphenwy])-4-methyl-2-trifluoromethyl- 1 pentyl}-1H-inclole-3-carbanitrile; 2-[4-(5-Fluorc>-2,3-dihydrobenzofuran-7-yl)-2-hydro=xy-4-methyl-2- . trifluoromethy/Ipentyl}- 1 H-indole-5-sulfonic acid dinsethylamide;

1,1,1-"Trifluoro-4~(5-fluoro-2,3 -dihydrobenzofura-n-7-yl) -4-methyl-2-(5-phenyl- . 1H-inedol-2-ylmethyl)pentan-2-ol; 2.[4-C 5-tert-Butyl-2-hydroxyphenyl)-2-hydroxy-=4-methyl-2-trifluoromethyl- ) penty=1}-1H-indole-3-carbonitrile; 2-[2-BElydroxy-4-(2-hydroxy-3-isopropylphenyl)—4-methyl-2-triftuoromethyl- penty=1]-1H-indole-3-carbonitrile; 2.[2-Hydroxy-4-(2-hydroxy-3,5-dimethylphenyl )-4-methyl-2-trifluoromethylpen®yl]- 1 H-ixndole-3-carbonitrile; 2-[2—Hydroxy-4-(5-hydroxy-2,4-dimethylphenyh }-4-methyl-2-triflucromethylpen-tyl]- 1 H-imndole-3-carbonitrile;

} 2-[4—(5-tert-Butyl-2-methoxyphenyl)-2-hydroxy=-4-methyi-2-trifluoromethylpent=yl}- 1H-i mdole-3-carbonitrile; 2 [4—(5-tert-Butyl-2-methoxyphenyl)-2-hydroxy~-4-methyl-2-trifluoromethylpent yl]- 1-mesthyl-1H-indole-3-carbonitrile; 2-2 _Hydroxy-4-(5-isopropyl-2-methoxyphenyl D-4-methyi-2-triftuoromethylpentyl]- 1H-mndole-3-carbonitrile; 22 -Hydroxy-4-(5-isopropyl-2-methoxyphenyl )-4-methyl-2-trifluoromethylpenttyl]- 1-m_ethyl-1H-indole-3-carbonitrile; 2-[2=-Hydroxy-4-(2-hydroxy-5-methanesulfonyP phenyl)4-methyl-2- trifl-uoromethylpentyl]-1H-indole-3-carbonitrile;

2-[2-Hydroxy-4-(2-methoxy-5-methylphenyl)-=}-methy}-2-triflucromethylpentyt ]-4-methyl- 1H- indole-6-carbonitrile;

: 11, 1-Trifluoro-4-methyl-2-quinolin-4-ylmeth yl-4-o-tolylp entan-2-ol; 1,1,1-Trifluoro-4-methyl-2 -quinolin-4-ylmeth yl-4 -m-tolylpentan-2-ol; : 5 ’ L1, 1-Trifluoro-4-(2-fluorophenyl)-2-(1H- _ind©l-2-ylmethyl)-4-methylpentan-2-ol; 1,1, -Trifluoro-4-(2-fluorophenyl)-4-methyl-2-quinolin-4-ylmethylpentan-2-ol; 1,1,1-Trifluoro-4-(3-fluorophenyl)-2-(1H- _indol-2-ylmethyl)-4-methylpentan-2-0l5

L1,1 Trifluoro-4-(3-fluorophenyl)-4-methyl ~2-quinolin-4-ylmethylpentan-2-ol;

L1, |-Trifluoro-4-(4-fluorophenyl)-2-(1 H-inclol-2-ylmethyl)-4-methylpentan-2-ol 3 1,1,1 Trifluoro-4-(4-fluorophenyl)-4-methyl —2-quinolin-4-ylmethylpentan-2-ol; 3-(4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3 -quinolin-4-ylmethylbutyl)phenol; 1,1 1-Trifluoro-4-methyl-2-quinolin-4-ylmethyl-4-(2-trifluoromethylphenyl)pent= an-2-ol; 1,1,1-Trifluoro-2(1H- indol-2-ylmethyl)4-maethyl-4-(4-trifluoromethylphenyl)pentan-2-ol; 1,1,1 “Trifluoro-4-methyl-2-quinolin-4-ylme thyl-4-(4-trifluoromethylphenyl)penttan-2-ol; 4-(3-Chlorophenyl)-1,1,1-trifluoro-2-( 1H-in dol-2-ylmethyl)-4-methylpentan-2-0 1; 4-(3-Chlorophenyl)-1,1,1 -trifluoro-4-methy1-2-quinolin-4-ylmethylpentan-2-ol; 4-(4-Dimethylaminophenyl)-1,1,1-trifluoro—2- 1H-indol-2-ylmethyl)-4-methylpentan-2-ol; 4-Biphenyl-3-yl-1,1,1 -trifluoro-4-methyl-2—quinolin-4-ylmethylpentan-2-ol;

4-(3-Bromophenyl)-1,1,1 -trifluoro-2-(1H- _indol-2-ylmethyl)-4-methylpentara-2-ol; 4-(2-Difluoromethoxy-5-fluorophemyl)-1,1,1-triffuoro-2-(1H _indol-2-ylmetWhyl)-4- methylpentan-2-0l; 4-Biphenyl-3-yl-1,1,1 ~trifluoro-2-( 1H-indol-2-ylmethy!)-4-methylpentan-2—ol; 4-(4-Dimethylaminophenyl)-1,1,1 —trifluoro-4-methyl-2-quinolin-4-ylmethy/lpentan-2-ol;

2-[4-(5-Fluoro-2-methylphenyl)-2 —hydroxy-4-methyl-2-triflucromethylpermtyl}-1,6- dibydropyrrolo[2,3-c]pyridin-5-on.e; 2-[4-(5-Fluoro-2-methylphenyl)-2 ~hydroxy-4-methyl-2-trifluoromethylperatyl}-6-methyl-1 ,6- 1-5 dihydropyrrolo[2,3-c]pyridin-5-orae; 2-[4-(5 ~Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-triflucromethylpertyl]-4-methyl- 1,4- dihydropyrrolo(3,2-b]pyridin-5-oxe; 2:0 1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-2-(6-methoxy- 1H-pyrrolo[3,2-c]pyridin-2- ylmethyl)-4-methylpentan-2-ol; 2-[4-(5-Fluoro-2-methylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpe mntyl]-5-methyl-1 »S- dihydropyrrolo{3,2-c]pyridin-6-oxe;

2-[4-(S -Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpe=ntyl]-1 »Ja- dihydropyrrolo[3,2-c]pyridin-6-one; 2-{4-(5-Fluoro-2-methylpbenyl)-2 -hydroxy-4-methyl-2-trifluoromethylpe=ntyl]-1,7- =30 dihydropyrrolo[3,2-c]pyridine-4, 6-dione;

6-[4-(5 ~Fluoro-2-methylphenyl)-2 -hydroxy-4-m_ethyl-2 -trifluoromethylpentyl]-3—methyl-1,7- dihydrcypyrrolof2,3-dlpyrimidine-2,4-dione; : 2-[4-(5-Chloro-2,3 -dihydrobenzofuran-7-yl) -2-kaydroxy-4-methyl-2-trifluorometibylpentyl]-1 ,6-

dihydreopyrrolof2,3-c]pyridin-5-one; 2-{4(SS Chioro-2,3-dihydrobenzofaran-7-y)-2-Thydroxy-4-methyl-2-trifluoromet=hylpentyl]-6- methy 1-1, 6-dihydropyrrolo[2,3-c]pyridin-5-one=;

2-[4~(=5-Chloro-2,3-dihydrobenzofuran-7 -yi) -2—hydroxy-4-methyl-2-trifluorome=thylpentyl]-1 4 dihyd-xopyrrolo[3,2-b]pyridin-5-one; 2-[4-C5-Chloro-2,3 dihydrobenzofuran-7-yl)-2 —hydroxy-4-methyl-2-trifluorome=thylpentyl}-4- methsyl-1,4-dihydropyrrolo[3,2-bjpyridin-5-on-«;

2-[4-€/5-Chloro-2,3-dihydrobenzofuran-7-yl)~2- -hydroxy-4-methyi-2-trifluorome=thylpentyl]- 1,5-

dihy@ropyrrolo[3,2-c]pyridin-6-one;

2-[4-«(5-Chloro-2,3-dihydrobenzofuran-7-yl)-22 -hydroxy-4-methyl-2-trifluoromeethyipentyl]-5- meth yl-1,5-dihydropyrrolo[3,2-c]pyridin-6-orme;

4-(5—Chloro-2,3-dihydrobenzofuran-7-yi)-1,1 1-triflucro-2-(6-methoxy-5,6-dihmydro-1H-

pyrrolo[3,2-c]pyridin-2-ylmethyl)-4-methylpentan-2-ol;

2-[4—(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluorommethylpentyl}-1,7-

dihy=dropyrrolo[3,2-c]pyridine-4,6-dione; 6-[4—(5-Chloro-2,3-dihydrobenzofuran-7-yl)- 2-hydroxy-4-methyl-2-trifluoronethylpentyl]-3- metknyl-1,7-dihydropyrrolo[2,3-dpyrimidine—2,4-dione;

2-[4 -(3-Dimethylaminomethylphenyl)-2-hydaroxy-4-methyl-2 -trifluoromethyly=entyl]-1H- indcole-5-carbonitrile;

1,1,1-Trifluoro-2-( 1H-indol-2-ylmethyl)-4-methyl-4-(3 -morpholin-4-ylmethyliohenyl)pentan-2- ol; 1,1,1-Trifluoro-4-methyl4-(3-moxpholin-4-ylmethylpheny)-2-(1H-pyrrolo[2, 3-dlpyridazin-2- ylmethyl)pentan-2-ol; 1,1,1-Triflucro-4-(5 fluoro-2-methylphenyl)-4-methyl-2-(5 -morpholin-4-ylme=thyl-1H-indol-2- ylmethyl)pentan-2-ol;

1,1,1 “Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-(5 -morpholin-4-ylmeethyl-1H- pyrrolo[2,3 -c]pyridin-2-ylmethyl)pentan-2-ol; {2-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent=yi}-1#-indol-5- yl}phenylmethanone; {24-(5-Fluoro-2-methylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpent=yl}- 1H- pyrrolo[2,3-c]pyridin-5-yl} phenylmethanone; {2-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpeneyl}-1H-indol-3- yl} furan-2-ylmethanone; {2- [4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl -2-triflucromethylpenwtyl]-1H- pyrrolo[2,3-¢clpyridin-5-yl} furan-2-ylmethanone;

1,1,1-Triftuoro-2~(1 H-indol-2-ylmethyl)-4-methyl-4-pyridin-2-ylpentan-2-01; 4-(3-Chloro-2-fluoro-5 _trifluoromethylbenzy!)-5,5,5-trifluoro-4-hydroxy-2-mmethyl-2- phenylpentanenitrile;

1,1,1-Trifluoro-4-methyl-4-pyri din-4-yl-2-quinolin-4-ylmethylpentan-2-ol;

2-(=,6-Dimethylpyridin-4-ylmethyl)-1,1, 1-tarifluoro-4-(5-fluoro-2-methc>xyphenyl)-4- me®thylpentan-2-ol; 2-[23+(2,6-Dimethylpyridin-4-ylmethyl)-4,4 ,4 trifluoro-3-hydroxy-1,1-d—imethylbutyl]-4- flueorophenol; ; 1,M ,1-Trifluoro-4,4-dimethyl-5-phenyl-2-quuinolin-4-ylmethylpentan-2- al; 1, M,1-Trifluoro-4-(5-fluoro-2-methoxyphemnyl) -4-methyl-2-pyridin-4-yLmethylpentan-2-ol; 4-"Fluoro-2-[4,4,4-trifluoro-3-(2-flucropyrk din-4-ylmethyl)-3-hydroxy- 1,1- dizxnethylbutyl]phenol; 2—[3-(2-Bromopyridin-4-ylmethyl)-4,4,4-tifluoro-3-hydroxy-1,1-dimesthylbutyl)-4- flmoropheno; 2—(6,8-Dimethylquinolin-4-ylmethyl)-1,1, 1rifluora-4-(5-fluoro-2-me thoxyphenyl)-4- mmethylpentan-2-ol; 4—[4-(5-Fluoro-2-methoxyphenyl)-2-hydreoxy-4-methyl-2-trifluoromet=hylpentyl]pyridine-2- caarbonitrile; 2 ,6-Dichloro-4-[4-(5-fluoro-2-methoxyphuenyl)-2-hydroxy-4-methyl-22- tr—ifluoromethylpentyl]nicotinonitrile; 4 [4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome #thylpentyl]quinolin-2-ol; 2= 6-Dichloro-4-[4-(5-fluoro-2-hydroxyplmenyl)-2-hydroxy-4-methyl-2=- tarifluoromethylpentyllnicotinonitrile;

Z2-(2-Chloro-8-methylquinolin-4-ylmethy1)-1,1,1-trifluoro-4-(5 -fluorca-2-methoxyphenyl)-4- rethylpentan-2-ol;

2-(2,6-Dichloroquinolin-4-ylmetixyl)-1,1,1-trifluoro-4-(5-fluoro-2-methox ys phenyl)-4- methylpentan-2-ol;

2-[3-(2-Chloro-8-methylquinolin ~4-ylmethyl)-4,4,4-triftuoro-3-hydroxy-1,. 1-dimethylbutyl]-4- fluorophenol;

23 -(2,6-Dichloroquinolin-4-ylrmethyl)-4,4,4-trifluoro-3 -hydroxy-1,1-dinethylbutyl]-4- fiuorophenol;

4-23 -Dihydrobenzofuran-7-yl)—2-(2,6-dimethylpyri din-4-ylmethyl)-1,1, M -trifluoro-4- methylpentan-2-ol; 2-(2,6-Dimethylpyridin-4-ylmethyl)-1,1,1 -trifluoro-4-(3-flucrophenyl)-4—methylpentan-2-ol;

2-(2,6-Dimethylpyridin-4-ylmethyl)-1,1,1 -trifluoro-4-(4-fluorophenyl)-4—methylpentan-2-ol; 11,1 “Trifluoro-4-(5-fluoro-2-m ethylphenyl)-4-methyl-2-quinolin4-yime=thylpentan-2-ol; 2-(2,6-Dimethylpyridin-4-ylme#thyl)-1,1,1-trifluoro-4-(5 -fluoro-2-methylphenyl)-4- methylpentan-2-ol; 2-(2,6-Dimethylpyridin-4-ylme-thyl)-1,1,1-trifluoro-4-methyl-4-m-tolylp e=ntan-2-ol; 1,1,1-Trifluoro-4-(5 -fluoro-2-methoxyphenyl)-4-methyl-2-(2-methylquiraolin-4- ylmethyl)pentan-2-ol; 4-Fluoro-2-(4,4,4-trifluoro-3-h vdroxy-1,1 -dimethyl-3-quinolin-4-ylmetimylbutyl)phenol; 4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(2-methylquinolira4- ylmethyDbutyl]phenol;

WO» 2005/030213 PCT/US2004/031009 2-(2,6-Dimethylpyridin-4-ylmethyl)-1,1 ,1-triftuoro-4-(4-fluoro-2-methomcyphenyl)-4- methylpentan-2-ol; 1,1,1-Trifluoro-4-(5 -fluoro-2-methoxypehenyl) -A-methyl-2-(7-methylquimnolin-4-

ylmethyl)pentan-2-ol; 2-[3-(2,6-Dimethylpyridin-4-yimethyl) —4.4 4-trifluoro-3-hydroxy-1 ,1-di_methylbutyi]-5- fluorophenol;

2-(5,7-Dimethylquinolin-4-ylmethyl)-1. ,1,1-trifluoro-4-(5 -fluoro-2-metinoxyphenyl)-4-

. methylpentan-2-ol; 1,1,1 -Trifluoro-4-(4-fluorophenyl)-4-nethyl-2-(2 -methylquinolin-4-ylrmnethyl)pentan-2-ol;

1,1,1-Trifluoro-4-(3-fluorophenyl)-4-rmethyl-2-(3 -methyl-1H-indol-2-y—1methyl)pentan-2-ol;

1,1,1-Trifluoro-2-(1H. indol-2-ylmethsw/1)-4-methyl-4-(2-trifluoromethyMphenyl)pentan-2-ol; 1,1,1-Trifluoro-4-(5-fluoro-2 -methoxysphenyl)-2-(7-fluoro-4-methylquasnolin-8-yl)-4-

methylpentan-2-ol;

4-(2,6-Dimethylphenyl)-1,1,1-trifluore-2-(14- -indol-2-yimethyl)-4-me#thylpentan-2-ol; 2-(3-Bromo-1H-indol-2-ylmethyl)-1, 1 I-trifluoro-4-(3-fluorophenyl)-<3-methylpentan-2-ol;

43,4-Dimethylphenyl)-1,1,1-trifluoro-2-(1H: -indol-2-ylmethyl)-4-me—thylpentan-2-ol; 1,1,1-Trifluoro-4-(3-fluoro-4-methylohenyl)-2-( 1H-indol-2-ylmethyl)—4-methylpentan-2-ol;

300 1,1,1-Trifluoro-4-(4-fluoro-3-methylohenyl) -2-(1H-indol-2-ylmethyl) —4-methylpentan-2-ol;

1,1,1-Trifluoro-4-(3-fluoro-4-methyliohenyl)-4-methyl-2-quinolin-4-y Amethylpentan-2-ol;

1,1,1-T-ifluoro-4-(4 fluoro-2-methylphenyl)-4-methyR -2-quinolin-4-ylmethylpentan-2-ol; 4-(3,4-Dimethylphenyl)-1,1, 1-trifluoro-4-methyl-2-quainolin4-ylmethylpentan-2~ ol; 4-(2,5-Dimethylpbenyl)-1,1, 1-trifluoro-2-(1 H-indo}- 2 -ylmethyl)-4-methylpentan—2-ol; 1,1,1-Txifluoro-2-(1H -indol-2-ylmethyl)-4-(2-methoxy-5 -methylphenyl)-4-methyylpentan-2-0};

N 10 4-Methayl-2-[4,4,4-triflucro-3 -hydroxy-3-(1H -indol-2=-ylmethyl)-1, 1-dimethylbut_yl}phenol; 4-(2,5- Dimethylphenyi)-1,1, 1-trifluoro-4-methyl-2-q uinolin-4-ylmethylpentan-2 -ol; 1,1,1-Trifluoro-4-(2-methoxy-5 -methylphenyl)-4-mesthyl-2-quinolin-4-ylmethylpoentan-2-ol; : 4-(2,5~Dimethoxyphenyl)-1,1,1 -trifluoro-4-methyl-2- -(1L H-pyrrolo[2,3-c]pyridin—2- ylmetimyl)pentan-2-ol; 1,1,1-Tnfluoro-4-(5-fluoro-2-methoxyphenyl)-4-me ~thyl-2-(7H-pyrrolo[2,3-d]py~rimidin-6- ylmethyl)pentan-2-ol; 1,1, 1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-(4-methoxy-7H-pyrrolo[2,3-d] pyrimidin-6- ylmetkayl)-4-methylpentan-2-ol; ’ 25 2-24 —Dimethyl-7H-pyrrolo[2,3-d]pyrimidin-6-ylm-ethyl)-1,1,1-trifluoro-4-(5-fluoro-2- ) methowxyphenyl)-4-methylpentan-2-ol; 2-(2-A mino-4-chloro-7H-pyrrolo[2,3-dlpyrimidin-6s-ylmethyl)-1,1,1-trifluoro-4—(5-fluoro-2- methoxyphenyl)-4-methylpentap-2-ol; 2-(2,4&-Dimethyl-7H-pyrrolof2,3 -d]pyrimidin-6-ylmuethyl)-1,1,1-triftuoro-4-(5-fluoro-2- methy./Iphenyl)-4-methylpentan-2-ol;

2-(5-ChRoro-1H-pyrrolo[2,3 -c]pyridin-2-ylmetkayl)-1,1,1-trifluoro-4-(5 -fluoro-2-rnethylphenyl)- . 4-methy=lpentan-2-ol; 4-(5-Brcomo-2-methoxyphenyl)-1,1, 1-trifluoro—4-methyl-2-(5-piperidin-1-yl- 1 H-goyrrolof2,3- c]pyridi-n-2-ylmethyl)pentan-2-ol; 1,1,1-Tr=ifluoro-4-(5 -fluoro-2-methoxyphenyl)—4-methyl-2-(5 -morpholin-4-yl-1®-pyrrolo[2,3- c]pyridi_n-2-ylmethyl)pentan-2-ol;

4-(5-Breomo-2-methoxyphenyl)-1,1,1-triflucro —4-methyl-2-(5-morpholin-4-yl- 1 Fad-pyrrolo[2,3- c]pyridin-2-ylmethyl)pentan-2-ol; 1,1, 1-Terifluoro-4-(5-fluoro-2-methylphenyl)-4--methyl-2-(5 -morpholin-4-yl-1H-gpyrrolo[2,3- c]pyridMn-2-ylmethyl)pentan-2-ol; 2-(5-Di _methylamino-1H-pyrrolo[2,3-c]pyridira-2-ylmethyl-1,1, 1-trifluoro-4-(5- methan- esulfonyl-2,3-dihydrobenzofuran-7-yl) —4-methylpentan-2-ol; 1,1,1-T-riftuoro-4-(5-methanesulfonyl-2,3-dihysdrobenzofuran-7-yl)-4-methyl-2-C S-piperidin-1- yl- 1 H-poyrrolo[2,3-c]pyridin-2-ylmethyl)pentam-2-ol; 2-(5-Di. methylamino-1H-pyrrolo[2,3-c]pyridira-2-ylmethyl)-1,1,1-triflucro-4-(5- fluoro-2- methylgphenyl)-4-methylpentan-2-ol;

2-[5-(E~thylmethylamino)- 1 H-pyrrolo[2,3-c]py-smidin-2-ylmethyi]-1,1,1-trifluoro-=4-(5-flucro-2- methylgphenyl)-4-methylpentan-2-ol; 4-(5-Chkaloro-2,3-dihydrobenzofuran-7-yl)-2-[ 5 -(ethylmethylamino)- 1 H-pyrrolo[ =2,3-¢]pyridin-2- ylmeth—vl]-1,1,1-trifluoro-4-methylpentan-2-ol ;

2-[5-(Bthylmesthylamino)- 1H.-pyrrolo[2,3-c]pyridin-22 -ylmethyl]-1 ,1,1-trifluoro-4-(5-£luoro-2- methoxyphen_yl)-4-methylpentan-2-ol;

1,1, 1-Trifluoxo-4-methyl-2-(5-morpholin-4-yl-15- ~py~r1rolof2,3 -c]pyridin-2-ylmethyl)—4- phenylpentam-2-ol;

11,1 -Trifluoxo-4-(3-fluorophenyl)-4-methyl-2-(5 -meorpholin-4-yl- 1H-pyrrolo[2,3-c}gpyridin-2- ylmethyl)perntan-2-ol;

1,1,1-Trifluoxo-4-(5 -fluoro-2-methylphenyl)-4-methm yl-2-(5-pyrrolidin-1 -yl-1H-pyrrolo[2,3- c]pyridin-2-y/imethyl)pentan-2-ol; 1,1,1-Trifluoro-4-methyl-4-phenyl-2-(5-pyrrolidin- Bt -yi- | H-pyrrolo[2,3-c}pyridin-2-

ylmethyl)pertan-2-ol; 4'-Methoxy—3’-[4,4,4-trifluoro-3-hydroxy-1,1-dime—thyl-3-(5 -morpholin-4-yl-1 H-py=xmolo[2,3- cIpyridin-2-ylmethyl)butylJbiphenyl-2-carbonitrile;

2-(5-Diethylamino-1H-pyrrolo[2,3-clpyridin-2-ylm-ethyl)-1,1,1 -trifluoro-4-(5-fluoro-2-

methylpheny/1)-4-methylpentan-2-ol; . 1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-2-[5-( sopropylmethylamino)- 1 H-pyrreolo{2,3- : c]pyridin-2- ylmethyl]-4-methylpentan-2-ol;

1,1,1-Triftuoro-2-[5-(isopropylmethylamino)-1 H-p —ymolo[2,3-clpyridin-2-ylmethyl } -4-methyl- 4-phenylperatan-2-ol; 2-(5-DiethyXamino- 1 H-pyrrolo[2,3-c]pyridin-2-ylnmethyl)-1,1,1-trifluoro-4-methyl-<3- phenylpentan-2-ol;

4-(3-Bromopahenyl)-1,1, 1-trifluoro-4-methyl-2-(5-morp_holin-4-yl-1H-pyrrolo {2,3-c]pyr-idin-2- ylmethyl)pexatan-2-ol; 1,1,1-Trifluc>ro-4-(4-fluorophenyl)-4-methyl-2-(5-morpwholin-4-yl-1H-pyrrolo[2,3-c]pyr=idin-2-

ylmethyl)pemtan-2-ol; : 1,1,1-Triflucro-4-(4-fluorophenyl)-4-methyl-2-(5-pyrroolidin-1-yl-1H-pyrrolo[2,3-c}pyr-idin-2- ylmethyl)pemtan-2-ol;

. ’ 1,1,1-Triflueoro-4-methyl-2-(5-morpholin-4-yl-1 H-pyrr—olo[2,3-¢]pyridin-2-ylmethyl)-4—(3- pyrimidin-5 ~ylpbenyl)pentan-2-ol; 2-[5-(2,6-D=methylmorpholin-4-yl)-1H-pyrrolof2,3 -clwpoyridin-2-yimethyl]-1,1,1-triflucero-4-(5-

fluoro-2-me=thylphenyl)-4-methylpentan-2-ol; 2-[5-(Ethylmmnethylamino)-1H-pyrrolo[2,3-c]pyridin-2- ylmethyl}-1,1,1 -triflucro-4-metizayl-4- phenylpent=an-2-ol;

2-[5-(Ethylamethylamino)-1H-pyrrolo[2,3-clpyridin-2— ylmethyl]-1,1,1-triftuoro-4-(3- fluorophen~y1)-4-methylpentan-2-ol; 1,1,1-Triflcaoro-4-(3-flucrophenyl)-4-methyl-2-(5-pyrmrolidin-1-yl-1H-pyrrolo[2,3-c]py~ridin-2- ylmethyl)p=entan-2-ol;

- 25 2-(5-Diethsylamino-1H-pyrrolo[2,3-c]pyridin-2-yimetlayl)-1,1,1-triflucro-4-(3 -fluoroplhenyl)-4- methylpentan-2-ol; 1,1,1-Trifliaoro-4-(3-fluorophenyl)-2-[S-(isopropylme- thylamino)-1H-pyrrolo[2,3-c]py-ridin-2- ylmethyl]-=4-methylpentan-2-ol;

3°-{3-[5-(Fthylmethylamino)-1H-pyrrolo[2,3 -cJpyridime-2-ylmethyl]-4,4 4-trifluoro-3B-hydroxy- 1,1-dimettmylbutyl}-4’-methoxybiphenyl-2-carbonitrile 5

2-[5-(Ethylmethylamino)-1H-pyrrole[2, 3-c]pyridin-2-y/lmethyl]}-1,1,1-trifluoro-4-(2—methoxy- 5-pyrimid#n-5-ylphenyl)-4-methylpentan-2-ol; 3°-{3-[5-(MBthylmethylamino)-1H-pyrrolo[2,3-c]p yridir-2-ylmethyl]-4,4,4-trifluoro-33-hydroxy- 1,1-dimetlaylbutyl}-4>-hydroxybiphenyl-2-carbonitrile 5

4’-Hydroxxy-3’-[4,4,4-trifluoro-3-hydroxy-1,1 -dimethy~1-3-(5-morpholin-4-yl-1H-pymrrolof2,3- cJpyridin-—2-ylmethyl)butylbiphenyl-2-carbonitrile;

1,1,1-TrifMuoro-4-(5-fluoro-2-methylphenyl)-4-methyl —2~(5-morpholin-4-ylmethyl- 8 H-

pyrrolo[3, 2-b]pyridin-2-ylmethyl)pentan-2-ol; 2-(5-Dime=thylaminomethyl-1 H-pyrrolo[3,2-b]pyridin—2-ylmethyl)-1,1,1-trifluoro-4—(5-fluoro- 2-methylpshenyl)-4-methylpentan-2-ol;

1,1,1-Trif Tuoro-4-(5-fluoro-2-methylphenyl)-4-methyl -2-[5-(4-methylpiperazin-1-yBMmethyl)- 1H-pyrroR o[3,2-b)pyridin-2-ylmethyl]pentan-2-ol; . 4-(5-Chlowro-2,3-dikydrobenzofiuran-7-yl)-2-(5-dimeth_ylaminomethyl-14-pyrrolo[3 ,2- blpyridin—2-ylmethyl)-1,1, 1 -trifluoro4-methylpentan—2-ol;

4-(5-Chlowro-2,3-dihydrobenzofuran-7-y1)-1,1,1-triflucaro-4-methyl-2-(5-morpholin-—4-ylmethyl- 1H-pyrroMo[3,2-b]pyridin-2-ylmethyl)pentan-2-ol; 4-Chloro—2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3 —(5-morpholin-4-ylmethyl-1 F=-

pyrrolo[3_,2-b]pyridin-2-ylmethyl)butyllphenol;

1,1,1-Trifluoro-4-(5 -fluoro-2-methylphenyl)-4-methyl-2-(4-methyl-1-pyrro=lo[3 ,2-c]pyridin-2- ylmethyl)pentan-2-ol; 4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-1, 1,1-trifluoro-4-methyl-2-(4-methmyl- 15. -pyrrolo[3,2-

cJpyridin-2-ylmethyl)pentan-2-01; 1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-(5 -methyl-1H-pyrxolo[2,3-c]pyridin-2- ylmethyl)pentan-2-ol;

4-(5-Chloro-2,3-dihydrobenzofuran-7-y1)-1,1,1 -trifluoro-4-methyl-2-(5-metlhyl-1H-pyrrolo[2,3- c]pyridin-2-ylmethyl)pentan-2-ol; 2-[2-Hydroxy-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methyl —2- trifluoromethylpentyl}-4-methy1-1H-pyrrolo[3,2-c]pyridine-6-carbonitrile;

2-{4-(5-Chloro-2,3 -dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluorcomethylpentyl]-1H- pyrrolo[3,2-blpyridine-5-carbomitrile; 1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2{5 H-pyrrolo[3 2-d_Jpyrimidin-6-

: 20 ylmethyl)pentan-2-ol; 2-[4-(5-Chloro-2,3-dihydroben zofuran-7-yl)-2-hydroxy-4-methyl-2-trifluor=omethylpentyl]- 1 H- pyrrolo[2,3-c]pyridine-5-carbomnitrile;

2-[4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluor omethylpentyl]-1H- pyrrolo[3,2-b]pyridine-5-carboxylic acid methyl ester; 1-{2-[4-(5-Chloro-2,3-dihydrobenzofuran-7-y})-2-hydroxy-4-methyl-2-trifl uoromethylpentyl]- 1H-pyrrolo[3,2-b]pyridin-5-yl } ethanone;

4-(5-Chloro-2,3-dihydrobenzo furan-7-yl)-1,1, 1 -triflucro-4-methyl-2-(6 H-p-ymolo{2,3- glquinoxalin-7-ylmethyl)pentan-2-ol;

2-[4-(5-Chloro-2,3-dihydro benzofuran-7-y})-2-hydroxy-4-methyR -2-trifluoromethylpentyl}-1H- pyrrolo[3,2-b]pyridine-5-camrboxylic acid amide;

2-[4-(5-Chloro-2,3-dihydro-benzofuran-7-yl)-2-hydroxy-4-methy}-2-trifluoromethylpentyl]-1H-

} pyrrolo[3,2-b]pyridine-5-caarboxylic acid; {2-[4-(5-Chloro-2,3-dihydi—obenzofuran-7-yl)-2-hydroxy-4-meth_yl-2-trifluoromethylpentyl]- 1H-pyrrolo[3,2-b]pyridin-5» -yl} morpholin-4-ylmethanone;

4-(5-Chloro-2,3-dihydrobemzofuran-7-yl)-1,1,1 -trifluoro-2+(5-hy=droxymethyl-1H-pyrrolof3,2- b)pyridin-2-ylmethyl)-4-meethylpentan-2-ol; 2-(5-Aminomethyl-1 H-pyr-rolo[3,2-b]pyridin-2-ylmethyl)-4-(5 -c=hloro-2,3-dibydrobenzofuran- 7-yl)-1,1,1-triflucro-4-metThylpentan-2-ol; 1,1,1-Trifluoro-4-(5-fluorce-2-methylphenyl)-4-methyl-2-(5H-py~rrolo[3,2-c]pyridazin-6- ylmethyl)pentan-2-ol; 4-Fluoro-2-[4,4,4-trifluoro -3-hydroxy-1,1-dimethyl-3-(SH-pyrrolo[3,2-c]pyridazin-6- ylmethyl)butyl]phenol; 4-Fluoro-2-[4,4,4-trifluoro- -3-hydroxy-1,1-dimethyl-3-(SH-pyrrolo[ 3,2-d]pyrimidin-6- ylmethyl)butyl]phenol;

2-(6-Chloro-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-1,1,1-triffuomo-4-(5-fluoro-2-methylphenyl)- 4-methylpentan-2-ol; 4-(5-Chloro-2,3-dihydrobesnzofuran-7-yl)-2-(6-chlora-1H-pyrrodof3,2-b]pyridin-2-ylmethyl)- 1,1,1-triftuoro-4-methylpe ntan-2-ol;

1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-me thyl-2-(3-methyl- | H-pyrrolo{2 5 3-clpyridin- 2-ylmethyl)pentan-2-ol; 1,1,1-Trifluoro-4-(3-fluorophenyl)-4-methyl-2-(3-m ethyl- 1H-pyrrolo[2,3-c]pyridina-2- ylmethyl)pentan-2-ol; " 5-Fluoro-2-[4,4,4-triflucro-3-hydroxy-1,1-dimethyl—3-(3 -methyl-1H-pyrrolof2,3-cWpyridin-2- ylmethyl)butylJphenol; 4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifl uoro-4-methyl-2-(SH-pyrrolo[ 3 2- ’ d]pyrimidin-6-ylmethyl)pentan-2-ol; 4-(5-Chloro-2,3-dihydrobenzofuran-7-y1)-1,1,1-trifl uoro-4-methyl-2-(3 -phenyl-7F®-pyrrolof2,3- clpyridazin-6-ylmethyl)pentan-2-ol;

1,1,1-Trifluoro4-(5-fluoro-2-methylphenyl)-4-metkyl-2-(3-phenyl-7H-pyrrolo [2,3 _¢]pyridazin- 6-ylmethyl)pentan-2-ol; 1-{2-[4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2-haydroxy-4-methyl-2-trifluorome=thylpentyl]-

1H-pyrrolo[3,2-b]pyridin-5-y1}-2,2-dimethylpropara-1-one; 2-[5-(1-tert-Butyl-1-hydroxy-2,2-dimethylpropyl)- 1 H-pyrrolo[3,2-b]pyridin-2-ylnethyl]-4-(5- chloro-2,3-dihydrobenzofuran-7-y1)-1,1,1-trifluoro—4-methylpentan-2-ol;

1-{2-[4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluorome=thylpentyl}- 1H-pyrrolo[3,2-b]pyridin-5-yl} propan-1-one; 1-{2-[4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2-laydroxy-4-methyl-2-trifluoromeethylpentyl]- 1H-pyrrolo[3,2-b]pyridin-5-yl}-2-methylpropan-1-©ne;

: 1,1,1-Trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl- 1 H-pyrrolo[ 73 ,2-c]pyridin- 2-ylmethyl)pentan-2-ol;

1,1,1-Trifluoro-4-(2-methoxy-5-thiophen-3 -ylphenyl)-4-methyl-2-(4-methyl- 1 H-mpyrrolof3,2- ¢Ipyridin-2-ylmethyl)pentan-2-ol;

1,1,1-Trifluoro-4-(4-methoxybiphenyl-3 -y1)-4-methyl-2-(4-methyl-1H-pyrrolo[3 =2-c]pyridin-2- ylmethyl)pentan-2-ol; 5-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-methyl- 1H-pyrrolo[3,2—c]pyridin-2- ylmethyl)butyl]phenol;

4-Thiophen-3-yl-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3 -(4-methyl-1H-pyrr—olo[3,2- c]pyridin-2-ylmethyl)butyl]phenol; 3-(4,4 4-Trifluoro-3-hydroxy-1,1-dimethyd-3-(4-methyl-1H-pyrrolo[3 ,2-clpyridimn-2- ylmethyl)butylJbiphenyl-4-ol; 1,1,1-Trifluoro-4-methyl-2-(3-methyl-1 H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-4-(S-pyrimidin-5- yl-2,3-dihydrobenzofuran-7-yl)pentan-2-o01; 1,1,1-Trifluoro4-(2-methoxy-5-pyridin-3 —ylphenyl)-4-methyl-2-(3-methyl- 1 H-pmyrrolo[2,3- cIpyridin-2-ylmethyl)pentan-2-ol; 4-Pyridin-3-yl-2-[4,4,4-trifluoro-3-hydrox y-1,1-dimethyl-3-(3-methyl-1 H-pyrrolo{2 3- cJpyridin-2-ylmethyl)butyljphenol;

1,1,1-Trifluoro-4-(5-fluoro-2,3-dihydrobe nzofuran-7-yl)-4-methyl-2-(SH-pyrrolo[3,2- d]pyrimidin-6-ylmethyl)pentan-2-ol; 1,1,1-Trifluoro-4-(2-methoxy-5-pyridin-3—ylphenyl)-4-methyl-2-(5-phenoxy-1 HH —pyrrolo[2,3- cIpyridin-2-ylmethyl)pentan-2-ol;

V0 2005/030213 PCT/USS2004/031009 1,1,1-Trifluoro-4-methyl-4-phenyl -2-(3-phenyl-7H-pyrrolof2,3-clpyridazin-6-yMmethyl)pentan- 2-ol; 1,1,1 -Trifluoro-4-(3-fluorophenyl)-4-xuethyl-2-(3-phenyl-7H-pyrrolof2,3 -clpyriidazin-6- 5S ylmethyl)pentan-2-ol; 1,1,1-Triflucro-4-(5-fluoro-2,3-dihydxobenzofuran-7-yt)-4-methyl-2-(SH-pyrro 0[3,2- d]pyrimidin-6-ylmethyl)pentan-2-ol; 1Q 1,1,1-Trifluoro-4-(2-methoxy-5-pyridin-3 -ylphenyl)-4-methyl-2-(5-phenoxy-1F-pyrrolo[2,3- c]pyridin-2-ylmethyl)pentan-2-ol; 1,1,1-Trifluoro-4-methyl-4-phenyl-2—(3-phenyl-7H-pyrrolo[ 2,3-c]pyridazin-6-y/imethyl)pentan- 2-0l; 1:5 1,1,1-Trifluoro-4-(3-fluorophenyl)-4—methyl-2-(3-phenyl-7H-pyrrolo[2,3-c]pyr—idazin-6- ylmethyl)pentan-2-ol; 1,1,1-Trifluoro-4-methyl-4-(3-morphuolin-4-ylmethylphenyl)-2-(5-phenyl- 1 H-psyrrolo[2,3- 2 0 c]pyridin-2-ylmethyDpentan-2-ol; 1,1,1-Trifluoro-4-(3-fluorophenyl)-2 -[5-(4-fluorophenyl)-1 H-pyrrolo[2,3-c]pymridin-2- ylmethyl]-4-methylpentan-2-ol; 2.5 2-(5-Dimethylamino-1H-pyrrolo[2,3 -c]pyridin-2-ylmethyl)-1,1,1-trifluoro-4-(S-fluoro-2- methoxyphenyl)-4-methylpentan-2-ol; 2-(5-Dimethylamino-1 H-pyrrolo[2,3 -c]pyridin-2-ylmethyl)-1, 1,1 -trifluoro-4-{=t-flucro-2- methoxyphenyl)-4-methylpentan-2-ol; x0 1,1,1-Trifluoro-4-(3-fluorophenyl)-4 -methyl-2-(4-methyl-1 H-pyrrolo[2,3-c]py—Tidin-2- ylmethyl)pentan-2-ol;

1, 1,1-Trifluoro-4-(4-fluoro-2-methoxypheryl)-4-methyl-2-(4-methyl- 1 H-pyrreolof2,3-cjpyridin- 2—ylmethyl)pentan-2-0l; 2—~[3-(5-Dimethylamino- 1H-pyrrolof2,3-clwpyridin-2-ylmethyl)-4,4,4-trifluoro—3-hydroxy- 1,1- dimethylbutyl]-4-fluorophenol; 2 —[3-(5-Dimethylamino- 1 H-pyrrolo[2,3-c] ~pyridin-2-ylmethyl)-4,4,4-trifluoro—3-hydroxy-1,1- d imethylbutyl]-5-fluorophenol; 5 -Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1 —dimethy}-3-(4-methyl-1H-pyrrolo[ 22,3-c]pyridin-2- y-1methyl)butyl]phenol; 4-(5-Bromo-2-methoxypheny)-1,1,1-triflmioro-4-methyl-2-(1H-pyrrolo [2,3-¢c_Jpyridin-2- y*Imethyl)pentan-2-ol;

A -Bromo-2-[4,4,4-trifluoro-3-hydroxy-1, 1 -dimethyl-3-(1H-pyrrolo{2,3-c]pyr-idin-2- y~Imethyl)butyljphenol; . 20 L,1,1-Trifluoro-4-(2-methoxy-5-pyrimidir-5-ylphenyl)-4-methyl-2-(1H-pyrrolof 2,3-clpyridin- 2-ylmethyl)pentan-2-ol; 23-(3-[1,3]Dioxan-2-yiphenyl)-1,1,1-triflueoto-4-methyl-2-(1H-pyrrolo[2,3-c]oyridin-2- ’ w/imethyl)pentan-2-ol; : 1,1,1-Trifluoro-4-(4-methoxybiphenyl-3-=yl)-4-methyl-2-(1 H-pyrrolo[2,3-c]p- yridin-2- sy/lmethyl)pentan-2-ol; 1,1, 1-Trifluoro-4-(2-methoxy-5-pyridin-3=- -ylphenyl)-4-methyl-2-(1 H-pyrrolcs[2,3-clpyridin-2- w/lmethyl)pentan-2-ol;

1,1,1-Trifluoro-4—(2-methoxy-5-thiophen-3 -ylpheny])-4—methyl-2-(1H-pyrrolo[2,3-c_]pyridin-2- ylmethyl)pentan-2-ol; 1,1,1-Triftuoro-4—methyl-4-(3 -morpholin-4-ylmethylphesnyl)-2-(1H-pyrrolo[2,3 ~C]pyridin-2-

ylmethyl)pentan-22-ol;

i 3-[4,4,4-Trifluorc>-3-hydroxy-1,1-dimethyl-3-(1 H-pyrro- 10[2,3-c]pyridin-2- ylmethyl)butyl Jox phenyl-4-ol;

4-Thiopben-3-yl—2-[4,4,4-trifluoro-3-hydroxy-1,1-dimesthyl-3 -(1H-pyrrolo[2,3-c]pyr=idin-2- ylmethyl)butyl]phenol; 4-Thiophen-3-yl—2-[4,4,4-trifluoro-3-hydroxy-1,1-dime—thyl-3-(1H-pyrrolo [2,3-clpymridin-2- ylmethyl)butylJpThenol;

4-Thiophen-3-yl—2{4,4,4-trifluoro-3-hydroxy-1,1-dime thyl-3-(1H-pyxrolo[2,3 -c]pymridin-2- ylmethyl)butyl phenol; 4’.Methoxy-3°-[<1 4,4-rifluoro-3-hydroxy-1,1-dimethy} -3-(4-methyl-1H-pyrrolo[2,3-¢]pyridin-

2-ylmethyl)butyl Jbiphenyl-2-carbonitrile; 4’-Methoxy-3°-[<4,4,4-trifluoro-3-hydroxy-1,1-dimethy}_-3-(1H-pyrrolo[2,3-c]pyridira-2- ylmethyl)butyl]b dphenyl-3-carbonitrile;

1,1,1-Trifluoro-4 -(2-methoxy-5-pyridin-3-ylphenyl)-4-muethyl-2(4-methyl-1H-pyrr-olo[2,3- c]pyridin-2-ylme: thyl)pentan-2-ol; 4-(3-Chlorophen ~yl)-1,1, 1-triflucro-4-methyl-2-(1H-pyr—rolo[3,2-c]pyridin-2-ylmeth=/pentan-2- ol;

1,1,1-Trifluoro-4- -(2-methoxy-5-pyrimidin-5-ylphenyl)—4-methyl-2-(1 H-pyrrolo[3,2 -c]pyridin- 2-ylmethyl)pentaa n-2-o0l;

4-Pyridin-3-yl-2-[4,4,4-trifluoro-3-hydroxy-1 ,1-dimethyl-3-(1H-pyrrolo[_3,2-c]pyridin-2~ ylmethyl)butyl]phenol;

1,1,1-Trifluoro-4-methyl-4-(3 -morpholin-4-ylmethylphenyl)-2-(1H-pyrreolo[3 ,2-c]pyridin-2- ylmethyl)pentan-2-ol;

1,1,1-Trifluoro-4-(2-methoxy-5-pyridin-3-ylphenyl)-4-methyl-2-( 1H-pymrolo[3,2-c]pyridin-2- ylmethyl)pentan-2-ol;

1,1,1-Trifluoro-4-methyl —4-(3-pyridin-3-ylphenyl)-2-(1H-pyrrolo[3,2-c] pyridin-2-

: ylmethyl)pentan-2-ol;

1,1,1-Trifluoro-4-methyl —4-(3-pyrimidin-5-ylphenyl)-2-(1 H-pyrrolo[3,2 ~c]pyridin-2-

ylmethyl)pentan-2-ol; 1,1,1-Trifluoro-4-methyl —4-(3-pyridin-3-ylphenyl)-2-(1 H-pyrrolo[2,3-c Bpyridin-2- ylmethyl)pentan-2-ol;

1,1,1-Trifluoro<4-methy}—4-(3-pyrimidin-5-ylphenyl)-2-(1LH-pyrrolo[2,3- -c]pyridin-2- ylmethyl)pentan-2-ol; 4-(5-Chloro-2,3-dihydrobenzofuran-7-y1)-1,1,1-trifluoro-4-methyl-2-(5 —pyridin-2-yl-1 H-indol- 2-ylmethyl)pentan-2-ol;

2-(5-Bromo-1H-indol-2-ylmethyl)-4-(5-chloro-2,3-dihydrobenzofuran-"7-yl)-1,1,1-triflucro-4- methylpentan-2-ol;

- 1,1,1-Trifluoro-4-(3-fluoro-2,3-dihydrobenzofuran-7-yl)-2-(5-methanes= ulfinyl- 1 H-indol-2- : 30 ylmethyl)-4-methylpentan-2-ol;

7-7 3-(5-Bromo-1H indol-2-ylmethyl)-4,4,4—tifluoro-3-hydroxy-1 ,1-dimethylbuty=1]-2 3- di“hydrobenzofuran-5-sulfonic acid amide; 7—[3-(5-Bromo-1H-indol-2-ylmethyl)-4,4,4 —trifluora-3-hydroxy-1,1-dimethylbutyw1]-2,3- di_hydrobenzofuran-5-sulfonic acid dimethy’lamide; 2—(1-Benzenesulfonyl-5-pyridin-3-yl-1 H-irmdol-2-yimethyl)-1,1,1-trifluoro-4-(5-luoro-2,3- dimhydrobenzofuran-7-yl)-4-methylpentan-2-ol; : 10 3 —{2-[4-(5-Fluoro-2,3-dihydrobenzofuran-"7-yl)-2 “hydrox y-4-methyi-2-trifluorormethylpentyl]- 1_#-indol-5-yl} benzonitrile; 1 1,1-Trifluoro—4~(5-fluoro-2,3-dihydroberazofuran-7-yl)-4-methyl-2-(5-pyridin-=4-yl-1 H-indol- 2 -ylmethyl)pentan-2-ol; 1,11 -Trifluoro-4-(5-fluoro-2,3-dihydroberazofuran-7-yl)-4-methyl-2-(5 -pyridin- 3-yl-1H-indol- 2=-ylmethyi)pentan-2-ol; 1,1,1.Trifluoro-4-(5-fluoro-2,3 -dihydrobenzofuran-7-yl)-4-methyl-2-(5-pyrimid_in-5-yl- 1H- imndol-2-ylmethyl)pentan-2-ol; 2» _{2-[4-(5-Fluoro-2,3-dihydrobenzofuran—7-yl)-2 -hydroxy-4-methyl-2-trifluorommethylpentyl]-

I H-indol-5-yl}benzamide; 2-[5-(4-Dimethylaminophenyl)-1H-indol-2-ylmethyl]-1,1,1 -trifluoro-4-(5-fluore-2,3- cdikydrobenzofuran-7-yl)-4-methylpentan—2-ol;

NM ,1,1-Trifluoro-2-(7-fluoro-4-methyl-1H-i ndol-2-ylmethyl)-4-(5-methanesulforn y1-2,3- dihydrobenzofuran-7-yl)-4-methylpentan—2-ol;

2-[2-Hydroxy-4-(5-methanesulfo_nyl-2,3-dihydrobenzofuran-7-yl)-4-rnethyl-2- trifluoromethylpentyl]-1H-indole=-5-carbonitrile; 2-[2-Hydroxy-4-(5-methanesulfosnyl-2,3-dihydrobenzofuran-7-yl)-4-mmethyl-2-

trifluoromethylpentyl}-1H-indole=-6-carbonitrile;

1,1,1-Trifluoro-2-(7-fluoro-1H-i_ndol-2~ylmethyl)-4-(5-methanesulfcanyl-2,3- dihydrobenzofuran-7-yl)-4-meth-ylpentan-2-o};

1,1,1-Trifluoro-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4--methyl-2-(4-methyl- 1H- indol-2-ylmethyl)pentan-2-ol; 4-Methanesulfonyl-2-[4,4,4-triflwioro-3-hydroxy-1,1-dimethyl-3-(5-tacifluoromethyl- 1H-indol-2- ylmethyl)butyl]phenol;

1,1,1-Trifluoro-2-(7-fluoro-5-meethyl-1 H-indol-2-ylmethyl)-4-(S-me thanesulfonyl-2,3- dihydrobenzofuran-7-yl)-4-meth_ylpentan-2-ol; 7-Fluoro-2-[2-hydroxy-4-(5-metThanesulfonyl-2,3-dihydrobenzofurara-7-yl)-4-methyl-2-

triflucromethylpentyl]-1H-indole=-5-carbonitrile; 2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromesthylpentyl]-1 H-indole-4- carboxylic acid methyl ester;

2-[4-(5-Fluoro-2-hydroxypheny~1)-2-hydroxy-4-methyl-2-trifluorome=thylpentyl]-1 H-indole-4- carboxylic acid methyl ester; 2-[4-(5-Fluoro-2-methoxypheny®)-2-hydroxy-4-methyl-2-triftuorome=thylpentyl]-1.4-indole-4- carboxylic acid;

2-[4-(5-Fluoro-2-methoxypheny®)-2-hydroxy-4-methyl-2-triflnioromethylpentyl]-1 H-indole-4- carboxylic acid amide;

2-[4~(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-tri—fluoromethylpentyl}- 1 H-indo=le-4- carboxylic acid amide; iE 5 2-[4-(5-Fluoro-2-methoxxyphenyl)-2 -hydroxy-4-methyl-2-tri_fluoromethylpentyl]-1H-indomle-4-

A carbonitrile; 2-[4-(5 -Fluoro-2-hydrox: yphenyl)-2-hydroxy-4-methyl-2-tri—fluoromethylpentyl]- 1H-indo-1e-4- carbonitrile; 2-(4-Ethyl-1H-indol-2-ylmethyi)-1,1,1-trifluoro-4-(5-fluoreo-2 -methoxyphenyl)-4- methylpentan-2-ol; : 2-[3-(4-Ethyl-1 H-indol—2-ylmethyl)-4,4 4-trifluoro-3-hydroexy-1, 1-dimethylbutyl]-4- fluorophenol; 4-(5-Chloro-2,3-dihydrobenzofuran-7-y1)-1,1,1-trifluoro-2—(2-isopropyl-SH-pyrrolo[3,2— dlpyrimidin-6-ylmethyl )-4-methylpentan-2-ol; 1,1,1-Trifluoro-4-(5-flu_oro-2-methylphenyl)-2-(2-isopropy~1-5SH-pyrrolo[3 ,2-d]pyrimidiry-6- ylmethyl)-4-methylpentan-2-ol; 1,1,1-Trifluoro-4-(5-flu oro-2-methoxyphenyl)-2-(2-isopropoyl-5H-pyrrolo[3,2-d]pyrimiJin-6- ylmethyl)-4-methylpen-tan-2-ol; 4-Fluoro-2-[4,4,4-triflu_oro-3-hydroxy-3-(2-isopropyl-SH-poyrrolo[3,2-d]pyrimidin-6-ylomethyl)- 1,1-dimethylbutyl]pheraol; 4-(5-Chloro-2,3-dihydrobenzofuran-7-yi)-1,1,1-trifluoro-4 -methyl-2-(2-pyrrolidin-1-yl—5H- pymolo[3,2-d]pyrimidim-6-ylmethyl)pentan-2-ol;

1,1,1-Trifluoro4-(5-fluoro-2-methylphenyl) -4-methyl-2-(2—pyrrolidin-1-yl-5H-pyrrolo[3 2m d}pyrimidin-6—ylmethyl)pentan-2-ol;

1,1,1-Trifluoro-4-(5-fluoro-2 -methoxypheny!)-4-methyl-2-C 2-pyrrolidin-1-yl-SH: -pyrrolo[3,2- d]pyrimidin-6—ylmethyl)pentan-2-ol; 4-Fluoro-2-[4, 4,4-trifluoro-3-hydroxy-1,1-dimethyl-3~(2 -pywsmolidin-1-yl-5SH-pyrrolo[3,2- dpyrimidin-6 -yimethyl)butyljphenol;

4-(5-Chloro-2.,3-dihydrobenzofuran-7-yl)-1,1,1 -trifluoro-4—methyl-2-(2-phenyl-SH-pyrrolof 3 ,2- dipyrimidin-6 -ylmethyl)pentan-2-ol; 1,1,1-Trifluor-o-4-(5-fluoro-2-methyiphenyl)-4-methyl-2-(2 -phenyl-5H-pyrrolo[3,2- d)pyrimidin-6G-ylmethyl)pentan-2-ol; 1,1,1-Trifluox-o-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2—(2-phenyl-5H-p yrrolo[3,2- d]pyrimidin-6-ylmethyl)pentan-2-ol; 4-Fluoro-2-[4 4 4-trifluoro-3-hydroxy-1,1-dimethyl-3-(2-p=henyl-5H-pyrrolof3,2-d] pyrimidl in-6- ylmethyl)but/l}phenol; 4-(5-Chloro-22,3-dihydrobenzofuran-7-y1)-2-(2-chloro-5 H-—pyrrolo[3,2-d]p yrimidin-6-ylmesthyl)- 1,1,1-trifluor«o-4-methylpentan-2-ol;

1,1,1-Trifluoxo-4-methyl-4-phenyl-2-(2-phenyl-5H-pyrroleo|3,2-d]pyrimidin-6- yimethyl)perxtan-2-ol; 1,1,1-Trifluo ro-4-(3-fluorophenyl)-4-methyl-2-(2-phenyl-=SH-pyrrolof3,2-d]pyrimidin-6- ylmethyl)peratan-2-ol;

4-[4,4,4- Tra fluoro-3-hydroxy-1, 1-dimethyl-3-(2-phenyi-5H-p yrrolo[ 3,2-d]lpyrimidin-Ge- ylmethyl)bwatyl]benzonitrile;

1,1,1-Triflvaoro-4-(2-methoxy-5 -methylphenyl)-4-met-hyl-2-(2-pyrrolidin-1-yl-SH-pyr=xolo[3 \2- d)pyrimidix-6-ylmethyl)pentan-2-ol; :

11, 1-Trifliacro-4-(2-methoxy-5-methylphenyl)-4-mehyl-2-(2-pyrrolidin-1-yl-SH-pyr=rolo[3 2- dlpyrimidimn-6-ylmethyl)pentan-2-ol;

1,1,1-Triflwioro—4-(4-fluoro-2-methoxyphenyl)-4-metlhyl-2-(2-pyrrolidin-1-yl-5H-pyrr—olo[ 3,2- d)pyrimidin-6-ylmethyl)pentan-2-ol; : 5-Fluoro-2--[4,4,4-trifluoro-3-hydroxy-1,1 -dimethyl-33-(2-pyrrolidin-1-yl-5 H-pyrrolo[ 3,2-

dlpyrimidi n-6-ylmethyl)butyl[phenol; 2-(5-Ethorxy-1 H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-1 ,1,1-trifluoro-4-(5-fluoro-2- methylphe nyl)-4-methylpentan-2-ol;

1,1,1-Trifl-uoro-4-(5-fluoro-2-methoxyphenyl)-4-metchyl-2-(5-phenyl-1 H-pyrrolo[2,3 —c]pyridin- 2-ylmethy 1)pentan-2-ol; 1,1,1-Trifl uoro-4-(5-fluoro-2-methylphenyl)-4-meth=y1-2-(6-methyl- 1 H-pyrrolo[3,2-c=]pyridin-2- yimethyDpoentan-2-ol;

1,1,1-TrifE uoro-4-(5-fluoro-2-methylphenyl)-4-methy}-2-(4-methyl- 1H-pyrrolo[3,2-=]pyridin-2- yimethyl)goentan-2-ol; 4-(5-Brom0-2-methoxyphenyl)-2-(5-dimethylamino —1H-pyrrolo[2,3-c]pyridin-2-ylnmethyl)-

1,1,1-trifluaoro-4-methylpentan-2-ol;

4(5-Bromo-2-methoxyplaenyl)-1,1,1-trifluoro-2-(S-isopropoxy— 1H-pyrrolo[2,3-c]pyridin-2- - : ylmethyli)-4-methylpentara-2-ol; 1,1,1-Trifluoro4-(5-fluor-o-2-trifluoromethylphenyl)-2-(5-isopr-opoxy- 1H-pyrrolo[2,3- c]pyridin-2-ylmethyl)-4-rmethyipentan-2-ol; 4-(5-Chloro-2,3-dihydrataenzofuran-7-yl)-1,1, 1 -trifluoro-4-methyl-2-(6-methyl- 1H-pyrrolo[3,2- clpyridin-2-ylmethyl)pen_tan-2-ol; 1,1,1-Trifluoro-2-(5-isopmopoxy- 1 H-pyrrolo[2,3-c]pyridin-2-ylamethyl)-4-(2-methoxy-5- pyrimidin-5-ylphenyl)-4--methylpentan-2-ol; 1,1,1-Trifluoro-2-(5-isopmropoxy-1H-pyrrolof2,3-¢ Jpyridin-2 -ylamethyl)-4-(4-methoxybipher=yl- 3-yD)-4-methylpentan-2-cl;

1,1,1-Trifluoro-2-(5-isopmropoxy-1H-pyrrolo[2,3-c Ipyridin-2-yl-methyl)-4-(2-methoxy-5- thiophen-3-ylphenyl)-4-rmnethylpentan-2-ol; . 2-(5-Dimethylamino-1H—pyrrolo{2,3-c]pyridin-2-ylmethyl)-1,1 ,1-trifluoro-4-methyl-4- phenylpentan-2-ol; 1,1,1-Trifluoro-4-(2-metkaoxy-5-pyrimidin-5-ylphenyl)-4-meth~1-2-(5-piperidin-1-yl-1H- . pyrrolo[2,3-c]pyridin-2-y~Imethyl)pentan-2-ol; 1,1,1-Trifluoro-4-(4-mettaoxybiphenyl-3-yl)-4-methyl-2-(5-pip eridin-1-yl-1 H-pyrrolo(2,3- clpyridin-2-ylmethyl)permtan-2-ol; 1,1, 1-Trifluoro-4-(2-metla0xy-5-pyridin-3-ylphenyl)-4-methyl-2-(5-piperidin-1-yl-1H- pyrrolo[2,3-c]pyridin-2-y~Imethyl)pentan-2-ol;

2-(5-Dimethylamino-1H—pyrrolo[2,3-c]pyridin-2-ylmethyl)-1,1 ,1-trifluoro-4-(2-methoxy-5— pyrimidin-5-ylphenyl)-4—methylpentan-2-ol;

4-Bromo-2-[3-(5-chloro- 1H-pyrrolof2,3-c]pyridin-2-ylmethyl)-4,4 _4-trifluoro-3-hydroxy-1,1- } dimethylbutyl]phenol; 2-[3-(5-Chloro-1H-pyrro10(2,3-c]pyridin-2-ylmethyl)-4,4,4-trifluomro-3 -hydroxy-1,1- dimethylbutyl}-4-fluorophenol; 2-[2-Hydroxy-4-(4-hydroxybiphenyl-3-yl)-4-methyl-2-trifluorome —thylpentyl}- 1H-pyrrolo[2,3- cIpyridin-5-ol; 1,1,1-Trifluoro-2-(5-isopropoxy-1H-pyrrolo[2,3 -¢]pyridin-2-ylmet=hyl)-4-methyl-4-(5-phenyi- 2,3-dihydrobenzofuran-7 -yl)pentan-2-ol; 2-[2-Hydroxy-4-(2-meth.oxy-5-pyrimidin-5-ylphenyl)-4-methyl-2-triftuoromethylpentyl]-14- pymrolo[2,3-c]pyridin-5-0l;

Trifluoromethanesulfonic acid 2-[4-(5-fluoro-2-methylplaenyl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]- 1 &-pyrrolo[2,3cJpyridin-5-yl ester;

So 20 2-[5-(2,6-Dimethylmorpolin-4-yl)-1H-pyrrolo{2,3-c]pyridin-2-ylmmethyl]-1,1,1-trifluoro-4- methyl-4-phenylpentan-2-ol; 1,1,1-Trifluoro-4-(3-fluorophenyl)-4-methyl-2-(5-piperidin-1-yl-1 &-pyrrolo[2,3-c]pyridin-2- ylmethyl)pentan-2-ol; 1,1,1-Trifluoro-4-methyl -4-phenyl-2-(5-piperidin-1-yl-1H-pyrrolo I 2,3-c]pyridin-2- yimethyl)pentan-2-ol; 1,1, 1-Trifluoro-4-(3-fluo xophenyl)-2-(5-isopropoxy- 1 H-pyrrolof 2, 3-c]pyridin-2- ylmethyl)-4- methylpentan-2-ol;

1,1,1-Trifluorome-2-(5-isopropoxy-1H-pyrrolo[2,3~] Dyridin-2-ylmethyl)-4-methyl—4- phenylpentan-22-ol; 1,1,1-Trifluorc>-4-methyl-4-(3 -morpholin-4-ylmeth=yiphenyl)-2-(5-piperidin-1-yl- - 1H-

pyrrolo[2,3-c]gp)yridin-2-ylmethyl)pentan-2-ol; 1,1,1-Trifluorc-4-methyl-4-(3-morpholin-4-ylmeth ~yIphenyl)-2-(5 -morpholin-4-y~1-1H- pyrrolo[2,3-c]mpyridin-2-ylmethyl)pentan-2-ol;

2-(5-Diethylarmino- 15-pyrrolo[2,3-c]pyridin-2-ylmaethyl)-1,1,1 -trifluoro-4-(2-me=thoxy-5- pyrimidin-5-yMphenyl)-4-methylpentan-2-ol; 4-(5-Chloro-2 3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-2-(5 -methoxy-1H-pyrrcolo[3,2- blpyridin-2-yl:-methyl)-4-methyipentan-2-ol;

1,1,1-Trifluoreo-4-(5-fluoro-2-methylphenyl)-2-(5-rmethoxy- 1 H-pyrrolo[3,2-5)py-xidin-2- ylmethyl)-4-nethylpentan-2-ol; : . 4-(5-Chloro-2 ,3-dibydrobenzofuran-7-yl)-2-(5-chlcro-1H-pyrrolo[2,3-c]pyridin-. 2-ylmethyl)-

1,1,1-trifluoro--4-methylpentan-2-ol; 1,1,1-Trifluoreo-4-(5-fluoro-2-methylphenyl)-2-(4-rmethoxy-1H-pyrrolo[3,2-c]pymridin-2- ylmethyl)-4-methylpentan-2-ol;

2-[4-(5-Fluorc-2-methylphenyl)-2-hydroxy-4-methmyl-2-trifluoromethylpentyl]-1 ,5- dihydropyrroleo(3,2-c]pyridin-4-one; 2-[4-(5-Fluorco-2-methylphenyl)-2-hydroxy-4-methmyl-2-trifluoromethylpentyl]-1 ,4- dibydropyrroleo(3,2-blpyridin-5-one;

2-[4-(5-Fluorco-2-methylphenyl)-2-hydroxy-4-methmyl-2-trifluoromethylpentyl]-S -hydroxy-1,6- dihydropyrroleo(2,3-c]pyridin-7-one;

2-(5-Chloro- 1 #Z-pyrrolo[2,3-c]pyridin-2-ylmethyl)-1,1 1-triflucro-4-(5-methanesulfonyl-2 53- dihydrobenzofimran-7-yl)-4-methylpentan-2-ol;

2-(5-Chloro-1F#-pyrrolo[2,3-c]pyridin-2-ylmethy])-1,1 , 1-trifluoro-4-(2-methoxy-5-thiophesn-3-

ylphenyl)-4-me=thylpentan-2-ol; 2-[2-Hydroxy-23-(5 -methanesulfonyl-2,3-dihydrobenzo furan-7-yl)-4-methyl-2- trifluoromethyl pentyl]-1H-pyrrolo[3,2-b}pyridine-5-camrbonitrile;

2-(5-Chloro-1 FZ-pyrrolo[2,3-¢]pyridin-2-ylmethyl)-1,1 ,1 -trifluoro-4-methyl-4-(5- methylsulfanyl —2,3-dihydrobenzofuran-7-yl)pentan-2-w0};

4-(5-Bromo-2-mmethoxyphenyl)-2-(5-chloro-1H-pyrrol o[2,3 ~c]pyridin-2-ylmethyl)-1,1,1- : 15 trifluoro-4-methylpentan-2-ol;

1,1,1-Trifluoro —4-(5-fluoro-2-methoxyphenyl)-4-meth_yl-2-(7H-pyrrolo[2,3-d]pyrimidin-6& - ylmethyl)penta n-2-ol;

1,1,1-Trifluoro —4-(2-methoxy-5-naphthalen-1-ylpheny=1)-4-methyi-2-(5-morpholin-4-yl-177- pyrrolof2,3-c]p»yridin-2-ylmethyl)pentan-2-ol; 4-(2°-Chloro-4—methoxybiphenyl-3-yl)-1,1, 1 -trifluoro—4-methyl-2-(5-morpholin-4-yl-14- pyrrolof2,3-clpyridin-2-ylmethyl)pentan-2-ol;

. 2-(5-Chloro-1/-pyrrolof2,3-c]pyridin-2-ylmethyl)- 1,1 ,1-trifluoro-4-(2-methoxy-5-pyrimi din-5-

yiphenyl)-4-mesthylpentan-2-ol; 4’°-Methoxy-3°—[4 4 4-trifluoro-3-hydroxy- 1,1 -dimethw=y1-3-(5-piperidin- 1 -yl-1 H-pyrrolo[2_,3-

cJpyridin-2-ylmnethyl)butyl]biphenyl-2-carbonitrile;

4-(2’-Chloro-4-me#thoxybiphenyl-3-yl)-1,1,1 _triftuoro-4-m_ethyl-2-(5-piperidin-1-yl- 1 faf- pyrrolo[2,3-c]pyricin-2-ylmethyl)pentan-2-ol; 2-[3-(3-Dimethylamminomethyl-1H-pyrrolo[3,2-c]pyridin-2- -ylmethyl)-4,4,4-trifluoro-3— 5S hydroxy-1,1-dimethylbutyl]-4-fluorophenol; 1,1,1-Trifluoro-4-( 5-methanesuifonyl-2,3 -dihydrobenzofuman-7-yl)-4-methyl-2-(1H- pyrrolo[3,2-cIpyriclin-2-yimethyl)pentan-2-ol; 2-(3-Chloro-1H-psyrrolo[3,2-clpyridin-2-ylmethyl)-1,1,1-tmrifluoro-4-(5-fluoro-2- methoxyphenyl)-4 -methylpentan-2-ol; 1,1,1-Trifluoro-4-rmethyl-4-(5-methylsulfanyl-2,3-dihydro benzofuran-7-yl)-2-pyrrolof 3,2- b]pyridin-1-ylmetkaylpentan-2-ol; 1,1,1-Trifluoro4-C5-methanesulfonyl-2,3-dihydrobenzofu—ran-7-yl)-4-methyl-2-pyrroleo(3,2- blpyridin-1-ylmethylpentan-2-ol; 4-(5-Chloro-2,3-dahydrobenzofuran-7-yl)-1,1,1-trifluoro-48-methyl-2-(5-phenyl- 1 H-py—rrolo{2,3- clpyridin-2-ylmetiayl)pentan-2-ol; and 1,1,1-Trifluoro-4-C 5-fluoro-2-methylphenyl)-4-methyl-2-(_S-phenyl-1 H-pyrrolo[2,3-c]oyridin-2- ylmethyl)pentan-2. -ol, or a tautomer, procdrug, solvate, or salt thereof.

More preferred compounds of Formula (IA) include: 1,1,1-Trifluoro~4-5-fluoro-2-methoxyphenyl)-4-methyl-2 -(3-methyl-1H-pyrrolo[3,2-c]pyridin- 2-ylmethyl)pentan -2-ol; :

1,1,1-Trifluoro-4-(5-fluoro-2,3 -dihydrobenzofuran-7-yl)-4-methyl-2-(1 H-p- yrrolo[3 ,2-clpyridin- 2-ylmethyl)pentan-2-ol; 1,1,1-Trifluoro-4-(5-fluoro-2-rmethylphenyl)-4-methyl-2-(3-methyl-1H-pyrrolof2,3 -c]pyridin-2-

ylmethyl)pentan-2-ol;

2-(4,6-Dimethyl-1H-pyrrolo[3 ,2-c]pyridin-2-ylmethyl)-1,1,1 -trifluoro-4-(5 -fluoro-2- methoxyphenyl)-4-methylpentan-2-ol;

2-[4-(5-Fluoro-2-methoxyphemyl)-2-hydroxy-4 -methyl-2-triflucromethylpentyl}-14- pyrrolo[3,2-b]pyridine-5-carbonitrile; 1,1,1-Trifluoro-4-(5-fluoro-2-amethoxyphenyl)-4-methyl-2-(6-methyl- 1 H-p» yrrolo[3,2-c]pyridin- 2-ylmethyl)pentan-2-ol;

1,1,1-Trifluoro-4-(5-fluoro-2-amethoxyphenyl}-4-methyl-2-(4-methyl- 1 H-p» yrrolo[3,2-c]pyridin- 2-ylmethyl)pentan-2-ol; 2-[4-(5-Fluoro-2-methoxyphemyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1:-

pyrrolo[3,2-c]pyridine-6-carbonitrile; 2-[4-(5-Fluoro-2-methoxyphemyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- pyrrolo[2,3-c]pyridine-5-carbonitrile;

2-[4-(5-Fluoro-2-methoxyphemyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-14- pyrrolo[3,2-c]pyridine-4-carbonitrile; 1,1,1-Trifluoro-4-(5-fluoro-2-xmethoxyphenyl)-4-methyl-2-(5H-pyrrolo[3,2-dlpyrimidin-6- ylmethyyl)pentan-2-ol;

1,1,1-Trifluoro-4-(5-fluoro-2-mmethoxyphenyl)-4-methyl-2-thieno[2,3-d]py~ridazin-2- ylmethylpentan-2-ol;

1,1,1 -Tri_fluoro-4-(5-fluoro-2-methoxyphenyl)-<#-methyl-2-(SH-pyrrolo[3 ,2-c]p3wridazin-6- ylmethyl )pentan-2-ol; 1,1,1-Trifluoro4-(5-fluoro-2-methoxyphenyl)-<t-methyl-2-(2-methyl-5H-pyrrol_o[3,2- dlpyrimi_din-6-ylmethyl)pentan-2-ol; oo 1,1,1-Trii fluoro-4-(5-fluoro-2-methylphenyl)4-muethyl-2-(1 H-pyrrolo[2,3-dlpyr—idazin-2- ylmethyR )pentan-2-ol;

CL . 10 2-(4,6-D-imethyl-1H-pyrrolo[3,2-c]pyridin-2-ylmmethyl)-1,1,1-trifluoro-4-(5-flucmro-2- methyylpkenyl)-4-methylpentan-2-ol; i 4-(5-Chl_oro-2,3-dihydrobenzofuran-7-yl)-2-(4,&5-dimethyl-1H-pyrrolo[3,2-c]pyxxidin-2- ylmethyN)-1,1,1-trifluoro-4-methylpentan-2-ol; 4-(5-Chl oro-2,3-dihydrobenzofuran-7-yl)-1,1,1 —tifluoro-4-methyl-2-(6-methyl—1H-pyrrolo[3,2- cIpyridim-2-ylmethyl)pentan-2-ol; 1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-mnethyl-2-(6-methyl-1 H-pyrrolol 3,2-c]pyridin-2- ylmethyMl)pentan-2-ol; 2-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-nethyl-2-trifluoromethylpentyl]- “1 H-pyrrolo[3,2- blpyridire-5-carbonitrile; 2-[4-(5-CChloro-2,3-dihydrobenzofuran-7-yl)-2-Enydroxy-4-methyl-2-trifituorome=thylpentyl]-1H- pyrrolo{=3,2-b]pyridine-5-carbonitrile; 1,1,1 -Tri_fluoro-4-(5-fluoro-2-methylphenyl)-4-mmethyl-2-(5 H-pyrrolo[3,2-d]lpyr—midin-6- ylmethyl )pentan-2-ol;

;

4-(5-Chloro-2,3-dihydrosbenzofuran-7-yl)-1,1,1 -trifluoro-4-meth—yl-2-(5H-pyrrolo[3,2- d]pyrimidin-6-ylmethyl »pentan-2-ol; 4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-meth yl-2-(3-methyl- 1H-pyrrolo[2,3-

. 5 c]pyridin-2-ylmethyl)pentan-2-ol; 1,1,1-Trifluoro-4-(5-flucro-2-methylphenyl)-4-methyl-2-(5 H-py—rrolo[3 ,2-¢]pyridazin-6- ylmethyl)pentan-2-ol; 1,1,1-Trifluoro-4-(5-fluero-2-methoxyphenyl)-2-(7-fluoro-1H-p-ymolo[2,3-c]pyridin-2- ylmethyl)-4-methylpent-an-2-ol; 1,1,1-Trifluoro-4-(5-fluero-2-methoxyphenyl)-4-methyl-2-(4-mesthyl-1 H-pyrrolo[2,3-c]pyridira- 2-ylmethyl)pentan-2-ol;

2-(5,7-Dichloro-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-1,1,1-trif Juoro-4-(5-fluoro-2- methoxyphenyl)-4-methaylpentan-2-ol; 1,1,1-Trifluoro-4-(5-fluero-2-methoxyphenyl)-4-methyl-2-(5-tri flucromethyl-1H-pyrrolo[2,3- clpyridin-2-ylmethyl)peentan-2-ol; 1,1,1 -Trifluoro-4-(5-fluero-2-methoxyphenyl)-2-(5-methoxy-1 Fad-pyrrolo[2,3-c]pyridin-2- ylmethyl)-4-methylpent-an-2-ol; ) 25 1,1,1-Trifluoro-4-(5-fluero-2-methylphenyl)-4-methyl-2-(4-methhyl -1 H-pyrrolo{2,3-c}pyridin-2- ylmethyl)pentan-2-ol; 1,1,1-Trifluoro-4-(5-flueoro-2-methylphenyl)-2-(5-isopropoxy- 1 24-pyrrolo[2,3-c]pyridin-2- ylmethyl)-4-methylpent an-2-ol;

1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-2-(5-methoxy- 1 H-poyrrolo[2,3-c]pyridin-2- ylmethyl)-4-methylpent an-2-ol;

4-(5-Chloro-2,3-Aihydrobenzofuran-7-yl)-1,1,1-trifluorce-2-(5-methoxy-14-pyrrolo 2,3- c]pyridin-2-ylmewuthyl)-4-methylpentan-2-ol;

1,1,1-Trifluoro-4 —(5-fluoro-2-methylphenyl)-2-(7-fluoro-1H-pyrrolo [2,3-clpyridin-2-ylrmethyl)- 4-methylpentan-2-ol; 4-(5-Chloro-2,3-clihydrobenzofuran-7-yi)-1,1,1-trifluorco>-4-methyl-2-(5 -trifluoromethyl—1H- pyrrolo[2,3-c)p ymridin-2-ylmethyl)pentan-2-ol;

2-(5-Dimethyl anino-1H-pyrrolo[2,3-c}pyridin-2-ylmetHhyl)-1,1,1-trifluoro-4-(5-fluoro-2- methylphenyl)-4 —methylpentan-2-0i; 1,1,1-Trifluoro—® -(5-fluoro-2-methoxyphenyl)-2-(5-chleoro-1 H-pyrrolo[2,3-clpyridin-2 — ylmethyl)-4-metihylpentan-2-ol; 4-(5-Bromo-2,3-~ dihydrobenzofuran-7-yl)-1,1,1-trifluor-o-4-methyl-2-(1H-pyrrolo[2,3-c-]pyridin- 2-ylmethyl)pent=an-2-ol; 1,1,1-Trifluoro-43 -methyl-4-(5-methyl-2,3-dihydrobenzeofuran-7-yl)-2-(1H-pyrrolof2,3- c}pyridin-2-ylme=thyl)pentan-2-ol; } 4-(5-Chloro-2,3 —dihydrobenzofuran-7-yl)-1,1,1-trifluor-o-4-methyl-2-(1 H-pyrrolo{ 2,3 -c=Ipyridin- 2-ylmethyl)pentz=an-2-ol;

: 1,1,1-Trifluoro-<3-(5-fluoro-2-methoxyphenyl)-4-methy~1-2-pyrrolo[2,3-b]pyridin-1- ylmethylpentan- 2-ol; 2-Benzo[b]thiopwhen-2-ylmethyl-1,1,1-trifluoro-4-( 5-fliaoro-2-methoxyphenyl)-4-methy.slpentan- 2-ol;

1,1,1-Triftuoro-4-(5-fluoro-2-methoxyphenyl)-4-meth _yl-2-thieno[2,3 -c]pyridin-2- ylmethylpentan-2-ol; 1,1,1-Trifluor-o-4-(5-fluoro-2-methoxyphenyl)-4-metha yl-2-[4-((Z)prop enyl)-3-vinylpyr-azol-1-

ylmethyllpentan-2-ol; 4-(5-Chloro-2 3-dihydrobenzofuran-7-yl)-2,4-dimethyl-1 -thieno[2,3-c]pyridin-2-ylpen—tan-2-0; 4-(5-Fluoro-2-methylphenyl)-2,4-dimethyl-1-thieno[22 3 -c]pyridin-2-ylpentan-2-ol;

1,1,1-Trifluoxro-4-(5-fluoro-2-methylphenyl)-4-methy-1-2-(1H-pyrrolof3,2-c]pyridin-2- ylmethyl)pen tan-2-ol; 1,1,1-Trifluoxo-4-methyl-4-(5-methyi-2,3-dihydrobernzofuran-7-yl)-2-(1H-pyrrolo[3,2—

c]pyridin-2-y~1methyl)pentan-2-ol; 4-(5-Chloro~2,3-dihydrobenzofuran-7-yi)-1,1,1-triflu-oro-4-methyl-2-(1 H-pyrrolo[3,2-=c]pyridin- 2-ylmethyl) pp entan-2-ol;

4-(5-Bromo-23-dihydrobenzofuran-7-yl)-1,1,1-triflu_oro-4-methyl-2-(1H-pyrrolo[3,2- <]pyridin- 2-ylmethyl)p» entan-2-o]; 2-(3-Dimethylaminomethyl-1 H-pyrrolo[3,2-clpyridiia-2-ylmethyl)-1,1,1-trifluoro-4-(5= -flucro- 2-methoxyphenyl)-4-methylpentan-2-ol;

1,1,1-Trifluosro-4-(5-fluoro-2-methoxyphenyl)-4-met—hyl-2-pyrrolo{3,2-c]pyridin-1- ylmethylpen¢an-2-ol; 1,1,1-Trifluo»xo-4-(5-fluoro-2-methoxyphenyl)-4-met hyl-2-pyrrolo[3,2-blpyridin-1-

ylmethylpen tan-2-ol;

1,1,1-Trifluoro-4-(5—fiu oro-2-methoxyphenyl)-2-furof3 ,2-clpyridin-2-3/imethyl-4- methylpentan-2-ol; 4-(5-Chloro-2,3-dihy/drobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-p yrrolo[3,2-b]pyridin-1- ylmethylpentan-2-ol; 1,1-Difluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[3- ,2-c]pyridin-2- ylmethyl)pentan-2-ol;

1,1,1-Trifluoro-4-(5— fli oro-2-methoxyphenyl)-4-methyl-2-thienof3,2-<lpyridin-2- ylmethylpentan-2-o0l ; 4-{(5-Chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1 -trifluoro-4-methyl-2-thieno[3,2-¢]pyridin-2- ylmethylpentan-2-ol;

1,1,1-Trifluoro-4-(5—fluoro-2-methylphenyl)-4-methyl-2-pyrrolo[3,2-&»]pyridin-1- ylmethylpentan-2-ol; 1,1,1-Trifluoro-4 «5 —floro-2-methylphenyl)-4-methyl-2-thieno[3,2-c] goyridin-2-

ylmethylpentan-2-ol; 2-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorometinylpentyl}-1 H-indole-6- carboxylic acid dimethylamide;

{2-[4-(5-Fluoro-2-h:ydroxyphenyl)-2-hydroxy-4-methyl-2-trifluvorometthylpentyl]-1 A-indol-6- yl}morpholin-4-ylmeth anone; 2-{4~(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl}-14-indole-6- carboxylic acid dimethy/lamide;

2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorometiaylpentyl]- 1 H-indole-6- carboxylic acid dimethy/lamide;

{2-[4-(5 -Fluoro-2 -methoxyphenyl)-2-hydroxy-4-rnethyl-2 -trifluoromethylpentyl]—1H-indol-6- yl} morpoholin4-ylmethanone; 2-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-mmethyl-2-trifluoromethylpentyl}—4-methyl-1H- indole-6&-carbonitrile; 2-[4-(5—Fluoro-2-hydroxyphenyl)-2-hydroxy-4-m ethyi-2-trifluoromethylpentyl]-1 H-indole-6- carboxylic acid amide; 2-[4«5—Fluoro-2-methoxyphenyl)-2-hydroxy-4-nethyl-2-trifluoromethylpentyl]- _1H-indole-6- carboxy~lic acid amide; 4-Fluor-o-2-[4,4,4-trifluoro-3-hydroxy- 1,1 -dimetimyl-3-(5-nitro- 1 H-indol-2- ylmethy/1)butyl}phenol; 2-[4-(5—Fluoro-2-methoxypbenyl)-2-hydroxy-4-methyl-2-trifluoromethylipentyl]- 1H-indole-6- carboni-trile; 2-[4-(5—Fluoro-2-hydroxyphenyl)-2-hydroxy-4-mmethyl-2-trifluoromethylpentyl]- B H-indole-6- carboni trile;

N-{2-[®& -(5-Fluoro-2-methoxyphenyl)-2-hydroxy—4-methyl-2-trifluoromethylpent yl}-1H-indo}- 5-yl}ac-etamide; 1,1,1-Twrifluoro-4-(4-fluoro-2-methoxyphenyl)-2-«7-fluoro-4-methyl-1 H-indol-2-=yimethyl)-4- methylpentan-2-ol; 5-Fluor o-2-[4,4,4-trifluoro-3-(7-fluoro-4-methyl- 1H-indol-2-ylmethyl)-3-hydrox—y-1,1- dimethsylbutyl]lphenol;

2-[4-(3-[1,3 IDioxolan-2-ylphenyl)-2-hydroxy-4-methy/1-2-trifluoromethylpentyl]- 1H-indomle-5- carbonitrile=;

2-[4-(5 -Flumoro-2-methoxyphenyl)-2-hydroxy-4-methy-1-2-trifluoromethylpentyl]-1 H-indoRe-5- carboxylic acid-2-tritnethylsilanylethyl ester;

2- [4-(4-Flvaoro-2-hydroxyphenyl)-2-hydroxy-4-methyX-2-triflucromethylpentyl]-4-methyl -1H- -

indole-6-carbonitrile ;

{2-[4-(5-Fuoro-2-methoxyphenyl)-2-hydroxy-4-mettnyl-2-trifluoromethylpentyl]-1H-ind «o}-5- yl} piperid@n-1-ylmethanone; 2-[4-(5-Flvaoro-2-me thoxyphenyl)-2-hydroxy-4-methy~1-2-trifluoromethyipentyl]-1H-indo le-5-

. carboxylic acid methylamide;

{2-[4-(5-F duoro-2-methoxyphenyl)-2-hydroxy-4-mettmyl-2-trifluoromethylpentyl]-1 H-ind. ol-5- yl} pyrroliciin-1-ylmethanone; 1-{2-[4-(5—Fluoro-2-methoxyphenyl)-2-hydroxy-4-me=thyl-2-trifluoromethylpentyl]-1 H-ixadole-

5-carbonyl }piperidin-4-one; - 2-[4-(5-Flvaoro-2-me thoxyphenyl)-2-hydroxy-4-methy»1-2-trifluoromethylpentyl]-1 H-indo le-5- carboxylic acid (2-hydroxyethyl)amide;

{2-[4-(5-Fduoro-2-methoxyphenyl)-2-hydroxy-4-metha yl-2-trifluoromethylpentyl]-1 H-ind=cl-5- y1}(4-hydr<oxypiperidin-1-yD)methanone; {2-[4-(5-Fduoro-2-methoxyphenyl)-2-hydroxy-4-metin yl-2-trifluoromethylpentyl]- 1 H-indeol-5- yl} (3-hydreoxypyrrolidin-1-yl)methanone;

2-{4-(5-Flraoro-2-methoxyphenyl)-2-hydroxy-4-methy-1-2-trifluoromethylpentyl]- 1 4-indoTe-5- carboxylic acid cyanomethylamide;

({2-[4-(5- —Fluoro-2-methox yphenyl)-2-hydrox s/-4-methyl-2-trifluorometizaylpentyl}- 1H-indole-

S-carbon—yl}amino)acetic acid methyl ester;

Co 5 2-[4-(5-F~luoro-2-methoxyphenyl)-2-hydroxy-<4-methyl-2-trifluoromethyXIpentyl]-1 H-indole-5- carboxyl®c acid carbamoylmethylamide; 4-({2-[4— (5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromeethylpentyl]-14- indole-5—carbonyl }amino)butyric acid methyl ester; ’ 10 (§2-[4-(5=-Fluoro-2-methox yphenyl)-2-hydrox y-4-methyl -2-trifluorometihylpentyl]-1H-indole- 5-carbon_yl}amino)acetic acid; 4-({2-[4—(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorom_ethylpentyl]-1H- indole-5—carbonyl}amino)butyric acid; 2-[4-(3-IDimethylaminome thylphenyl)-2-hydreoxy-4-methyl-2-triftuorormethylpentyl]-14- indole-5—carbonitrile; 4-Fluoro=-2-[4,4,4-trifluoro-3-hydroxy-1,1-dinmiethyl-3-(5-trifluoromethyM-1H-indol-2- ylmethyl)butylJphenol; 2-[4-(5-B3romo-2,3-dihydrobenzofuran-7-yl)-=2-hydroxy-4-methyl-2-trifl—uoromethylpentyl]-4- methyl-1 H-indole-6-carbonitrile; ‘ 2-{2-Hycdroxy-4-(5-methanesulfonyl-2,3-dihy=drobenzofuran-7-yl)-4-me@thyl-2- trifluorommethylpentyl]-4-methyl- 1 H-indole-6—carbonitrile; 2-{4-(5-B3romo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifl—uoromethylpentyl]-1H- indole-5-—carboxylic acid;

2-[4-(5-Bromo-2,3-dihydrobenzofuran-7—y})-2-hydroxy-4-methyl-2-trifluoromethylpentyl]- 1H4- indole-5-carboxylic acid arnide; 2-[4-(5-Bromo-2,3-dihydrobenzofuran-7 —yl)-2-hydroxy-4-methyl-2-trifluoreomethylpentyl]- 1H-

: 5 indole-5-carboxylic acid dimethylamide; 2-[4-(5-Bromo-2,3-dihydrobenzofuran-7 —yl)-2-hydroxy-4-methyl-2-trifluor <wmethylpentyl]-14- indole-5-carboxylic acid cyanomethylammide;

{2-[4-(5-Bromo-2,3-dihydrobenzofuran- 7-yl)-2-hydroxy-4-methyl-2-triflucsromethylpentyl]- 1H-indol-5-yl} pyrrolidin- 1-ylmethanone=;

{2-[4-(5-Bromo-2,3-dihydrobenzofuran— 7-yl)-2-hydroxy-4-methyl-2-triflucromethylpentyl]- 1 H-indol-5-yl}morpholin-4-yimethanone=;

2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydxoxy-4-methyl-2-trifluoromethylpe=ntyl]-1 H-indole-5- carboxylic acid amide; . {2-[4-(5-Fluoro-2-methoxyphenyl)-2-hy«droxy-4-methyl-2-trifluoromethylpwentyl]- 1 H-indol-5-

yl}morpholin-4-ylmethanone;

- 2-(4-Benzo[1,3]dioxol-4-y1-2-hydroxy-4--methyl-2-trifluoromethylpentyl)- i 4-methyl-1 H-indole-6-carbonitrile;

1,1,1-Trifluoro-4-methyl-4-phenyl-2-qui nolin-4-ylmethylhexan-2-ol; 2-[2-Hydroxy-4-methyl-4-(5-methylsulfaanyl-2,3-dihydrobenzofuran-7-yI)- 2-trifluoromethylpentyl]-1 H-indole-3-ca xbonitrile;

7-(4,4,4-Trifluoro-3-hydroxy-1,1-dimetimyl-3-quinolin-4-ylmethylbutyl)- 2,3-dihydrobenzofuran-5-carbonitrile;

2-[2-Hydroxy-4-(2-hydroxy-5 -methylphenyy])-4-methyl-2-trifluoromethylpen_tyi}- 22 -methyl-1H-indole-6-carbonitrile; 1,1,1-Trifluoro-4-(5-fluoro-2,3-dihydroben =ofuran-7-yl)-4- rmethyl-2-(5-methylsulfanyl-1H-indol-2-ylrmethyl)pentan-2-ol; 2-[2-Hydroxy-4-(5-methanesuifonyl~2-metThoxyphenyl)-4-methyl-2-trifluoro—mmethyl- pentyl]- 1 H-indole-3-carbonitrile;

X,1,1-Trifluoro-4-(5-flucro-2,3-dihydroben zofuran-7-yl)-4-methyl-2-(5-phemmyl- 1 H-indol-2-ylmethyl)pentan-2-ol; 2-{4-(5-tert-Butyl-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyt— pentyl]-1 H-indole-3-carbonitrile; 2-[2-Hydroxy-4-(2-hydroxy-5-isopropylph «nyl)-4-methyl-2-trifluoromethyl — poentyl]-1H-indole-3-carbonitrile; 2-[2-Hydroxy-4-(2-hydroxy-3,5-dimethylp henyl)-4-methyl-2-trifluoromethy—Ipentyl]- 1 H-indole-3-carbonitrile; 2-[2-Hydroxy-4-(5-hydroxy-2,4-dimethylp Jhenyl)-4-methyl-2-trifluoromethy=Ipentyl]- 1 H-indole-3-carbonitrile; 2-[4-(5-tert-Butyl-2-methoxyphenyl)-2-hyroxy-4-methyl-2-triflucromethylpoentyl]- 1 H-indole-3-carbonitrile; 2-[2-Hydroxy-4-(5-isopropyl-2-meth.oxyph_enyl)-4-methyl-2-trifluoromethylmpentyl]- 1 H-indole-3-carbonitrile; 2-[2-Hydroxy-4-(2-methoxy-5-methylphen yl)-4-methyl-2-trifluoromethylper=ityl]-4-methyl-1H- indole-6-carbonitrile;

1,1,1-Trifhaoro-4-methyl-2-quinolin-4-ylmethyl-4-o-tolylpentan-2-ol; 1,1,1-Triflvaoro-4-methyl-2-quinolin-4-ylmethyl-4-#»-tolylpentan-2-ol;

1;1,1-Triflvaoro-4-(2-fluorophenyl)-2-(1 H-indol-2-y~1methyl)-4-methylpentan-2-ol ; 1,1,1-Triflv-ioro4-(2-fluorophenyl) -4-methyl-2-quirolin-4-ylmethylpentan-2-ol;

1,1,1-Trifluaoro-4-(3-fluorophenyl)-2-(1 H-indol-2-y~Imethyl)-4-methylpentan-2-ol ; 1,1,1-Trifl aoro-4-(3-fluorophenyl)-4-methyl-2-quiriolin-4-ylmethylpentan-2-ol; 1,1,1-TriflL 10r0-4-(4-fluorophenyl)-2-(1 H-indol-2-3-Imethyl)-4-methylpentan-2-ol_;

1,1,1-Trifli_10ro-4-(4-fluorophenyl)-4-methyl-2-quirtolin4-ylmethylpentan-2-ol; 3-(4,4.4-Tr-ifluoro-3-hydroxy-1,1-dimethyl-3-quinoe lin4-ylmethylbutyl)phenol;

1,1,1-Triflu soro-4-methyl-2-quinolin-4-ylmethyl-4-€2-trifluoromethylphenyl)pentaan-2-ol; 1,1,1-Trifl aoro-2-(1H-indol-2-ylmethyl)-4-methyl—4-(4-trifluoromethylphenyl)pe ntan-2-ol; 1,1,1-Triflx_soro-4-methyl-2-quinolin-4-yimethyl-4-€4-trifluoromethylphenyl)pent=an-2-ol;

4-(3-Chloreophenyl)-1,1,1-trifluoro-2-(1 H-indol-2-yImethyl)-4-methylpentan-2-ol ; 4-(3-Chloroophenyl)-1,1,1-trifluoro-4-methyl-2-quirnolin-4-yimethylpentan-2-ol;

4-(4-Dimet-hylaminophenyl)-1,1,1 -trifluoro-2-(1 H-&ndol-2-ylmethyi)-4-methylpertan-2-ol;

. 4-Biphenyl -3-yl-1,1,1-trifluoro-4-methyl-2-quinoliz-4-ylmethylpentan-2-ol;

4-(3-Bromophenyl)—1,1, 1-trifluoro-2-(1 H-ind 0l-2-ylmethyl)-<4-methylpentan-2-ol; 4-(2-Difluorometho-xy-5-flucrophenyl)-1,1,1 ~trifluoro-2-(1H—indol-2-ylmethyl)-4-

methylpentan-2-ol;

4-Biphenyl-3-yl-1, 1 ,1-trifluoro-2-(1H-indol-2-ylmethyl)-4-mmethylpentan-2-ol; 4-(4-Dimethylamin«phenyl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-yimethylpentan-2-ol;

2-[4-(5-Fluoro-2-meethylphenyl)-2-hydroxy-4 -methyl-2-triflhm oromethylpentyl]-1,6- dihydropyrrolo[2,3—c]pyridin-5-one;

. 2-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4 -methyl-2-triflumoromethylpentyl]-6-methyl-1,6-

dihydropyrrolo[2,3—c]pyridin-5-one; 1,1,1-Trifluoro-4-(S-fluoro-2-methylphenyl)-2-(5-methoxy-1 H-pyrrolo[3,2-bJpyridin-2- ylmethyl)-4-methylpentan-2-ol;

2-[4-(3-Dimethylaminomethyiphenyi)-2-hydroxy-4-methyl-2-triflucromethylpentyl}- 1 H- indole-5-carbonitril e; 1,1,1-Trifluoro-2-( L H-indol-2-ylmethyl)-4-methyl-4-pyridin—2-ylpentan-2-ol;

1,1,1-Trifluoro-4-me ethyl 4-pyridin-4-yl-2-quinolin-4-ylmeth_ylpentan-2-ol; 1,1,1-Trifluoro-4-nmethyl-2-quinolin4-ylmethyl-4-o-tolylpenstan-2-ol; 1,1,1-Trifluoro-4-muethyl-2-quinolin-4-ylmethyl-4-n-tolylperatan-2-ol;

1,1,1-Trifluoro-4-(S-flucro-2-methoxyphenyl)-4-methyl-2-p ywridin-4-ylmethylpentan-2-ol;

4-Fluoro-2-[4,4,4-trifluoro—-3-(2-flucropyridin-4-ylmethyl)-3-hydromsxy-1,1- dimethylbutyl]phenol; 2-[3-(2-Bromopyridin-4-yl methyl)-4,4,4-trifluoro-3-hydroxy-1,1-dlimethylbutyl]-4-

fluorophenol; 2-(6,8-Dimethylquinolin-4 —ylmethy!)-1,1, 1-trifluoro-4-(5-fluoro-2—methoxyphenyl)-4- ) methylpentan-2-ol; 4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorommethylpentyljpyridine-2- carbonitrile; 2,6-Dichloro-4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-meth =y1-2- trifluoromethylpentyl]nico tinonitrile;

2,6-Dichloro-4-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyes1-2- triflucromethylpentyllnico tinonitrile; 2-(2,6-Dichloroquinolin-4—ylmethyl)-1,1,1 -trifluoro-4-(5-fluoro-2—methoxyphenyl)-4- methylpentan-2-ol; 2-[3-(2-Chloro-8-methylquiinolin-4-ylmethyl)-4,4,4-trifluoro-3-hyciroxy-1,1-dimethylbutyl]-4- fluorophenol; 2{3-(2,6-Dichloroquinolira-4-ylmethyl)-4,4 4-trifluoro-3-hydroxy~—1,1 -dimethylbutyl}-4- fluorophenol; 4-(2,3-Dihydrobenzofuran—7-yl)-2-(2,6-dimethylpyridin-4-ylmethye/l)- 1,1, 1-triflucro4- methylpentan-2-ol;

2-(2,6-Dimethylpyridin-4-yimethyl)-1,1,1-triftluoro-4-(3-fluorophe=nyl)-4-methylpentan-2-ol;

2-(2,6-Dimethwylpyridin-4-ylmethyl)-1,1,1 -trifluoro-4-(~4-fluorophenyl)-4-methylpentan--2-ol; 1,1,1-Trifluoros-4-(5-fluoro-2-methylphenyl)-4-methyl— 2-quinolin-4-ylmethylpentan-2-o=1; 2-(2,6-Dimeth=ylpyridin-4-ylmethyl)-1,1,1-trifluoro-4-( 5-fluoro-2-methylphenyl)-4- methylpentan-22-o0l; 2-(2,6-Dimeth-ylpyridin-4-ylmethyl)-1,1, 1 -trifluoro-4-rmethyl-4-m-tolylpentan-2-ol;

1,1,1-Trifluorc-4-(5-fluoro-2-methoxyphenyl)-4-methsy]-2-(2-methylquinolin-4- ylmethyl)pentzan-2-ol; 4-Fluoro-2-(4, 4,4-trifluoro-3-hydroxy- 1,1 -dimethyl-3-equinolin-4-ylmethylbutyl)phenol 5

4-Fluoro-2-[4, 4.4-trifluoro-3-hydroxy-1,1 -dimethyl-3- «(2-methylquinolin-4- ylmethyl)buty]phenol; 2-(2,6-Dimeth_ylpyridin4-ylmethyl)-1,1, 1-trifluoro-4-(4-fluoro-2-methoxyphenyl)-4- methylpentan—2-ol;

1,1,1-Trifluorco-4-(5-fluoro-2-methoxyphenyl)-4-meth=yl-2(7-methylquinolin-4- ylmethyl)pent=an-2-ol; 2-[3-(2,6-Dim_ethylpyridin-4-ylmethyl)-4 ,4,4-trifluoro—3-hydroxy-1,1-dimethylbutyl]-5—

fluorophenol; 1,1,1-Trifluorco-4-(4-fluorophenyl)-4-methyl-2-(2-methylquinolin-4-ylmethyl)pentan-2—ol; 1,1,1-Trifluorco-4-(3-fluorophenyl)-4-methyl-2-(3-metkayl- 1 H-indol-2-ylmethyl)pentan-—2-0l;

1,1,1-Trifluore-2-(14-indol-2-ylmethyl)-4-methyl -4-(2-trifluoromethylphenyl)pentan-2= -ol;

: 1,1,1-Trifl_uoro-4-(5-fluoro-2-methoxyphenyl)-2-(7-Eluoro4-methylquinolin-8-y~1)-4- methylpenmatan-2-ol; 4-(2,6-Dirmnethylphenyl)-1,1,1-trifluoro-2-(1H-indol- 2-yImethyl)-4-methylpentarn-2-ol;

2-(3-Bromrmo-1H-indol-2-ylmethyl)-1,1,1-trifluoro-4-«3-fluorophenyl)-4-methylp ~entan-2-0l; 4-(3,4-Dirnethylphenyl)-1,1,1-trifluoro-2-(1 H-indol- 2-ylmethyl)-4-methylpentara-2-ol;

1,1,1-TrifMuoro4-(3-fluoro-4-methylphenyl)-2-( 1 H-@nd ol-2-ylmethyl)-4-methylgpentan-2-ol; 1,1,1-TrifMuoro-4-(4-fluoro-3-methylphenyl)-2-(1 H-And ol-2-ylmethyl)-4-methylgpentan-2-ol; 1,1,1-Trif Tuoro-4-(3-fluoro-4-methylphenyl)-4-meth yl-2-quinolin-4-ylmethylpemntan-2-ol;

1,1,1-Trif Tuoro-4-(4-fluoro-2-methylphenyl)-4-meth yl-2-quinolin-4-yimethylpemntan-2-ol; 4-(3,4-Dirmnethylphenyl)-1,1,1-trifluoro-4-methyl-2-cquinolin-4-ylmethylpentan-2=2-oi;

4-(2,5-Dimmethylphenyl)-1,1,1-trifluoro-2-(1H-indol—2-yimethyl)-4-methylpentazn-2-ol; 1,1,1-Trif luoro-2-(1H-indol-2-ylmethyl)-4-(2-methowxy- 5-methylphenyl)-4-metlaylpentan-2-ol; 4-Methyl—2[4,4,4-trifluoro-3-hydroxy-3-(1H-indol-2-ylmethyl)-1,1-dimethylbumtyl Jphenol;

4-(2,5-Dimmethylphenyl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-=2-ol; 1,1,1-Trif_Tuoro4-(2-methoxy-5-methylphenyl)-4-me=thyi-2-quinolin-4-yImethyl pentan-2-ol;

4-(2,5-Dimmethoxyphenyl)-1,1,1-trifluoro4-methyl-22-(1 H-pyrrolo[2,3-c]pyridin—2- ylmethyl) pentan-2-ol;

1,1,1-Trifluoro-2-(1 H-i ndol-2-ylmethyl)-4-methyl-4-(2-triflucoromethylphenyl)pentan-2=-ol; 1,1,1-Trifluoro-4-(5-flumoro-2-methoxyphenyl)-4-methyl-2-( 7 -pyrrolo[2,3-d)pyrimidira-6- yimethyl)pentan-2-ol; : 1,1,1-Trifluoro-4-(5-flvmoro-2-methoxyphenyl)-2(4-methoxy- 7H-pyrrolo[2,3-d]pyrimiTin-6- . ] ylmethyl)-4-methylpen_tan-2-ol; 2-(2,4-Dimethyl-7 H-pywrr0lo[2,3-d]pyrimidin-6-ylmethyl)-1,1 ,1-trifluoro-4-(5-fluoro-2— methoxyphenyl)-4-met hylpentan-2-ol; 2-(2-Amino-4-chloro-7” H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl)-1,1,1 -trifluoro-4-(5-flucoro-2- methoxyphenyl)-4-methylpentan-2-ol; and 2-(5-Chloro-1H-pyrroleo|2,3-c]pyridin-2-ylmethyl)- 1,1, 1-trifli10ro-4-(5-fluoro-2-methyMphenyl)- 4-methylpentan-2-ol, or a tautomer, prodrug, solvate, or salt thereof,

Most preferred compotands of Formula (IA) include: 1,1,1-Trifluoro-4-(5-flvacro-2-methoxyphenyl)-4-methyl-2-(3—methyl- L H-pyrrolo[3,2-¢_Jpyridin- 2-ylmethyl)pentan-2-ok; 1,1,1-Trifluoro-4-(5-flaoro-2,3-dihydrobenzofuran-7-yl)-4-meethyl-2 (1 H-pyrrolof3,2-c=]pyridin- 2-ylmethyl)pentan-2-0K; 1,1,1-Trifluoro-4-(5-flugoro-2-methylphenyl)-4-methyl-2-(3-naethyl-1H-pyrrolo[2,3 -c]p—yrdin-2- yimethyl)pentan-2-oi; 2-(4,6-Dimethyl-1H-py~rrolo[3,2-c]pyridin-2-ylmethyl)-1,1,1 -~trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-metThylpentan-2-ol;

2-{4-(5-Fluoro-2-methoxyphenyl)-2-hydroxsw-4-methyl-2-trifluoromethylpent=yl]-14- pyrroRo[3,2-b]pyridine-5-carbonitrile;

1,1,1—Trifluora-4-(5-fluoro-2-methoxypheny~1)-4-methyl-2-(6-methyl-1H-pyrr-olo[3,2-c]pyridin- 2-ylmethyl)pentan-2-ol;

1,1,1—Trifluoro-4-(5-flucro-2-methoxypheny)-4-methyl-2-(4-methyl-1H-pyrr—olo[3,2-c]pyridin- 2-ylnethyl)pentan-2-ol;

2-[4-€5-Fluoro-2-methoxyphenyl)-2-hydrox—y-4-methyl-2-trifluoromethylpent=yl}-4-methyl-1 H- pyrro lo[3,2-c]pyridine-6-carbonitrile; 2-[4-&(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent=yl]- 14-

pyrro=10[2,3-c]pyridine-5-carbonitrile; 2-[4-a&(5-Fluoro-2-methoxyphenyl)-2-hydrox y-4-methyl-2-triftuoromethylpent=yl]- 1 4- pyrroslof3,2-cJpyridine-4-carbonitrile;

1,1,1—Trifluoro-4-(5-fluoro-2-methoxyphensyl)-4-methyl-2-(5H-pyrrolo[3,2-d_Jpyrimidin-6- ylmexthyl)pentan-2-ol; 1,1,1—Trifluoro-4-(5-fluoro-2-methoxyphensyl)-4-methyl-2-thieno{2,3-d]pyridl azin-2- ylmethylpentan-2-ol;

1,1,1 —Trifluoro-4-(5-fluoro-2-methoxyphensyl)-4-methyl-2-(SH-pyrrolo[3,2-¢ _Jpyridazin-6- ylme-thyl)pentan-2-ol; 1,1,1—Trifluoro-4-(5-fluoro-2-methyiphenyl )-4-methyl-2-(1 H-pyrrolo[2,3-d}p=yridazin-2-

ylme-thyl)pentan-2-ol;

2-(4,6-Dimethyl-1 H-pyrxolo[3,2-clpyridin-2-ylmethyl)-1,1, 1-tr=ifluoro-4-(5-fluoro-2- methylphenyl)-4-methyl pentan-2-ol; 4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2-(4,6-direthyl- 1 H-ppyrrolo[3,2-c]pyridin-2-

ylmethyl)-1,1,1-trifluoro-4-methylpentan-2-ol; 4-(5-Chloro-2,3-dihydro benzofuran-7-yi)-1,1, 1 -trifluoro-4-met=hyl-2-(6-methyl- 1 H-pyrrolo[ 8 2- clpyridin-2-ylmethyl)pextan-2-ol;

1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-(6-me=thyl-1 H-pyrrolo[3,2-c]pyridim-2- ylmethyl)pentan-2-ol,; 2-[4-(5-Fluoro-2-methylphenyl)-2-bydroxy-4-methyl-2-trifluor—omethylpentyl]- 1 H-pyrrolo[3 _2- blpyridine-5-carbonitrile;

2-[4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-mettmyl-2-triflucromethylpentyl]-1_H- pyrrolo[3,2-b]pyridine-5 —carbonitrile;

: 1,1,1-Trifluoro-4-(5-fluoxo-2-methylphenyl)-4-methyl-2-(5 FI-p—ymrolo[ 3,2-dlpyrimidin-6-

ylmethyl)pentan-2-o0l; 4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1-triflucro-4-methhyl-2-(SH-pyrrolo[3,2- d]pyrimidin-6-ylmethyl)pentan-2-ol;

4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-1, 1,1-trifluoro-4-maetihyl-2-(3-methyl-1H-pyrrolo[2 ,3- clpyridin-2-ylmethyl)peritan-2-ol; 1,1,1-Trifluoro-4-(5-fluoxo-2-methylphenyl)-4-methyl-2-(5 H-p=/molo[ 3,2-clpyridazin-6- ylmethyl)pentan-2-ol;

1,1,1-Trifluoro-4-(5-fluorro-2-methoxyphenyl)-2-(7-fluoro- 1 H-yrrolo[2,3-c]pyridin-2-

ylmethyl)-4-methylpentan-2-ol; ’

1,1,1-Irifluoro-4-(5-fluoro-2-methoxyphenyl)-4—methyl-2-(4-methyl-1H-pyrrolo[ 2.3 -cJpyridin- 2-ylmeathyl)pentan-2-ol;

2-(5,7—Dichloro-1H-pyrrolo[2,3-clpyridin-2-yimeethyl)-1,1,1-trifluoro-4-(5 -fluoro—2- methoxyphenyl)-4-methylpentan-2-ol; 1,1,1-"Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4 —methy}-2-(5-trifluoromethyl-1/—pyrrolo[2,3- ¢lpyriedin-2-ylmethyl)pentan-2-ol;

1,1,1-"Trifluoro4-(5-fluoro-2-methoxyphenyl)-2- ~(5-methoxy- 1H. -pyrrolo[2,3-c]p-yridin-2-

: ylmetTayl)-4-methylpentan-2-ol; 1,1,1—Trifluoro-4~(5-fluoro-2-methylphenyl)-4-rmethyl-2-(4-methyl-1 H-pyrrolo[ 2=,3-c]pyridin-2-

‘ 15 ylmethyl)pentan-2-ol; 1,1,1—Trifluoro-4~(5-fluoro-2-methylphenyl)-2-( 5-isopropoxy- 1 4-pyrrolof2,3-c]oyridin-2- ylmet=hyl)-4-methylpentan-2-ol; i 20 1,1,1—Trifluoro-4-(5-flucro-2-methylphenyl)-2-{ 5-methoxy-1H-pyrrolo[2,3-c]pymridin-2-

’ ylmethyl)-4-methylpentan-2-ol; 4-(5-&Chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1—trifluoro-2-(5 -methoxy-1 H-pyrrolo[2,3- ¢Jpyr-idin-2-ylmethyl)-4-methylpentan-2-ol;

1,1,1 —Trifluoro-4-(5-fluoro-2-methylphenyl)-2-o(7-fluoro- L H-pyrrolo[2,3-clpyrid_in-2-ylmethyl)- 4-me-thylpentan-2-ol; 4-(5--Chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1 —triflucro4-methyl-2-(5-trifluoromsmethyl-1H- : 30 pyrrolo[2,3-clpyridin-2-ylmethyl)pentan-2-ol;

: 2-(5-Dimethylamino-1H-pyrrolo[2,3-clpyridin-2-ylm ethyl)-1,1,1-trifluoro-4-(5-flueoro-2- methylpheny1)-4-methylpentan-2-ol; 1,1,1-Trifluo: xo-4~(5-fluoro-2-methoxyphenyl)-2-(5-chloro-1H-pyrrolo[2,3-c]pyridi n-2- ylmethyl)-4-mmethylpentan-2-ol; 4-(5-Bromo- 2,3-dihydrobenzofuran-7-yl)-1,1,1-triflu-cro-4-methyl-2-(1 H-pyrrolo[22,3-c]pyridin- 2-ylmethyl)pmentan-2-ol;

1,1,1-Triflucero4-methyl-4-(5-methyl-2,3-dihydroberazofuran-7-yI)-2-(1. H-pyrrolo[2,3- ¢Jpyridin-2-w/imethypentan-2-ol; 4-(5-Chloro—2,3-dihydrobenzofuran-7-yl)-1,1,1-triflu_cro-4-methyl-2-(1 H-pyrrolo[=2,3-¢]pyridin- 2-ylmethyl)entan-2-ol;

1,1,1-Triflucoro-4-(5-fluoro-2-methoxyphenyl)-4-met"hyl-2-thieno[2,3-cpyridin-2- ylmethylpen—tan-2-ol; 4-(5-Chloro—2,3-dihydrobenzofuran-7-yl)-2,4-dimethm yl-1-thieno[2,3-c]pyridin-2-yBpentan-2-ol;

} 4-(5-Fluoro-2-methylphenyl)-2,4-dimethy!-1-thieno[ 2,3 -c]pyridin-2-ylpentan-2-ol= . 1,1,1-Triflucoro-4-(5-fluoro-2-methylphenyl)-4-methye/1-2 (1 H-pyrrolo[ 3 ,2-clpyridira-2- ylmethyl)pemntan-2-ol;

1,1,1-Triflucoro-4 -methyl-4-(5-methyl-2,3-dihydrobemzofuran-7-yl)-2-( 1 H-pyrrolo[3,2- clpyridin-2-wylmethyl)pentan-2-ol; 4-(5-Chloro—2,3-dihydrobenzofuran-7-yl)-1,1,1-trifl us oro-4-methyl-2-(1 H-pyrrolo[ 3,2-c]pyridin-

2-ylmethyl)oeuatan-2-ol;

4-(5-Bromo-2,3-dihydxrobenzofuran-7-yl)-1,1,1 -trifluoro-4-metayl-2-(1H-pyrrolo[3,2-c]pyridin- 2-ylmethyl)pentan-2-01; 2-(3-Dimethylaminom ethyl-1 H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-1,1,1-trifluoro-4~(5-fluoro-

2-methoxyphenyl)-4-methylpentan-2-ol; : 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-pyrreolo[ 3,2-b]pyridin-1- ylmethylpentan-2-ol;

1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-furo[3,2-c]pyr-idin-2-ylmethyl-4-

methylpentan-2-ol; 4-(5-Chloro-2,3-dihyd robenzofuran-7-yl)-1,1, -trifluoro-4-metlhyl -2-pyrrolo{3,2-b]pyridin-1- ylmethylpentan-2-ol;

1,1-Difluoro-4-(5-flucro-2-methoxyphenyi)-4-methyl-2-(1 H-p3y~rolo[3,2-c]pyridin-2- ylmethyl)pentan-2-ol; 1,1,1-Trifluoro-4-(5-fLuoro-2-methoxyphenyl)-4-me thyl-2-thier=o[ 3,2-c]pyridin-2-

ylmethylpentan-2-ol; 4-(5-Chloro-2,3-dihyd robenzofuran-7-yl)-1,1, 1-trifluoro-4-met_hyl-2-thienof3,2-c]pyridin-2- ylmethylpentan-2-ol;

1,1,1-Trifluoro-4-(5-fl uoro-2-methylphenyl)-4-methyl-2-pyrrol o[3,2-b]pyridin-1- ylmethylpentan-2-ol; 1,1,1-Trifluoro-4-(5-fL uoro-2-methylphenyl)-4-methyl-2-thienom[3, 2-c]pyridin-2- ylmethylpentan-2-ol;

2-[4-(2,3-Dihydroben=zofuran-7-yl)-2-hydroxy-4-methyl-2-trifl_ioromethylpentyl]-4-methyl-1H- indole-6-carbonitrile;

4-Fluoro-2-[4,4,4-trifluoros -3-hydroxy-1,1 -dimethyl-3-(5-nitro-1.#-indol-2- ylmethyl)butyl]phenol; 2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluo=romethylpentyl]-1 H-indole-6— carbonitrile; 2-(4-(5-Fluoro-2-hydroxygpheny!)-2-hydroxy-4-methyl-2-trifluomromethylpentyl}-1.A4-indole-6— carbonitrile;

N-{2-[4-(5-Fluoro-2-meth oxyphenyl)-2-hydroxy-4-methyl-2-tri-fluoromethylpenty1}-1H-indoX- 5-yl} acetamide; 1,1,1-Trifluoro-4-{4-fluor©-2-methoxyphenyl)-2-(7-fluoro-4-me=thyl-14-indol-2-ylmethyl)-4— methylpentan-2-ol; 5-Fluoro-2-[4,4,4-trifluoro-3-(7-fluoro-4-methyl- 1 H-indol-2-ylt=methyl)-3-hydroxy-1,1- dimethylbutyl]phenol; 2-[4-(3-[1,3]Dioxolan-2-y~Iphenyl})-2-hydroxy-4-methyl-2-triflu=oromethylpentyl ]- 1 #-indole-S- carbonitrile; 2-{4-(4-Fluoro-2-hydroxy-phenyl)-2-hydroxy-4-methyl-2-trifluo- romethylpentyl]-4~methyl- 1 FZ - indole-6-carbonitrile; {2-[4-(5-Fluoro-2-methoxxyphenyl)-2-hydroxy-4-methyl-2-trifhiyoromethylpentyl]- 1 H-indol-5 - yl}piperidin-1-ylmethanome; 2-[4-(5-Fluoro-2-methoxy/phenyl)-2-hydroxy-4-methyl-2-triflucoromethylpentyl]-1 H-indole-5 - carboxylic acid methylanmmide;

} {2-[4-(5-Fluoro-2- methoxyphenyl)-2-hydroxy-4-methyl-2-trifleoromethylpentyl]-1H-indos}-5- - yl}pyrrolidin-1-ylrmethanone; 2-[4-(5-Fluoro-2-mmethoxyphenyl)-2-hydroxy-4 -methyl-2-triflu ©romethylipentyl}-1 H-indol-e-5- carboxylic acid (2—hydroxyethyl)amide; {2-[4-(5-Fluoro-2—methoxyphenyl)-2-hydroxy-4-methyl-2-trifl woromethylpentyl]-1H-indcl-5- yl} (3-hydroxypyri—olidin-1-yl)methanone;

2-[4-(5-Fluoro-2-ruethoxyphenyl)-2-hydroxy-4-methyl-2-trifiu oromethylpentyl]-1H-indoK e-5- carboxylic acid cyanomethylamide; ({2-[4-(5-Fluoro-=22-methoxyphenyl)-2-hydroxy-4-methyl-2-tri#fluoromethylpentyl]-1H-incHole- 5-carbonyl}amincs)acetic acid methyl ester;

2-[4-(5-Fluoro-2-mmethoxyphenyl)-2-hydroxy-4-methyl-2-triflumoromethylpentyl]-1 H-indo3e-5- carboxylic acid camrbamoylmethylamide; 4-({2-[4-(5-Fluore>-2-methoxyphenyl)-2-hydroxy-4-methyl-2-&rifluoromethylpentyl]-1H-

indole-5-carbonyl }amino)butyric acid methyl ester; 4-Fluoro-2-[4,4,4—trifluoro-3-hydroxy-1,1-dimethyl-3-(5-trifliz_oromethyl-1H-indol-2- ylmethyl)butyljpienol;

2-[4-(5-Bromo-2,33-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-triflucromethylpenty lt ]-4- methyl-1H-indole=-6-carbonitrile; 2-[2-Hydroxy-4-( 5-methanesulfonyl-2,3-dihydrobenzofuran-7 -yl)4-methyl-2- trifluoromethylpemtyl]-4-methyl-1H-indole-6-carbonitrile;

2-(4-(5-Bromo-2, 3-dihydrobenzofuran-7-yl)-2-hydroxy-4-met-hyl-2-trifluoromethylpenty 1-1 H- indole-S-carboxyMic acid amide;

: 2-[4-(5-Bromo-2,3 -dihydrobenzofuran-7-yl)-2-hydroxy-4-rmethyl-2-triflucromethylpentyl]- "14- indole-5-carboxyliec acid dimethylamide; 2-[4-(5-Bromo-2,3 -dihydrobenzofuran-7-yl)-2-hydroxy-4-ruethyl-2-trifluoromethylpentyl}- 1H- indole-5-carboxyliec acid cyanomethylamide; {2-[4-(5-Bromo-2, 3-dihydrobenzofuran-7-yl)-2-hydroxy-4—methyl-2-trifluoromethylpentyl l- 1H-indol-5-yl} pyrmrolidin-1-ylmethanone; {2-]4-(5-Bromo-2, 3-dihydrobenzofiran-7-yl)-2-hydroxy-4 -methyl-2-trifluoromethylpentyl 3- 1H-indol-5-y1} mompholin-4-ylmethanone; 2-[4-(5-Fluoro-2-mnethoxyphenyl)-2-hydroxy-4-methyl-2-tacifluoromethylpentyl}-1 #-indole—35- carboxylic acid amide; {2-[4-(5-Fluoro-2—methoxyphenyl)-2-hydroxy-4-methyl-2—trifluoromethylpentyl]-1 H-indol —5- . yl} morpholin-4-ylmnethanone; 2~4-Benzo[1,3]dix0l-4-yl-2-hydroxy-4-methyl-2-trifluoromethylpentyl)-

Co 4-methyl-1H-indoMe-6-carbonitrile; 1,1,1-Trifluoro-4-rmethyl-4-phenyl-2 quinolin-4-ylmethylh €xan-2-ol; h 25 2-[2-Hydroxy-4-m_ethyl-4-(5-methylsulfanyl-2,3-dihydrobesnzofuran-7-yl)- 2-trifluoromethylp-entyl}- 1 H-indole-3-carbonitrile; 7-(4,4,4-Trifluoro- 3-hydroxy-1,1-dimethyl-3-quinolin-4-yl xnethiylbutyl)- 2,3-dihydrobenzofiuran-5-carbonitrile; 2-[2-Hydroxy-4-(2--hydroxy-5-methylphenyl)-4-methyl-2-taxifluoromethylpentyl]- 4-methyl-1H-indol_e-6-carbonitrile;

1,1,1-Trifluoro-4-(5-fluoro-2,3-dihyd=robenzofuran-7-yl)-4- methyl-2-(5-methylsulfanyl-1H-indol_-2-ylmethyl)pentan-2-ol;

= 2-[2-Hydroxy-4-(5-methanesulfonyl-2-methoxyphenyl)-4-methyl-2-triffluoromethyl- pentyl]-1H-indole-3-carbonitrile; : 2-[4-(5-tert-Butyl-2-hydroxyphenyl)—2-hydroxy-4-methyl-2-triflucrom «ethyl- : : pentyl]-1H-indole-3-carbonitrile; ) 190 2-[2-Hydroxy-4-(2-hydroxy-S-isopro-pylphenyl)-4-methyl-2-triftuorommethyl- pentyl]-1H-indole-3-carbonitrile; 2-[2-Hydroxy-4-(2-hydroxy-3,5-dimesthylphenyl)4-methyl-2-trifluorommethylpentyl]- 1 5 1H-indole-3-carbonitrile; 2-[2-Hydroxy-4-(5-hydroxy-2,4-dimeethylphenyl)-4-methyl-2-trifluoroomethylpentyl]- 1 H-indole-3-carbonitrile; »0 2-[4-(5-tert-Butyl-2-methoxyphenyl ®-2-hydroxy-4-methyl-2-trifluoron—methylpentyl]- 1H-indole-3-carbonitrile; 2-[2-Hydroxy-4-(5-isopropyl-2-metimoxyphenyl)-4-methyl-2 -trifluorormethylpentyl]- 1H-indole-3-carbonitrile; >»5 1,1,1-Trifluoro-4-methyl-2-quinolin—4-ylmethyl-4-o-tolylpentan-2-ol; 1,1,1-Trifluoro-4-methyl-2-quinolin—4-ylmethyl-4-m-tolylpentan-2-ol; =0 1,1,1-Trifluoro-4-(2-fluorophenyl)-2 «(1H-indol-2-ylmethyl)-4-methylyoentan-2-ol; ’ 1,1,1-Trifluoro4-(2-flucrophenyl)-4—-methyl-2-quinolin-4-ylmethylper-tan-2-ol;

1,1,1-Trifluoro-4-(3-fluorophenyl)-2-(1H-indo}-2-ylmeth yl)-4-methylpentan-2=--ol; 1,1,1-Trifluoro-4-(3-flucrophenyl )-4-methyl-2~quinolin-4-ylmethylpentan-2-o 1;

1,1,1-Trifluoro-4-(4-fluorophenyl)-2-(1 H-indol-2-ylmeth yl)-4-methylpentan-22-ol; 1,1,1-Trifluoro-4-(4-fluorophenyl)-4-methyl-2-quinolin-4-ylmethylpentan-2-o-1;

3-(4,4,4-Trifluoro-3-hydroxy-1,1~dimethyl-3-quinolin-4- ylmethylbutyl)pheno1; 1,1,1-Trifluoro-4-methyl-2-quino lin-4-ylmethyl-4-(2-triflucromethylphenyl)peentan-2-ol; 1,1,1-Trifluoro-4-methyl-2-quino lin-4-ylmethyl-4-(4-trifluoromethylphenyl)p-entan-2-ol;

4-(3-Chlorophenyl)-1,1,1-triflucro-2-(1H-indol-2-ylmeth.y)-4-methyipentan-=2-ol; 4-(3-Chlorophenyl)-1,1,1-trifluoro-4-methyl-2-quinolin-4-ylmethylpentan-2-oml;

4-Biphenyl-3-y1-1,1,1-trifluoro-4 -methyl-2-quinolin-4-ylmethylpentan-2-ol; 4-(3-Bromophenyl)-1,1,1-trifluor o-2-(1 H-indol-2-ylmeth yl)-4-methylpentan-=2-ol; 4-(2-Difluoromethoxy-5-fluorophenyl)-1,1,1-trifluoro-2-(1 H-indol-2-ylmethy—1)-4-

methylpentan-2-ol; 4-(4-Dimethylaminophenyt)-1,1, 1 -trifluoro-4-methyl-2-quinolin4-ylmethylpentan-2-ol; 2-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl"1-6-methyl-1,6-

dihydropyrrolo[2,3-c]pyridin-5-omne;

nl WO 2005/03021=3 PC™T/US2004/031009 1,1,1-Triflucore-4-(5-fluoro-2-methylphenyt)-2-(5-rmethoxy- | H-pyrrolo[3 ,2-E5)pyridin-2- ylmethyl)-4—methylpentan-2-ol; 2-[4-(3-Dirmmethylaminomethylphenyl)-2-hydroxy-4&-methyl-2-trifluoromethy~lpentyl]-1H-

indole-5-car~bonitrile; 1,1,1-Triflucro-2-(1 H-indol-2-ylmethyl)-4-methyl—4-pyridin-2-ylpentan-2-o ; 1,1,1-Triflucoro-4-methyl-2-quinolin-4-ylmethyl-4- -o-tolylpentan-2-ol;

1,1,1-Triflueoro-4-methyl-2-quinolin-4-ylmethyl-4- sm-tolylpentan-2-ol; 4-Fluoro-2-[4,4 ,4-trifluoro-3-(2-fluoropyridin4-yl-methyl)-3-hydroxy-1, 1-

. dimethylbut=yl]phenol;

2-[3-(2-Brommopyridin-4-ylmethyl)-4,4 4-triflucro-3-hydroxy-1,1-dimeth.ylbwatyl]-4- fluorophenoml; 2-(6,8-Dime=thylquinolin-4-ylmethyl)-1,1,1-trifluor=0-4-(5-fluoro-2-methoxypohenyl)-4-

© 20 methylpentamn-2-ol; 4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-me=thyl-2-trifluoromethylperatyl Jpyridine-2- carbonitrile;_

2,6-Dichlorco-4-[4-(5-fluoro-2-methoxyphenyl)-2-bmydroxy-4-methyl-2- trifluoromet=hylpentyl]nicotinonitrile; 2,6-Dichlorc-4-[4-(5-fluoro-2-hydroxyphenyl)-2-h~ydroxy-4-methyi-2- trifluoromet” hylpentyljnicotinonitrile;

2-{3-(2,6-Di_chloroquinolin-4-ylmethyl)-4,4,4-triflvmoro-3-hydroxy-1,1-dimet=hylbutyl]-4- fluoropheno-1;

4-(2,3-Dihyd_robenzofuran-7-yl)-2-(2,6-dimethylpyridim-4-ylmethyl)-1,1,1-trifluoro—4- methylpentar-2-ol;

2-(2,6-Dimet-hylpyridin-4-ylmethyl)-1,1,1-trifluoro-4-( 3-fluorophenyl)-4-methylpen -tan-2-ol;

2-(2,6-Dimesthylpyridin-4-ylmethyl)-1,1,1-trifluoro-4-(4-fluorophenyl)-4-methylpen_tan-2-ol; 1,1,1-Trifluomxo-4-(5-fluoro-2-methylphenyl)-4-methyl—2-quinolin-4-ylmethylpentan_-2-ol;

2-(2,6-Dime®hylpyridin-4-ylmethyl)-1,1,1-trifluoro-4-¢5-fluoro-2-methylphenyl)-4- methylpentami-2-ol; 2-(2,6-Dimewthylpyridin-4-ylmethyl)-1,1,1-trifluoro-4-mnethyl-4-m-tolylpentan-2-ol;

1,1,1-Triflucexo-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-methylq uinolin-4- ylmethyl)pertan-2-ol; 4-Fluoro-2-(=4,4,4-trifluoro-3-hydroxy- 1,1-dimethyl-3 — quinolin-4-ylmethylbutyl)phe=nol;

. 20

4-Fluoro-2-[-4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3— (2-methylquinolin-4- ylmethyl)buttyl]phenol; 2-2,6-Dime=thylpyridin-4-ylmethyl)-1,1,1-trifluoro-4-e(4-fluoro-2-methoxyphenyl)-=3-

methylpentam-2-ol; 1,1,1-Triflucero-4-(5-fluoro-2-methoxyphenyl)-4-me th yl-2-(7-methylq uinolin-4- ylmethyl)per-tan-2-ol;

2-{3-(2,6-Dimxethylpyridin-4-ylmethyl)-4,4 4-trifluoro—3-hydroxy-1,1-dimethylbutyl ]-5- fluorophenoll;

1,1,1 ~Trifluoro-4-(4-fluorophenyl)-4-meth=yl-2-(2-methylquinolin-4-ylmethyl) pentan-2-ol; 1,1,1 ~Trifluoro-4-(3-fluorophenyl)-4-meth=yl-2-(3-methyl-1H-indol-2-ylmethy-T)pentan-2-ol; 1,1,1 -Trifluoro-2-(1H-indol-2-ylmethyl)-4—methyl-4-(2-trifluoromethylphenyl Jpentan-2-ol; 1,1,1 -Trifluoro-4-(5-fluoro-2-methoxypheryl)-2-(7-fluoro-4-methylquinolin-& -yI)-4- meth_ylpentan-2-ol; = 10 4-2, 6-Dimethylphenyl)-1,1,1-trifluoro-2-( 1H-indol-2-ylmethyl)-4-methylpen-tan-2-ol; 2-(3—Bromo-1H-indol-2-ylmethyl)-1,1,1-tr ifluoro-4-(3-fluorophenyl)-4-methy~Ipentan-2-ol; 4-(3, 4-Dimethylphenyl)-1,1,1-trifluoro-2-(C 1H-indol-2-ylmethyl)-4-methylpentan-2-ol;

1,1,1 -Trifluoro-4-(3-fluoro-4-methylpheny=1)-2-(1 H-indol-2-ylmethyl)4-methyIpentan-2-ol; 1,1,1 -Trifluoro-4-(4-fluoro-3-methylpheny~1)-2-(1 H-indol-2-ylmethyl)-4-meth »/Ipentan-2-ol; : 20 1,1,1 -Trifluoro-4-(3-fluoro-4-methylpheny~1)-4-methyl-2-quinolin-4-ylmethyly>entan-2-ol; 1,1,1 -Trifluoro-4-(4-fluoro-2-methyipheny—1}-4-methyl-2-quinolin-4-ylmethyly>entan-2-ol; 4-(3,-4-Dimethylphenyl)-1,1,1-trifluoro-4-rmethyl-2-quinolin-4-ylmethylpentara-2-ol;

4-(2,5-Dimethyiphenyl)-1,1,1-trifluoro-2-( 1H-indol-2-ylmethyl)-4-methylpentan-2-ol; 1,1,1 -Trifluoro-2-(1H-indol-2-ylmethyl)-4 —(2-methoxy-5-methylphenyl}-4-me=thylpentan-2-ol; 4-Me=thyl-2-[4,4,4-trifluoro-3-hydroxy-3-( lL H-indol-2-yimethyl)-1,1-dimethylt>utyl phenol; 4-(2,55-Dimethylphenyl)-1,1,1-trifluoro4-mnethyl-2-quinolin-4-ylmethylpentara-2-ol;

1,1,1-Trifluoro-4-(2-methoxy-5-xmethylphenyl)-4-methyl-2-quinolin-4 -ylmethylpentan-2-ol; 4-(2,5-Dimethoxyphenyl)-1,1,1-txiftluoro-4-methyl-2-( 1 H-pyrrolo{2,3—c]pyridin-2- ylmethyl)pentan-2-ol; 1,1,1-Trifluoro-2-(1 H-indol-2-ylamethyl)-4-methyl-4-(2-trifluorometh ~yiphenyl)pentan-2-ol, 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(7H-pyrrol_o[2,3-d]pyrimidin-6- ylmethyl)pentan-2-ol; 1,1,1-Trifluoro-4-(5-fluoro-2-me thoxyphenyl)-2-(4-methoxy-7H-pyrr—clo[ 2,3-d]pyrimidin-6- ylmethyl)-4-methylpentan-2-ol; 2+2,4-Dimethyl-7H-pyrrolo[2,3 —d]pyrimidin-6-ylmethyl)-1,1,1-triflueoro4-(5-fluoro-2- methoxyphenyl)-4-methylpentan ~2-ol; 2-(2-Amino-4-chloro-7 H-pyrrolo{2,3-dlpyrimidin-6-ylmethyl)-1,1,1-€rifluoro-4-(5 -fluoro-2- methoxyphenyl)-4-methylpentan -2-ol; and 2-(5-Chloro-1H-pyrrolo[2,3-c]pyrridin-2-ylmethyl)- 1,1, 1-trifluoro-4-(=S-fluoro-2-methylphenyl)- 4-methylpentan-2-ol, or a tautomer, prodrug, solvate, o»r salt thereof.

The invention also provides a method of making a compound of Fornmula (JA)

Bi 5 > +R

R=. R

R CF,

Ia) where R!, R?, R?, R%, and R® are as defined ahove, the method comprissing:

’ } (a) reacting an ester of Formula (II) with a suitable reducing agent in a suitable solvent to forms a diol of Forrmala (XI) 3 3

R HO CF; reduction R\ Ho_ CF,

R? OR" R2 OH

R' R! 0] 1] 1] ; (b) reacting the di ol of Formula (II) under suitable oxidative cleavage conditions to form ea ketone of Formula (IV) 3 3

R\ HQ Fs i oxidative NN 2 —_— 2

R R! cleavage R R' CF, ii wv ; and (c) reacting the ke=tone of Formula (IV) with a suitable orgzanometallic reagent RR*M where

M is Li or MgX and X is Cl, Br, or 1, in a suitable solvent to form the compound o=f

Formula (TA) ) 3 a 2 2 5

R R' CF, — R =! R4-R

NN 1A ; or (a’) reacting the trifluoroacetamide of Formula (X) with a vim yl magnesium bromide bearing R=2 and R? in a suitable solvent to provide the trifluoromethy-lenone of Formula (XI)

R?

JAN Mar

OQ R rR? 0

CoN Oe I 3 3 R CF,

CH, oC 15 X Xl :

(b’) reacting the trifluoromethylenone of Form ula (XI) with a suitable orgarocopper reagent gen erated from an organometallic reagent FRR*M where M is Li or MgX and a copper salt

Cu=X, where X is Cl, Br, or L, in a suitable solvent to form the ketone of Fo-rmula (IV) 3 2 3 0

J Rn EN

Co 2 NN —_— rR CF

R CF, Cux 3

Xl Iv ; and performing step (c) as set forth above.

The ins€ant invention is also directed to compounds of Formula (IB) 3

R H

5 2 4- R

R R’ R® R (IB) whereirm.: .

R' is an aryl or heteroaryl group, each optiorally independently substituted with one to three sLabstituent groups, wherein each substituent group of R'is Sindependently C;-Cs alkyl, C2~ Cs alkenyl, C>-Cs alkynyl, C;-Cy cycloalkyl, heterocyclyl, aryl, heteroaryl, Ci-Css alkoxy, CC; alkenyloxy, C,-C; alkynyloxy, aryloxy, acyl, C,-Cs alkoxycarbonyl, C—-Cs alkanoyloxy,

C-Cs alkanoyl, aroyl, aminocarbonyl, C;-Cs alkylaminoczabonyl, C;-Cs dialkylaminocarbonyl, aminocarbonyl oxy, C;-Cs alkylaminocartonyloxy, C;-Cs dialkylaminocarbonyloxy, C;-Cs alkan oylamine, C;-Cs alkoxycarbomnylamino, C;-Cs alkylsulfonylamino, aminosulfonyl., Ci-Cs alkylaminosuHifonyl, Ci-Cs dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, triflucromethoxy, nitro, or amino where in the nitrogen atom is optionally independently 1mono- or di-substituted by C;-Cs alkyl Or aryl; or ureido wherein eithemr nitrogen atom is optionally independently substituted with C,-Cs alkyl; or C,-Cs alky_lthio wherein the sulfur atom is optionally oxidized to a sv.alfoxide or sulfone,

wherein each substituent group of R' is optionally independently substoituted with one to three substituent groups selected from methyl, methoxy, balogexn, hydroxy, oxo, cyano, heteroaryl, heterocyclyl, ©r amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C;~Cs alkyl or aryl; or ureido wherein either nitrogen atom is optionally independently substituted -with C;-Cs alkyl;

R?and R? are each independently C,-Cs alkyl;

R* isC 1-Cs alkyl, C,-Cs alkenyl, or C,-Cs alkyny~1, each optionally independently substituted witlm one to three substituent groups, wherein each substituent group of R* is indegpendently C,-C; alkyl, hydroxy, halogen, or 0X_O;

R’ is a heteroaryl group optionally independentMy substituted with one to three substituent groups, wherein each substituent group of R® is indegpendently C,-Cs alkyl, C,-Cs alkenyl, C,-Cs allsynyl, C;-Cg cycloalkyl, heterocyclyl, aryl, heteroaryl, C;-Cs alkoxy, C,-Cs alksenyloxy, C,-Cs alkynyloxy, aryloxy, acyl_, C;-Cs alkoxycarbonyl, C;-Cs allkanoyloxy, aminocarbonyl, alkylaminocarbonyl, dialky—laminocarbonyl, aminocarbonyl oxy, C;-Cs allksylaminocarbonyloxy, Ci-Cs dialkylaminccarbonyloxy, C;-Cs alkanoylarmino, C,;-Cs alk=oxycarbonylamino, C,-Cs alkylsulfonyl amino, C)-Cs alkylaminosulfoenyl, C;-Cs diamlkylaminosuifonyl, halogen, hydroxy, carboxy, cyano, trifliaoromethyl, triffluoromethoxy, trifluoromethylthio, nitro , or amino wherein the nitrog-en atom is optionally independently mono- or di-subs—tituted by C;-Cs alkyl; or ureiedo wherein eitaher nitrogen atom is optionally independe=ntly substituted with C;-Cs alkyl; or C;-Cs allylthio wherein the sulfur atom is optional My oxidized to a sulfoxide or sulf<one, wherein each substituent group of R® is optionally independently substmituted with coe to three substituent groups selected from C,-C; alkyl, C;-Cs alkoxy, halogen,

hydroxy, oxo, cyano, heteroaryl, heterocyclyl, or amino wherein the niztrogen atom is optionally independently mono- or di-subostituted by C;-Cs alkyl or aryl; or ureido wherein either nitrogen atom is optiona lly independently substitute=d with Ci-Cs alieyl, or trifluoromethyl; and

R® is hydrogen, C;-C; alkyl, C,-C; alkenyl, C,-CC; alkynyl, carbocycle, heterocyclyl, aryl, heteroaryl, carbocycle-C;-Cs alkyl, carboxy, alkoxycarbonyl, aryl-C;-C; alkyl, aryl-C-Cg haloalkyl, heterocyclyl-C,-Cs alkyl, heteroar—y!-C;-Cy alkyl, carbocycle-aC;-Cy alkenyl, } aryl—C,-C; alkenyl, heterocyclyl-C,-Cs alkenyl, or heteroaryl-C>-Cs alkenyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R® is independently C-Cs alkyl, C>-Cs alkenyl, Co-Cs allcynyl, C;-Cs cycloalkyl, phenyl, C,-Cs alkkexy, phenoxy, Ci-Cs alkanol, aroyl, Ci-Cs allcoxycarbonyl, C,-Cs alkanoyloxy, aminocaarbonyloxy, C;-Cs alkylamirocarbonyloxy,

C,-Cs dialkylaminocarbonyloxy, aminocar¥bonyl, C;-Cs alkylaminoce=sbonyl, C;-Cs dialkylaminocarbonyl, C;-Cs alkanoylami-mo, C;-Cs alkoxycarbonyMamino, Ci-Cs alkcylsulfonylamino, C;-Cs alkylaminosulfomnyl, C;-Cs dialkylaminosul#fonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluorometh_yl, nitro, amino wherein the= nitrogen atom is optionally independently mono- or di-submstituted by C;-Cs alkyl; or —ureido wherein either nitrogen atom is optionally independe=ntly substituted with C,-Cs alkyl; or C;-Cs allkcylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein R © cannot be trifluoromethyl, or a tautormer, prodrug, solvate, or salt thereof.

Another aspect of the invention includes compounds of Formula (IB), wherein:

R' is thienyl, phenyl, naphthyl, dihydrob enzofuranyl, benzofuranyM, chromanyl, dihy-droindolyl, indolyl, dihydrobenzothimenyl, benzothienyl, be=nzodioxolanyl, ben=oxazolyl, benzisoxazolyl, benzpyrazol=yl, benzimidazolyl, thien®sl, quinolinyl,

pyridinyl, pyrimidinyl, or pyrazinyl, each optionally independeratly substituted with one to three substituent groups, wherein each substituen®t group of R! is independently C;-C; allkyl, C>-C; alkenyl, C-Ca alkynyl, C;-C; alkoxy, C»-Cs alkenyloxy, Ci-Cs alkanoyl, C;-C3 alkoxycarbonyl, C;-C3 alkanoyloxy, halogen, hydroxy, carboxy, cyano, trifluorormethyl, nitro, or C;-Cs alkylthio wherein the sulfur atom is optionally oxidized to a sulk foxide or sulfone, wherein each substituent group of R! is optionally indepen dently substituted with a substituent group selected from methyl, methoxy, halogen, hydroxy, oxo, cyano, heteroaryl, heterocyclyl, or amino wherein the nitrogen atom is optionally independently mono— or di-substituted by C;-Cs alkyl or aryX,;

R? and R? are each independently C,-Cs alkyl;

R*is CH;;

R® is an imidazolyl, pyridyl, indolyl, azaindolyl, diazeaindolyl, benzofiranyl, furanopyridinyl, furanop -yrimidinyl, benzothienyl, thienopyricdlinyl, thienopyrimidinyl, benzoxazolyl, oxazolop-yridinyl, benzothiazolyl, thiazolopymridinyl, benzimidazolyl, imidazolopyridinyl, imicilazolopyrimidinyl, imidazolopyridazirayl, imidazolopyrazinyl, quinolinyl, or isoquinolin yi group, each optionally independent] y substituted with one to three substituent groups, } 25 wherein each substituemnt group of R® is independently C,-€C; alkyl, C,-C; alkenyl, - phenyl, C,-C; alkoxy, methoxycarbonyl, aminocarbonyl, C; -C; alkylaminocarbonyl, . C,-C; dialkylaminocartoonyl, heterocyclylcarbonyl, hydroxy, fluoro, chloro, bromo, cyano, trifluoromethyl, or C,-C; alkylthio wherein the suclfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of R® is optionally indepen dently substituted with a substituent group selected from methyl, methoxy, fluoro, chloro, bromo,

WVWVO0 2005/030213 PCT/US2004/031009 trifluoromethyl, heterosaryl, heterocyclyl, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C,-Cs a_1kyl or aryl; and . R¢ is C;-Cs alkyl, C,-Cs alkemyl, C;-Cs cycloalkyl, phenyl, C3-Cs cycloalkyl-C,-C; alkyl, phenyl-C;-C; alkyl, phenyl- C;-C; haloalkyl, C;-Cs cycloalkyl-C=2-Cs alkenyl, phenyl-Ca-

Cs alkenyl, each optionall y independently substituted with cope to three substituent groups,

SE wherein each substituent gzroup of RS is independently C;-Cs al kyl, C,-C; alkenyl, C2-Cs alkynyl, Ci-C; alkoxy’, aminocarbonyl, C;-Cs alky laminocarbonyl, Ci-Cs dialkylaminocarbonyl, haleogen, hydroxy, oxo, carboxy, cyano, trifluoromethyl, nitro, or

C1-C; alkylthio wherein th_e sulfur atom is optionally oxidized tro a sulfoxide or sulfone, ar a tautomer, prodrug, solvate, or salt thereof,

Yet another aspect of the inventiomn includes compounds of Formula (JB), wherein:

R!is thienyl, phenyl, naphthyl, pyridyl, chromanyl, dibydrobenzofuraxmyl, or benzofuranyl, each : optionally independently substituted with one or two substituent groups, wherein each substituent group of R' is independently methyl _, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, hyclroxy, triffuoromethyl, cyano, or C;—Cs alkylthio wherein the sulfur atom is optionally o xidized to a sulfoxide or sulfone; R%and R® are each methyl;

R'is CHy;

R’ is a pyridyl, indolyl, azaindolyl, diazaindolyl, benzofi_aranyl, furanopyridinyl, thienopyridinyl, benzoxazoRyl, benzimidazolyl, quinolinyl, or i=soquinolinyl group, each optionally independently sulbstituted with one to three substituent groups,

wherein each substituent group of R= is independently methyl, phemyl, methoxycarbonyl, aminocarboryl, methylaminocarbomyl, dimmethylaminoaminocarbonyl, morpholinylca=xbonyl, hydroxy, fluoro, chloro, bromo, cyano, or trifluoromethyl; and

R® is Cy -Cs alkyl, C3-Cs cycloalkyl, C3-Cs cyclo=alkylmethyl-, or benzyl, each optionally independently substituted with one to three substituent groups, whe=rein each substituent group of R® is indepeendently methyl, methoxy, fluoro, chloro, bromo, cyano, trifluoromethyl, or hydroxy, or a tautorrmer, prodrug, solvate, or salt thereof.

Yet another aspect of the invention includes compounds of Formula (IB), wherein:

R! is phenyl, dihydrobenzofuranyl, or benzoffuranyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R' is independently C,-C; alkyl, C-C; alkenyl, C2-Cs alkynyl, C;-C; alkoxy, C,-C; alkenyloxy, C,-&C, alkanoyl, C;-C; alkoxycarbonyl, C ;1-C; allkcanoyloxy, halogen, hydroxy, carboxy, cyano, trifluoromethyl, nitro, or C;-C; alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone; and

R? and R® are each independently C;-Cs alkyl, or a tautomer, prodrug, solvate, or salt thereof.

Yet anothe x aspect of the invention includes compounds of Formula (IB), wherein:

R!is thiensy/], phenyl, naphthyl, pyridyl, chromanyl, di_hydrobenzofurany}, or benzofuranyl, each opticenally independently substituted with one om two substituent groups,

wherein -each substituent group of R' is independ: ently methyl, ethyl, methoxy, etho=ky, fluoro, chloro, bromo, hydroxy, trifluoromethyl, «cyano, or C;-C; alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide ox sulfone;

R’andR? are casch methyl;

Ris CH;

R® is a pywxidyl, indolyl, azaindolyl, diazaindo-lyl, benzofuranyl, furanopyridirmyl, thienopyri«dinyl, benzoxazolyl, benzimidazolyl, qu-inolinyl, or isoquinolinyl group, ezach optionally independently substituted with one to thi—ee substituent groups, wherein each substituent group of R® as independently methyl, phermyi, methoxy carbonyl, aminocarbonyl, methylaminocarbormyl, dimethyl aminocaminocarbonyl, morpholinylcarboryl, pyridinyl, hydroxy, fluoro, chloro, bromo, cyano, or trifluoromethyl; and

R® is C-Cs alkyl, Cs-Cs cycloalkyl, Cs-Cs cycloalksylmethyl-, or benzyl, each optionamlly independently substituted with one to three substitu ent groups, wherein each substituent group of R® is independ=ently methyl, methoxy, fluoro, chlosro, bromo, ¢ yano, trifluoromethyl, or hydroxy, or a tautoruer, pr-odrug, solvate, or salt thereof. ’ 25

In the above asp ects of the invention of the compounds of Formula (IB), it is preferred that R® is not hydrogen.

Representative c-ompounds of Formula (IB) according to the invention are appended hereto as

Table IB, wheres column A is the compound name acc=ording to standard nomenclature awnd column B is the «corresponding chemical structure.

: Preferre=d compounds of Formula (IB) include the following: 2-Cyclospropyl-4-(5-fluoro-2-methoxyphenyl)-4-methyl-1-(1 H-pyrrolo[3,2-c]pyridin-2- ylpentzan-2-ol; 2-Cyclampropyl-4-(5-fluoro-2-methylphenyl)-4-me thyl-1-(1H-pyrrolo[2,3-¢c]pyridin-2-yl Jpentan- 2-ol; 4-(5-Chmloro-2,3-dihydrobenzofuran-7-yl)-2-cyclopropyl-4-methyl-1-(1 H-pyrrolo[2,3-¢] pyridin- 2-yl)pemtan-2-ol; 2-Cyclopropyl-4-(5-flucro-2-methylphenyl)-4-methyl-1-(1 H-pyrrolo[ 3,2-c]pyridin-2-yl Jpentan- 2-0];

R 15 4-(5-Clmloro-2,3-dihydrobenzofuran-7-yl)-2-cyclopropyl-4-methyl-1-(1 H-pyrrolo[3,2-c} pyridin- 2-yl)pemntan-2-ol; 4-(5-Flraoro-2-methoxyphenyl)-2,4-dimethyl-1-(1_H-pyrrolo[2,3-clpyridin-2-yl)pentan-22-o0l; 5-(5-Flwioro-2-methoxyphenyl)-2,5-dimethyl-3-(1_H-pyrrolo[2,3-clpyridin-2-ylmethyl)hesxan-3- ol; 5-(5-Fluaoro-2-methoxyphenyl)-2,2,5-trimethyl-3- (1LH-pyrrolo[2,3-c]pyridin-2-ylmethyl Dhexan- 3-01; 2-Cyclohexyl-4-(S-fluoro-2-methoxyphenyl)-4-m ethyl-1-(1H-pyrrolo[2,3-c]pyridin-2- yl)penta=an-2-ol; 2-Cycloopentyl-4-(5-fluoro-2-methoxyphenyl)-4-maethyl-1-(1H-pyrrolo[2,3-c]pyridin-2- ylpentz=an-2-ol; 5-(5-Flvaoro-2-methoxyphenyl)-5-methyl-3-(1 H-p yrrolo[2,3-c]pyridin-2-ylmethyl)hexar-3-ol;

2-(5-Fluoro-2 —methoxyphenyl)-2,6-dimethyl-4-(1LH-pyrmrolo[2,3-c]p yridin-2-ylmethyl)heptan_-4- ol; ] 5 2-(5-Fluoro-2—methoxyphenyl)-2,5,5-trimethyl-4-(1H-p ymolo[2 ,3-c]pyridin-2-ylmethylhept as- 4-0}; 1,1-Difluoro-<}-(5-flucro-2-methoxyphenyl)-4-methyl-2- -(1 H-pyrrolo [2,3-clpyridin-2- ylmethyl)pent-an-2-ol;

1-Cyclobexyl —4-(5-fluoro-2-methoxyphenyl)-4-methyl-_2-(1H-pyrrolof2,3-c]pyridin-2- ylmethyl)pent-an-2-ol; 5-(5-Fluoro-2 -—methylphenyl)-2,5-dimethyl-3-(1 H-pyrrolo[ 2,3-c]pyridin-2-ylmethyl)hexan-3 —ol;

5-(5-Fluoro-2—methylphenyl)-2,2,5-trimethyl-3-(1 H-pymrrolo[2,3-c]pyridin-2-ylmethyl hexan -3- ol; 5-(5-Chloro-2-,3-dihydrobenzofuran-7-y1)-2,5-dimethyl —3-(1 H-pyrrolo[2,3-c]pyridin-2- ylmethyl)hex=an-3-ol; 2-Cyclobutyl—4-(5-fluoro-2-methoxyphenyl)-4-methyl- 1 -(1H-pyrrolo[2,3-c]pyridin-2- yl)pentan-2-ol; 2+(5-Fluoro-2—methoxyphenyl)-2,6,6-trimethyl-4-(1 H-p~- ymrolo[2,3-c]pyridin-2-ylmethyl)hept-an- 4-ol; 5-(5-Fluoro-2—methoxyphenyl)-5-methyl-3-(1 H-pyrrolom[2,3-c]pyridin-2-ylmethyl}hex- 1 -en-3- ol;

5-(5-Fluoro-2—methoxyphenyl)-5-methyl-3-(1 H-pyrrolos[2,3-c]pyridin-2-ylmethyl)hex- 1 -yn-33- ol;

1-Flvaoro4-(5-fluoro-2-methoxyphenyl)-4-methyl -2-( 1 H-pyrrolo[2,3-clpyridin-2- ylme=thyl)pentan-2-ol;

2,2-IDifluoro-5-(5-fluoro-2-methoxyphenyl)-5-methyl-3-(1H-pyrrolo[2,3-c]pyridin-2- ylme=thyl)hexan-3-ol; 2-Flvaoro-5-(5-fluoro-2-methoxyphenyl)-2,5-dimethyl-3-(1 H-pyrrolo{2,3-clpyridin-2- ylme=thylhexan-3-ol;

2-Flmioro-5-(5-fluoro-2-methoxyphenyl)-5-methy1-3-(1 H-pyrrolo{2,3-c]pyridin-2- ylme=thyl)hexan-3-ol; 5-(5—Fluoro-2-methoxyphenyl)-2,5-dimethyl-3-(1_H-pyrrolo{2,3-clpyridin-2-ylmethyl)he—x-1-en- 3-0lo 1,1,1 -Trifluoro-5-(5-fluoro-2-methoxyphenyl)-5-mmethyl-3-(1H-pyrrolo[2,3-c]pyridin-2- ylme=thyl)hexan-3-ol; 4~(5—Fluoro-2-methoxyphenyl)-4-methyl-2-pheny1-1-(1H-pyrrolof2,3-c]pyridin-2-yl)pen—tan-2- ol; 5-(5—Chloro-2,3-dihydrobenzofuran-7-yi)-2,2,5-trimethyl-3-(1 H-pyrrolo[2,3-c]pyridin-2 — ylme=thyl)hexan-3-ol;

5-(5—Fluoro-2-methylphenyl)-2,2,5-trimethyl-3-thieno[2,3-c]pyridin-2-ylmethylhexan-3-=ol; 1, 1-Diflucro-4-(5-fluoro-2-methoxyphenyl)-4-me thyl-2-(1 A-pyrrolo[3,2-cIpyridin-2- ylmes=thyl)pentan-2-ol;

5-(5—Fluoro-2-methoxyphenyl)-2,5-dimethyl-3-(1_H-pyrrolo[3,2-c]pyridin-2-ylmethyl)hemxan-3- ol;

5-(5-Fluoro-2-methoxyphenyl)-2,2,5-trimethyl-3-(1H-pyrrolof3,2-c]pyridin-2-ylme=thylhexan- 3-ol;

2-(1-Fluorocyclopropyl)-4-(5-fluoro-2 -methoxyphenyl)-4-methyl-1-(1 H-pyrrolo[2 _.3-c]pyridin- 2-y)pentan-2-ol; 2-(1-Fluorocyclopropyl)-4-(4-fluorophenyl)-4-methyl-1-quinolin-4-ylpentan-2-ol;

2-[4,4-Difluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl) Bbutyl]-4- fluorophenol; 5-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2,5-dimethyl-3-(1H-pyrrolo[3,2-c]lpyrid_in-2- ylmethyl)hexan-3-ol;

5-(5-Fluoro-2-methylphenyl)-2,5-dimethyl-3-(1 H-pyrrolo[3,2-c]pyridin-2-ylmeth—yl)hexan-3-ol; 5-(5-Fluoro-2-methylphenyl)-2,2,5-trimethyl-3-(1H-pyrrolo[3,2-c]pyridin-2-ylme=thyl }hexan-3- ol;

4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-1,1-difluoro-4-methyl-2-(1 H-pyrrolof3 ,2-clpyridin-2- ylmethyl)pentan-2-ol; 4-(5-Chloro-2,3-dihydrobenzofuran-7-y1)-1,1-difluoro-4-methyl-2-pyrrolo[3,2-b E pyridin-1-

ylmethylpentan-2-ol; 5-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2,2,5-trimethyl-3-(1H-pyrrolo[3,2-c]pxwridin-2- ylmethyl)hexan-3-o0l;

5-(5-Fluoro-2-methylphenyl)-2,2,5-trimethyl-3-(3-methyl-1H-pyrrolo[2,3-c]lpyri~din-2- ylmethyl)hexan-3-oi;

WO» 2005/030213 PCT/US2004/031009 5-(5-Chloro-2,3-dihydrobenzofuran-~7-yl)-2,5-dimethyl-3-(3-methyl- 1 H—pyrrolof2,3 -c]pyridin- : 2-ylmethyl)hexan-3-ol; 5-(5-Chloro-2,3-dihydrobenzofuran—7-yl)-2,5-dimethyl-3 -(5-phenyl-1 H=pyrrolo[2,3-c]pyridin- 2-ylmethyl)hexan-3-ol; 5-(5-Fluoro-2-methylphenyl)-2,2,5-trimethyl-3-(5-phenyl- 1 H-pyrrolo[2- ,3-c]pyridin-2- ylmethyl)hexan-3-ol; te 5-(5-Fluoro-2-methyiphenyl)-2,5-dizmethyl-3-(5-phenyl-1H-pyrrolof2,3 -cjpyridin-2- yimethyl)hexan-3-ol; 4-(5-Chloro-2,3-dihydrobenzofuran—7-yl)-1, I-difluoro4-methyl-2-(6-nethyl-1 H-pyrrolo(3,2- c)pyridin-2-ylmethyl)pentan-2-ol; 1,1-Difluoro-4-(5-methanesulfonyl—2,3-dihydrobenzofuran-7-yl)-4-methyl-2-(1 H-pyrrolo[2,3- clpyridin-2-ylmethyl)pentan-2-ol; 2-(5-Bromo- 1 H-indol-2-ylmethyl)- 1,1 -diftuoro-4-(5-methanesulfonyl-22,3-dihydrobenzofuran- 7-y1)-4-methylpentan-2-ol; and 2-[2-Diftuoromethyl-2-hydroxy-4-( S-methanesulfonyl-2,3-dihydroben=ofuran-7-yi)-4- methylpentyl]-4-methyl-1H-indole— 6-carbonitrile, or a tautomer, prodrug, solvate, or ssalt thereof.

More preferred compounds of Formula (IB) include; 2-Cyclopropyl-4-(5-fluoro-2-methosxyphenyl)-4-methyl-1-(1 H-pyrrolo [3,2-c]pyridin-2- yl)pentan-2-ol;

2-CyclopropyR -4-(5-fluoro-2-methylphenyl)-4-methyl-1-(174-pyrrolo[2,3-c]pyridin-2-yl)pentan- 2-ol; 4-(5-Chloro-2 ,3-dihydrobenzofuran-7-yl)-2-cyclopropyl-4-mmethyl-1-(1 H-pyrrolof2,3-cIpy=ridin-

2-yl)pentan-2—ol, 2-CyclopropyR-4-(5-fluoro-2-methylphenyl)-4-methyl-1-(1.24-pyrrolo[3,2-c]pyridin-2-yl)peentan- 2-ol;

4-(5-Chloro-2 ,3-dihydrobenzofuran-7-yl)-2-cyclopropyl-4-—methyl-1-(1 H-pyrrolo[3,2-c]py~ridin- 2-yl)pentan-2—ol; 4-(5-Fluoro-2—methoxyphenyl)-2,4-dimethyl-1-(LH-pyrrolce[2,3-c]pyridin-2-yDpentan-2-o-1;

5-(5-Fluoro-2—methoxyphenyl)-2,5-dimethyl-3-(1H-pyrroloe(2,3-c]pyridin-2-ylmethyl)hex=an-3- ol; 5-(5-Fluoro-2—methoxyphenyl)-2,2,5-trimethyl-3-(I H-pyrrolo[2,3-cJpyridin-2-ylmethyl)hexan- 3-0l;

2-Cyclopentyl -4-(5-fluoro-2-methoxyphenyl)-4-methyl-1-( 1H-pyrrolof2,3-c]pyridin-2- yl)pentan-2-ol ; 5-(5-Fluoro-2—methoxyphenyl)-5-methyl-3-(1H-pyrrolo[2,3% -c|pyridin-2-ylmethyl)hexan-3% -ol;

2-(5-Fluoro-2—methoxyphenyl)-2,6-dimethyl-4-(1H-pyrrolo=[2,3-c}pyridin-2-ylmethyl)hep@an-4- ol; 2-(5-Fluoro-2—methoxyphenyl)-2,5,5-trimethyl-4-(1 H-pyrramlo{2,3-c]pyridin-2-ylmethyl)he=ptan- 4-ol;

1,1--Difluoro-4-(5-fluoro-2-methoxyphenyl)-4~methyl-2-( 1H-pyrrolo[2,3-c]pyridin-2- ylm_ethyl)pentan-2-ol;

1 -C=yclohexyl-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[2 ,3-c]pyridin-2=2- ylmmethyl)pentan-2-ol; 5-(S-Fluoro-2-methylphenyl)-2,5-dimethyl-3-C 1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)lnexan-3-ol; 5-(S-Fluoro-2-methylphenyl)-2,2,5-trimethyl-3-(1 H-pyrrolo [2,3-c]pyridin-2-ylmethy X)hexan-3- ol; 5-(=5-Chloro-2,3 -dibydrobenzofuran-7-yl)-2,5—dimethyl-3-(1H-pyrrolo[2,3-c]pyridin- 2- “ylmrethyl)hexan-3-ol; 1,1 -Difluoro-4-(5-fluorc-2-methoxyphenyl)-4 -methyl-2-( 1H-pyrrolo[3,2-c]pyridin-2— ylnmethyl)pentan-2-ol; 5-(=5-Fluoro-2-methoxyphenyl)-2,5-dimethyl-3-(1 A-pyrrolo[3,2-c]pyridin-2-ylmethy 1)hexan-3- ol;

5-( 5-Fluoro-2-methoxyphenyl)-2,2,5-trimethy/1-3-(1 H-pyrrolo[3,2-c]pyridin-2-ylmetlhyl)hexan- 3-ol; 2-(_1-Fluorocyclopropyl)-4-(5-fluoro-2-metho xyphenyl)-4-methyl-1-(1H-pyrrolof2,3 -clpyridin- 2-ysDpentan-2-ol; 2-(C 1-Fluorocyclopropyl)-4-(4-fluorophenyl)-4-methyl-1-quinolin-4-ylpentan-2-ol; 2-[C4,4-Difluoro-3-hydroxy-1,1-dimethyl-3-(1_H-pyrrolo[3,2-c]pyridin-2-ylmethyl)bu_tyl]-4- flu _orophenol;

5-(5-Chloro-2,3-d#hydrobenzofuran-7-yl)-2,5-dimethyW-3-(1H-pyrrolo[3 ,2-clpyridin—2- ylmethyl)hexan-3—ol; 5-(5-Fluoro-2-met=hylphenyl)-2,5-dimethyl-3~( 1H-pyrr—olo[3,2-c]pyridin-2-ylmethyl hexan-3-ol;

5-(5-Fluoro-2-met=hylphenyl)-2,2,5-trimethyl-3-(1 H-p3w/rolo[3,2-c]pyridin-2-ylmeth =) hexan-3- ol; 4-(5-Chloro-2,3-d dihydrobenzofuran-7-yl)-1,1-difluoro—4-methyl-2-(1 H-pyrrolo[3,2-ac]pyridin-2-

ylmethyl)pentan-2-ol; 4-(5-Chloro-2,3-d-ihydrobenzofuran-7-yl}-1,1-difluoro —4-methyl-2-pyrrolo[3,2-5]pymridin-1- ylmethylpentan-2—ol;

5-(5-Chloro-2,3-d-hydrobenzofuran-7-yl)-2,2,5-trimetlhyl-3-(LH-pyrrolo[3,2-c]pyridllin-2- ylmethyDhexan-3—cl; 5-(5-Fluoro-2-me€hylphenyl)-2,2 5-trimethyl-3-(3-met-hyl- 1 H-pyrrolo[2,3-c]pyridin—2- ylmethyl)hexan-3 —ol;

5-(5-Chloro-2,3-d dhydrobenzofuran-7-yl)-2,5-dimethy=1-3-(3-methyl-1 H-pyrrolo[2,3 —c]pyridin- 2-ylmethyl)hexan—3-ol; 5-(5-Chloro-2,3-daihydrobenzofuran-7-y1)-2,5-dimethy 1-3~(5-phenyl-1 H-pyrrolo[2,3—c]pyridic-

2-ylmethyl)hexan—3-ol; 5-(5-Fluoro-2-met=hylphenyl)-2,2,5-trimethyl-3-(5-phenyl-1H-pyrrolo[2,3-c]pyridin—2- ylmethylyhexan-3—ol;

= 5-(5-Fluoro-2-met=hylphenyl)-2,5-dimethyl-3-(5-pheny=1-1 H-pyrrolo[2,3-c]pyridin-2— ylmethyl)hexan-3—ol;

4-(5—Chloro-2,3-dihydrobenzofuran-7-yl)-1,1-di fluoro-4-methyl-2-(6-methyl-1 H-pyrrolo[3,2- clpyxidin-2-ylmethyl)pentan-2-ol; 1,1-MDifluoro-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-(1:4-pyr=xolo [2,3- clpy xidin-2-ylmethyl)pentan-2-ol; 2-(5—Bromo-1H-indol-2-ylmethyl)-1,1-difluoro—4-(5-methanesulfonyl-2,3-dihydroberazofuran- 7-y1)-4-methylpentan-2-ol; and 2-[2—Difluoromethyl-2-hydroxy-4-(5-methanestalfonyl-2,3-dihydrobenzofuran-7-yl)-3- metlaylpentyl]-4-methyl-1H-indole-6-carbonitri Te, ora tautomer, prodrug, solvate, or salt thereof.

Mosst preferred compounds of Formula (IB) include: 2-C=yclopropyl-4-(5-fluoro-2-methoxyphenyl)-4--methyl-1-(1 H-pyrrolo[3,2-c]pyridin—2- yl)peentan-2-of; 2-Csyclopropyl-4-(5-fluoro-2-methylphenyl)-4-rmethyl-1-(1 H-pyrrolo[2,3-c]pyridin-2 —yl)pentan- 2-0l3 4-(5 -Chloro-2,3-dihydrobenzofuran-7-yl)-2-cyc lopropyl-4-methyl-1-(1 H-pyrrolof2,3 —c]pyridin- 2-y1)pentan-2-ol; 2-Csyclopropyl-4-(5-fluoro-2-methylphenyl)-4-rmethyl-1-(1 H-pyrrolo[3,2-c]pyridin-2 —yl)pentan- 2-0l3 4-(5—Chloro-2,3-dihydrobenzofuran-7-yl)-2-cye lopropyl-4-methyl-1-(1 H-pyrrolo[3,2 —c]pyridin- 2-ylD)pentan-2-ol;

5-(5-Fluoro-2-methoxyphen_yl)-2,5-dimethyl-3-(LH-pyrrolo[2,3-]pyridin-2-ylmethyl)hexan-3— . ol; 5-(5-Fluoro-2-methoxyphermyl)-2,2,5-trimethyl-3~(1 H-pyrrolof2, 3-c]pyridin-2-ylmethyl)hexan—

To 5 3-0 2-Cyclop entyl-4-(5-fluoro-=2-methoxyphenyl)-4-methyl-1-(1H-p —yrmrolo[2,3-c]pyridin-2- yl)pentan-2-ol; 2-(5-Fluoro-2-methoxyphexayl)-2,5,5-trimethyl-4-(LH-pyrrolo[2 5 3-c]pyridin-2-ylmethylheptara- 4-0l; 1,1-Difluoro-4-(5-fluoro-2 —methoxyphenyl)-4-methyl-2-(1-pymrrolo[2,3 -c]pyridin-2- ylmethyl)pentan-2-ol; 5-(5-Fluoro-2-methylpheny—1)-2,5-dimethyl-3-(1H-pymolo[2,3-c Jpyridin-2-ylmethyl)hexan-3-cl; 5-(5-Fluoro-2-methylphenyw1)-2,2,5-trimethyl-3-(1H-pyrrolo[2,3 ~c]pyridin-2-ylmethyl)hexan-=3- ol; 5-(5-Chloro-2,3-dihydrobe nzofuran-7-yl)-2,5-dimethyl-3-(1 H-pyrrolo[2,3-c]pyridin-2- ylmethyl)hexan-3-ol; 1,1-Difluoro-4-(5-fluoro-2—methoxyphenyl)-4-methyl-2-(1 H-py=rrolo[3,2-c]pyridin-2- ylmethyl)pentan-2-ol; 5-(5-Fluoro-2-methoxyphe=nyl)-2,5-dimethyl-3-(1H-pyrrolo[3,2=~clpyridin-2-ylmethyl)hexan-=3- ol; 5-(5-Fluoro-2-methoxyphe=nyl)-2,2,5-trimethyl-3-(1 H-pyrrolo[ 33,2-c]pyridin-2-ylmethyl)hexamn- 3-ol;

2-(1-Fluorocyclopropyl)-4-(5-fluor-o-2-methox yphenyl)-4-methyl-1-(1H-pyrrobo[2,3-c]pyridin- 2-yl)pentan-2-ol; 2-(1-Fluorocyclopropyl)-4-(4-fluoxophenyl)-4-methyl-1-quinolin-4-ylpentan-2 -ol; = 2-[4,4-Difluoro-3-hydroxy-1,1-dinnethyl-3-(1 H-pyrrolo[3,2-c]pyridin-2-ylmetiayl)butyl)-4- fluorophenol; 5-(5-Chloro-2,3-dihydrobenzofura n-7-yl)-2,5-dimethyl-3-(1 H-pyrrolo(3,2-c]pridin-2-

1-0 ylmethyl)hexan-3-ol; 5-(5-Fluoro-2-methylphenyl)-2,5-climethyl-3-(1H-pyrrolof3,2-c]pyridin-2-ylm ethyl)hexan-3-ol; 5-(5-Fluoro-2-methylphenyl)-2,2,S-trimethyl-3-(1H-pyrrolo[3,2-clpyridin-2-yk methyl) hexan-3-

ol 4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-1,1-difluoro-4-methyl-2-(1 H-pyrrola[3,2~c]pyridin-2-

oo ylmethyl)pentan-2-ol; 2.0 4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-1,1-difluoro-4-methyl-2-pyrrolo{3,2 -lpyridin-1- :- ylmethylpentan-2-ol; ’ 5-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2,2,5-trimethyl-3-(1 H-pyrrolo[3,2-c Jpyridin-2- ylmethyl)hexan-3-ol;

2.5 5-(5-Fluoro-2-methylphenyl)-2,2, S-trimethyl-3-(3-methyl-1H-pyrrolo[2,3-c]py/ridin-2- ylmethyl)hexan-3-o0l; 5-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2,5-dimethyl-3-(3-methyl-1H-pyrroLo[2,3-clpyridin-

3 0 2-ylmethyl)hexan-3-ol;

5-(5-Chloro-2,3 —dihydrobenzofuran-7-yl)-2,5-dimeth yl-3-(5-phenyl-1H-pyrrolo[2, 3-c]pyridin- 2-ylmethyl)hex=an-3-ol; 4-(5-Chloro-2,3 —dihydrobenzofuran-7-yl)-1,1-difluor=0-4-methyl-2-(6-methyi- 1 H-poyrrolo([3,2- cJpyridin-2-ylm_ethyl)pentan-2-ol; : 2-(5-Bromo- 1 H—indol-2-ylmethyl)-1,1-difluoro-4-(S--methanesulfonyl-2,3-dihydro benzofuran- 7-yl)-4-methylp -entan-2-ol; and 2-[2-Diflucrome=thyl-2-hydroxy-4-(5-methanesulfony]-2,3-dihydrobenzofuran-7-y_1)-4- methylpentyl}-4--methyl-1 H-indole-6-carbonitrile, or a tautomer, prodrug, solvate, or salt thereof.

The invention fwarther provides methods of making a compound of Formula (IB). One method of making a cormapound of Formula (IB) 3

R H

5

R> RY 1 6

R R

(IB) where R! is an Optionally substituted 2-methoxypherayl group and R%, R®, R*, R®, and RS are as defined above, t-he method comprising: (a) reacting amn optionally substituted phenol of Foermula (XXII) with an acrylo—yl chloride of

Formula @(XIII) in the presence of a suitabTle base, followed by cycli=zation of the intermedizmte ester by treatment with a suitable= Lewis acid to form a lactorme of Formula xv)

0

OH 0

Base R?

R' + Cl — a . R

RR R

Xi Xi Xv (b) reacting ®he lactone of Formula (XIV) with a suitzable amine HNR’'R”, followe=d by treatment of the intermediate phenol with methyl iodicde in the presence of a suitables base to form am amide of Formula (XV) 0]

Me R° O 2

R R" . 3 1. HNRR" ~

R — 3 N

R’ R' R 111} 2. Mel R

Base ’ Xv XV . (¢) reacting the amide of Formula (XV) with a suitable eorganometallic reagent REM, where

M is Li o=r MgX and X is Cl, Br, or ], in a suitable s«olvent to form a ketone of Formula

XV)

Me R° O OMe R® ©

R" RSM 6

N” R

R' Rr? ) —— = Rr?

R™

XV XVI . (d) reacting —the ketone of Formula (XVI) with a suitable organometallic reagent R_*R'M where Mis Li or MgX and X is Cl, Br, or J, in a suitable solvent to form the compound of Formu Ja (IB)

Me R® © OMe Rip ge

C. 6 R5R4 5 . R® RSR‘M 4_R

R R® —_— R' rR® R

Me

XVI IB,R!'= a

A second method for makin ga compound of Formula (IB) comp-ises: (@’) reacting an amide of WFormula (XVII) with a vinyl magnesium bromide bearing R?and R? of Formula (XVI) ira a suitable solvent to provide an enomie of Formula (XIX)

R®

MgBr . 0 AN 9 RR ©

J Oo XVII AN

N~ “CH —— 2X

Rg | 3 R Rg

CH

XVII XIX . (b’) reacting the enone o f Formula (XIX) with a suitable omrganocopper reagent generated - from an organometal lic reagent R'M, where M is Li or MgX, and a copper salt CuX, where X is Cl, Br, or 1, in a suitable solvent to form a ketome of Formula (XX) 3 2 3 0

TL Rw YE

RXR TTR R°®

CuX

XIX XX : and (c’) reacting the ketone of Formula (XX) with a suitable organometallic reagent R’R*M, where M is Li or Mg=X, and X is Cl, Br, or [, in a suitable solvent to form the compound of Formula (IB)

NL, Em NG 2 ——— 2 5

R 6 R aR rR! R R' R

XX 1B oe The instant invention is directed to compounds of Formula (IC) 3

R H

2 +R

Ic) 5 wherein:

R.! isan aryl or heteroaryl group, each optiornally independently substituted v=vith one to three substituent groups, wherein each substituent group of R! is independently C;-Cs alkyl, C>-C=s alkenyl, C2-Cs alkynyl, C;-Cs cycloalkyl, heterocyclyl, aryl, heteroaryl, C;-Cs alkoxy, C»-Cs alkenyloxy, C>-Cs alkynyloxy, aryloxy, acyl, C;-Cs alkoxycarbonyl, C;--C; alkanoyloxy,

C,-Cs alkanoyl, aroyl, aminocarbonyl, C;-Cs alkylaminoca—xbonyl, C;-Cs dialkylaminocarbonyl, aminocarbonyloxy, C,-Cs alkylaminocarbomnyloxy, C,-Cs dialkylaminocarbonyloxy, C;-Cs alkarmoylamino, C-Cs alkoxycarbommylamino, C;-Cs alkylsulfonylamino, aminosulfonyl , C;-Cs alkylaminosulf-onyl, C1-Cs dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, . trifluoromethoxy, nitro, or amino wheresin the nitrogen atom is optional E y independently mono- or di-substituted by C,-Cs alkyl Or aryl; or ureido wherein either —nitrogen atom is optionally independently substituted with C,-Cs alkyl; or C,-Cs alkylt-hio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of IR! is optionally independently substituted with one to three substituent groups selected from methyl, methoxy, halogen, hydroxy, oxo, cyano, heteroaryl, heterocyclyl, or amino wherein the ni_trogen atom is optionally independently mono- or di-substituted by C,-Cs alkyl or— aryl; or ureido wherein either nitrogen atom is optionally independently substitumted with C,-Cs alkyl;

ER? and R? are each independently C;-Cs alkyl;

RR! i5C-Cs alkyl, C,-C; alkenyl, or C>-C; alkynyl, each optionally independeently substituted with one to three substituent groups, wherein each substituent group of R* is independently C,-Cj alkyl, hydroxy, halogen, or 0X0;

MR’ is a heteroaryl group fused with a saturated or partially saturated carbocyclic ring optionally independently substituted with one to three substituent groups, wherein each substituent group of RR’ is independently C;-Cs alkyl, C;-Cs alkenyl, C>-Cs alkynyl, C;-Cg cycloalkyl, hetexocyclyl, aryl, heteroaryl, C;-Cs alkoxy, C;-Cs alkenyloxy, C,-Cs alkynyloxy, aryloxy, acyl, C;-C; alkoxycarbonyl, C;—Cs alkanoyloxy, aminocarbonyl, alkylaminocarbony/l, dialkylaminocarbonyl, aminocart-onyloxy, C;-Cs alkylaminocarbonyloxy, C;-Cs diaX¥kylaminocarbonyloxy, C;-Cs alkancoylamino, C-Cs alkoxycarbonylamino, C,-Cs alkyslsulfonylamino, C;-Cs alkylaminossulfonyl, C;-Cs dialkylaminosulfonyl, halogen, hydroxy, oxo, carboxy, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, or amino wherein the mmitrogen atom is optionally independently mono- ox di-substituted by Cy-Cs alkyl; or ureido wherein either nitrogen atom is optionally independently substituted with C,-C~ alkyl; or C,-C;s alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide omr sulfone, wherein each substituent group of R’ is optionally independently substituted with one to three substituent groups selected from C;-C; alkyl, C1-C; =alkoxy, halogen, hydroxy, oxo, cyano, heteroaryl, heterocyclyl, or amino wherein the nitrogen atom is optionally independently mono— or di-substituted by C;~Cs alkyl omr aryl; or ureido wherein either nitrogen atom is optionally independently substitiated with C;-C;s alkyl, or trifluoromethyl, and

TL WO 2005/030213 PCT/US2004/031009

R® is hydrogen, C,-Cs alkyl, C»-Cg alkenyl, C>-Cg alkynyM, carbocycle, heterocyclyl, aryl, heteroaryl, carbocycle-C-C; alkyl, carboxy, trifluorome=thyl, alkoxycarbonyl, aryl-C,-Cg alkyl, aryl-C,-C; haloalkyl, heterocyclyl-Ci-Cs alkyi, hewteroaryl-C,-Cs alkyl, carbocycle-

C,-Cy alkenyl, aryl-Co-Cg alkenyl, heterocyclyl-C-C=s alkenyl, or heteroaryl-C»-Cs alkenyl, each optionally independently substituted with asne to three substituent groups, wherein each substituent group of R® is independently €-Cs alkyl, C5-Cs alkenyl, C2-Cs alkynyl, C3-Cg cycloalkyl, phenyl, C,-Cs alkoxy, phenoxy, C;-Cs alkanoyl, aroyl, C;-Cs " 10 alkoxycarbonyl, C1-Cs alkanoyloxy, aminocarbonylox=y, C,-Cs alkylaminocarbonylox =, : Cy-Cs dialkylaminocarbonyloxy, aminocarbonyl, C; -Cs alkylaminocarbonyl, C,-Cs dialkylaminocarbonyl, C;-Cs alkanoylamino, C;-C 5 alkoxycarbonylamino, C;-Cs alkylsulfonylamino, C;-Cs alkylaminosulfonyl, C;-Css dialkylaminosulfonyl, halogemn, hydroxy, carboxy, cyano, oxo, trifluoromethyl, nitro, =mino wherein the nitrogen atomm is optionally independently mono- or di-substituted b=y C;-Cs alkyl; or ureido wherein either nitrogen atom is optionally independently subst=ituted with C,-Cs alkyl; or C{-Cs alkylthio wherein the sulfur atom is optionally oxidize to a sulfoxide or sulfone, or a tautomer, prodrug, solvate, or salt thereof.

Another aspect of the invention includes compounds of FormuBa (IC), wherein:

R' is thienyl, phenyl, naphthyl, dihydrobenzofuran—yl, benzofuranyl, chromany=l, dihydroindolyl, indolyl, dihydrobenzothienyl, b- enzothienyl, benzodioxolany=], ) benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzimmidazolyl, thienyl, quinoliny=1, pyridinyl, pyrirmidinyl, or pyrazinyl, each optionally inciependently substituted with ore to three substituent groups, wherein each substituent group of R! is independently &C,-C; alkyl, C,-C; alkenyl, C,-C, alkynyl, C;-C,; alkoxy, C>-Cs alkenyloxy, C;-C; alkancoyl, C;-C; alkoxycarbonyl, C;-C; alkanoyloxy, halogen, hydroxy, carboxy, cyano, t—xifluoromethyl, nitro, or C;-C; alkylthio wherein the sulfur atom is optionally oxidizec3 to a sulfoxide or sulfone,

wherein each substituent group of R! is optionally indeperdently substituted with a substituent group sselected from methyl, methoxy, halogen, hydroxy, oxo, cyano, heteroaryl, heterocyclyl, or amino wherein the nitrogen atom is optionally independently monc- or di-substituted by C;-Cs alkyl or aryl;

R? and R® are each independermtly C;-C; alkyl;

R'is CHy;

R® isa N-linked heteroaryl with a fused 5-7 membered saturated c arbocyclic ring optionally and independently substituted with one to three substituent grou ps, wherein each substittment group of RS} is independently C;—Cs alkyl, C;-C; alkenyl, phenyl, C;-C; alkoxy._, methoxycarbonyl, aminocarbonyl, C 1-C; alkylaminocarbonyl,

C;-C; dialkylaminocamrbonyl, heterocyclylcarbonyl, fluoro, chloro, bromo, cyano, trifluoromethyl, hydro=xyl, oxo, or C;-C; alkylthio wherein thes sulfur atom is optionally oxidized to a sulfoxide= or sulfone, wherein each substituent group of R® is optionally indepemndently substituted with a substituent group selected from methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, heteroaryl, heterocyclyl, or amino whereein the nitrogen atom is optionally independently mono- or di-substituted by C,-Cs alkyl or aryl; and

R® is C;-Cs alkyl, C;-Cs alkenyl, C3-Cs cycloalkyl, trifluoromethyl, phenyl, Ci-Cs cycloalkyl-C;-C; alkyl, gohenyl-C;-C; alkyl, phenyl-C;-C; haloa#lkyl, C;-Cs cycloalkyl-C,-

C; alkenyl, phenyl-C,-C=; alkenyl, each optionally independentMy substituted with one to three substituent groups, wherein each substituent group of RE is independently C;-Cs alkyl, Co-C; alkenyl, C,-C; } alkynyl, C;-Cs all<oxy, aminocarbonyl, C;-C; alkywslsminocarbonyl, CC;

WVO0 2005/030213 PaCT/US2004/031009 dialkylaminocarbonyl, halo ggen, hydroxy, carboxy, cyano, trifluoromethyl, nitro, or Ci-

C; alkylthio wherein the sul fur atom is optionally oxidized to a sulfoxide or sulfone, or a tautomer, prodrug, solvate, or ssalt thereof.

Yet another aspect of the invention includes compounds of Formula (IC), wherein:

R! is thienyl, phenyl, naphthyl, pyridyl, chromanyl, dihydrobenzofuranyl, or benzofuranyl, each optionally independently sub stituted with one or two substituent gro-ups, 1 wherein each substituent garoup of R® is independently methyl, etZhyl, methoxy, ethoxy, fluoro, chloro, bromo, hydmroxy, trifluoromethyl, cyano, or C,-Cs alkylthio wherein the sulfur atom is optionally oxzidized to a sulfoxide or sulfone; 1S R?and R? are each methyl;

R'is CH;

R® is a N-linked pyrrole, pyr-azole, or imidazole fused to a 5-7 membered saturated carbocyclic ring optionally sand independently substituted with omme to three substituent ’ groups, wherein cach substituerat group of R® is independently methyl, phenyl, methoxycarbonyl, aminocarbonyl, wnethylaminocarbonyl, dimethylaminoaminocarbomyl, morpholinylcarbonyl, fluoro, claloro, bromo, cyano, hydroxy, oxo, or trifluoromethyl; and

R® is C-Cs alkyl, C3-Cs cyclo alkyl, trifluoromethyl, C3-Cs cycloalk—ylmethyl-, or benzyl, each optionally independentl_y substituted with one to three substituent groups, wherein each substituent gmroup of R® is independently methyl, me=thoxy, fluoro, chloro, bromo, cyano, trifluoromet_hyl, or hydroxy,

VVO 2005/030213 PCT/USZR2004/031009 or a tautomer, prodrug, solvate, or salt thereof. ° Another aspect of the invention includes compounds of Formula (IC), wherein:

R' is thienyl, phenyl, naphthyl, dihydrobenzofuranyl, benzofuranyl, chromanyl, dihydroindolyl, indolyl, dihydrobenzothienyl, benzothienyl, berozodioxolanyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzimidazolyl, thienyB, quinolinyl, pyridinyl, pyrimidinyl, or pyrazinyl, each optionally independently substit-uted with one to three substituent groups, : wherein each substituent group of R! is independently C,-C; alkyl, C;-Cs =alkenyl, C;-C; alkynyl, C;-C; alkoxy, C;-C; alkenyloxy, C;-C; alkanoyl, C,-C; alkoxycarbonyl, C;-Cs alkanoyloxy, halogen, hydroxy, carboxy, cyano, trifluoromethyl, nitro, ar-yl, heteroaryl, heterocyclyl, or C;-Cj alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of R' is optionally independently subsstituted with a substituent group selected firom methyl, methoxy, halogen, hydroxy=, oxo, cyano, heteroaryl, heterocyclyl, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C;-Cs alkyl or aryl;

R? and R? are each independently C;-C; alkyl;

R'is CHy

R’ is a N-linked heteroaryl with a fused 5-7 membered saturated carbocyclic r-ing optionally and independently substituted with one to three substituent groups, wherein each substituent group of R® is independently C;-C; alkyl, C,-C; alkenyl, phenyl, C,-C; alkoxy, methoxy/carbonyl, aminocarbonyl, C;-C; alkylarminocarbonyl,

C:-C; dialkkylaminocarbonyl, heterocyclylcarbonyl, fluoro, chloro, bmromo, cyano,

trifluoronmaethyl, hydroxyl, oxo, or C1-C; alkylthio wherein the sulfur amtom is optionally oxidized to a sulfoxide or sulfone, where: in each substituent group of R’ is optionally independently Substituted with a substituent group selected from mewthyl, methoxy, fluoro, chloro, bromo, trifluceromethyl, heteroaryl, heterocyclyl, or amino wherein the "nitrogen atom is optiormally independently mono- or di-sub. stituted by C,-Cs alkyl or =aryl; and

RS is Cy-Cs akyl, C;-Cs alkenyl, C3-Cs cycloalkyl, trifluoromethyl, phenyl, C;-Cs cycloalkyl —C;-C; alkyl, phenyl-C,-C; alkyl, pkmenyl-C;-Cs haloalkyl, Cs-=Cs cycloalkyl-Co-

C; alkenyl_, phenyl-C,-C; alkenyl, each optiornally independently substi tuted with one to three substituent groups, wherein each substituent group of R° is indegpendently C;-C; alkyl, C- C; alkenyl, C,-Cs alkynyl, C;-C; alkoxy, aminocarbonyrs], C;-C; alkylaminoc=arbonyl, C,-C; dialkylan—minocarbonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, nitro, or C;-

C3 alkyltimio wherein the sulfur atom is optiomnally oxidized to a sulfoxiade or sulfone, or a tautomer, preodrug, solvate, or salt thereof.

Yet another aspeect of the invention includes compounds of Formula (IC), wher—ein:

R! is thienyl, phe=nyl, naphthyl, pyridyl, chromanyl, clihydrobenzofuranyl, or besnzofuranyl, each optionally Andependently substituted with one @or two substituent groups, wherein ach substituent group of R'is inde=pendently methyl, ethyl, mmethoxy, ethoxy, fluoro, chloro, bromo, hydroxy, trifluoromethyl, pyridinyl, pyrimi dinyl, pyrazinyl, cyano, or— C;-C; alkylthio wherein the sulfur- atom is optionally oxidiz—ed to a sulfoxide or sulfone; ‘ wherein eezch substituent group of R! is optionally independently smubstituted with a substituent group selected from cyano or halcogen,

R? and R® are each methyl;

R%is CH;

R® is a N-linked pyrrole, pyrazole, or imidazole fiased to a 5-7 memberecq saturated carbocyclic ring optionally and independently substituted with one to three substituent groups, wherein each substituent group of R® is independently methyM, phenyl, methoxyc=arbonyl, aminocarbonyl, methylaminmocarbonyl, dimethylzaminoaminocarbonyl, morpholinylcarboryl, fluoro, chloro, bromo, cyano, hydroxy, oxo, or trifluoromethyl; and

R® is C-Cs alkyl, C3-Cs cycloalkyl, trifluoromethyl, C;-Cs cycloalkylmethyl-, or benzyl, each optiormally independently substituted with one tao three substituent groups, wherein e=ach substituent group of Ris independently methyl, methoxy, fluro, chloro, bromo, cyano, trifluoromethyl; or hydroxy, or a tautomer, prodrug, solvate, or salt thereof.

Representative compounds of Formula (IC) according to she invention are appendecd hereto as

Table IC, where column A is the compound name accowrding to standard nomenclature and column B is the c omresponding chemical structure. . Preferred compoumnds of Formula (IC) include the following: 1-[4-(5-Fluoro-2 -mmethoxyphenyl)-2-hydroxy-4-methyl-2-tr=ifluoromethylpentyl]-1,5,6,7- tetrahydroindol-4—one;

1-[4-(5= -Fluoro-2-hydroxyphenyl)-2-hydrox so-4-methyl-2-trifluoromethylpent=yl-1,5,6,7- tetrahy—droindol-4-one; 1-[4-(2=,3-Dihydrobenzofuran-7-yl)-2-hydro=xy-4-methyl-2-trifluoromethylpemtyl}-1,5,6,7- tetrahy—droindol-4-one; 1-[4-(5= -Fluoro-2-methylphenyl)-2-hydroxy—4-methyl-2-trifluoromethylpenty-1}-1,5,6,7- tetrahy~droindol-4-one; 1-[2-H ydroxy-4-methyl-4-(5-pyrimidin-5-yM-2,3-dihydrobenzofuran-7-yl)-2- trifluor—-omethylpentyl]-1,5,6,7-tetrahydroindol-4-one; 1-[2-H ydroxy-4-(2-methoxy-5-pyrimidin-5—ylphenyl)-4-methyl-2-trifluorom -ethylpentyl]- 1,5,6,7 -tetrahydroindol-4-one; 1-[2-H -ydroxy-4-(2-hydroxy-5-pyrimidin-5-=ylphenyl)-4-methyl-2-trifluorome=thylpentyl]- 1,5,6,7 -tetrahydroindol-4-one; 1-[2-Hydroxy-4-(2-methoxy-5-pyridin-3-ylfohenyl)-4-methyl-2-trifluorometimylpentyl]-1,5,6,7- tetrahy=droindol-4-one; 1-[2-H ydroxy-4-(2-hydroxy-5-pyridin-3-ylp Thenyl)-4-methyl-2-trifluorometh~ylpentyl}-1,5,6,7- tetrahy«droindo!-4-one; and 1-[2-Hzydroxy-4-(5-methanesulfonyl-2,3-dih_ydrobenzofuran-7-yl)-4-methyl-2=2- trifluor-omethylpentyl]-1,5,6,7-tetrahydroind_ol-4-one, or a taumtomer, prodrug, solvate, or salt thereof.

More preferred compounds of Formula (IC) include the following:

.. 1-[2-Hycroxy-4-methyl-4-(5-pyrimidin-5-yl-2,3-dih ~ydrobenzofuran-7-yl)-2- triflucroamethylpentyl]-1,5,6,7-tetrahydroindol-4-one; 1-[2-Hydroxy-4-(2-methoxy-5-pyrimidin-5-ylpheny—1)-4-methyl-2-trifluvoromethyl-entyl]- 1,5,6,7-tetrahydroindol-4-one; 1-[2-Hydroxy-4-(2-hydroxy-5-pyrimidin-5-ylpheny ®)-4-methyi-2-trifluvoromethylpwentyl]- 1,5,6,7-tetrahydroindol-4-one; 1-[2-Hy droxy-4-(2-methoxy-5-pyridin-3-ylphenyl)- 4-methyl-2-trifluoromethylperatyl]-1,5,6,7- tetrahyd roindol-4-one; and 1-[2-Hy droxy-4-(2-hydroxy-5-pyridin-3-ylphenyl)-=4-methyl-2-trifluoromethylpem tyl]-1,5,6,7- tetrahydroindol-4-one, or a tautomer, prodrug, solvate, or salt thereof.

The most preferred compounds of Formula (IC) inc”Xude the following: 1-[2-Hy-droxy-4-methyl-4-(5-pyrimidin-5-yl-2,3-dibqydrobenzofuran-7-yl)-2- trifluoromethylpentyl]-1,5,6,7-tetrahydroindol-4-on_e; 1-[2-Hy droxy-4-(2-methoxy-5-pyrimidin-5-ylpheny1)-4-methyl-2-trifluoromethylgpentyl]- 1,5,6,7-tetrahydroindol-4-one; 1-[2-Hy droxy-4-(2-hydroxy-5-pyrimidin-5-ylpheny—1)4-methyl-2-trifluoromethyloentyl]- 1,5,6,7-tetrahydroindol-4-one; 1-[2-Hyrdroxy-4-(2-methoxy-5-pyridin-3-ylphenyl)—4-methyl-2-triflucromethylpexatyl]-1,5,6,7- tetrahydroindol-4-one; and

EP -[2-Hydroxy-4-(2-hydroxy-5-pyridin-3-ylphenyl)-4-methyl-2-trifluoromethylpeentyl]-1 ,5,6,7- tetrahydroindol-4-one, - Cr a tautomer, prodrug, solvate, or salt theres of. : 5 . "The invention further provides methods of rnaking a compound of Formula (ICD 3

R H

2 +R

R s R . R' R (10).

Cre synthetic sequence for making a compound of Formula (IC) is shown belo=w. 3

R\ HO CF, Reduction R Ho_ CF, R'SO,CH

R? OR —— = oH ———

R! rR! [e]

I} [1]

R® R! R* R! CF, R? rR R®

Vv Vv 1 (R{=-CH,) : A second method of making a compound oX Formula (IC) is shown below. 3 3 oxidative

R\ HO ss , Reduction R\\ HO_ CF, cleavage rR R — = OH —— =

R 1 0 R

I 1] rR} epoxide rR: =

R CF, R CF, R R® \Y) Vv 1{R4 = -CH,")

The instant invention is also directed to corxapounds of Formula (ID)

R® OH

BP oR

RL he RR (ID) wherein:

R' is an aryl €or heteroaryl group, each optionally i mdependently substituted withm one to three substituent groups, wherein each substituent group of R! is indep =endently C;-Cs alkyl, C;-Cs alkenyl, C;-Cs alkynyl, C;-Cg cycloalkyl, heterocyclyl, aryl, heteroaryl, C;-C; allkoxy, C:-Cs alkenylo=xy, C,-Cs alkynyloxy, aryloxy, acyl, <C;~Cs alkoxycarbonyl, C;-Cs alkanoyloxy,

C,-Cs glkanoyl, aroyl, aminocarbonyl , C;-Cs alkylaminocarbo-nyl, C;-Cs dialkylamminocarbonyl, aminocarbonyloxy, Ci-Cs alkylaminocarbonyl.oxy, Ci-Cs dialkylamminocarbonyloxy, Ci-Cs alkanoylammino, C,-Cs alkoxycarbonyla mino, C;-Cs alkylsulfFonylamino, aminosulfonyl, C1-Cs alkylaminosulfony1, C-Cs dialkylamminosulfonyl, halogen, hydroxy>, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, or amino wherein the= nitrogen atom is optionally irmdependently mono- o=x di-substituted by C,-C;s alkyl or aryl; or ureido wherein either nitr—ogen atom is optionally independently substituted with. C; -Cs alkyl; or C;-Cs alkylthio wherein the sulfur ateom is optionally oxidized to a sulfoxi de or sulfone, wheresin each substituent group of R' is optionally independently sub-stituted with one tao three substituent groups selected rom methyl, methoxy, halog en, hydroxy, 0X0, cyano, heteroaryl, heterocyclyl, omr amino wherein the nitrogen atom is . optiornally independently mono- or di-submstituted by C,-Cs alkyl or ar—yl; or ureido

Ce wherein either nitrogen atom is optionadly independently substituted_ with C;-Cs alkyl;

R? and R® are each independently C;-Cs alkyl, —wherein one or both are iradependently substituted with hydroxy, C1-C5 alkoxy, C;—C;s alkylthio wherein the su_lfur atom is optionally oxidized to a sulfoxide or sulforme, amino wherein the nitrogeen atom is optionally independently mono- or di-substitute=d by C,-Cs alkyl or aryl;

R* is C,-Cs alkyl, C;-Cs alkenyl, or C,-Cs alkynyl, each optionally independently substituted with one to three substituent groups, wherein =each substituent group of R! is independently Ci-C; alkyl, hydroxy, Faalogen, or 0X0;

R® is a heteroaryl group optionally independently substituted with one to three substituent groups, wherein each substituent group of R® is indepemdently C-Cs alkyl, C>-Cs alkenyl, C»-Cs alkynyl, C;-Cg cycloalkyl, heterocyclyl, - aryl, heteroaryl, C,-Cs alkosxy, C;-Cs

So alkenylowxy, C,-Cs alkynyloxy, aryloxy, acyl, c .C; alkoxycarbonyl, C;-Cs al kanoyloxy, aminoca_rbonyl, alkylaminocarbonyl, dialkylamminocarbonyl, aminocarbonyl oxy, Ci-Cs . 15 alkylam®nocarbonyloxy, C;-Cs dialkylaminocarbonyloxy, C4-Cs alkangylanmmino, C;-Cs ) alkoxycaarbonylamino, C;-Cs alkylsulfonylarmino, Ci-Cs alkylaminosulfo—nyl, C;-Cs dialkylamminosulfonyl, halogen, hydroxy, carboxy, cyano, triflioromethyl, . trifluoro methoxy, trifluoromethylithio, nitro, <or amino wherein the nitrogeen atom is optionally independently mono- or di-substituted by Ci-Cs alkyl; or ureiado wherein either ni trogen atom is optionally independently substituted with Ci-Cs alkswl; or Ci-Cs alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulf=one, wherein each substituent group of R® is optionally independently substituted with one fo three substituent groups selected ficom C;-Cs alkyl, C;-C; alkox_y, halogen, hydroxy, oxo, cyano, heteroaryl, heterocyclyl, or amino wherein the nitro gen atom is optio-nally independently mono- or di-subsstituted by C;-Cs alkyl or aryH; or ureido wherein either nitrogen atom is optionally independently substituted with C,-Cs alkyl , or trifluoromethyl; and

R¢ is hydrogzen, C;-Cs alkyl, C,-Cy alkenyl, C»-C g alkynyl, carbocycle, heterocyclyl, aryl, heteroaryl, trifluoromethyl, carbocycle-C,-Cs allkyl, carboxy, alkoxycarbonyl... aryl-C;-Cg alkyl, ary1-Cy-Cy haloalkyl, heterocyclyl-C1-Cg alkyl, heteroaryl-C,-Cs alkyl, ~carbocycle-

C,-Cs alkenyl, aryl-C»-Cg alkenwyl, heterocyclyl-C,-Cs alkenyl., or heteroaryl-C;-Cs alkenyl, each optionally independemntly substituted with one to three substituent groups, wherein each substituent group o#€ RS is independently C;-Cs alky=1, C,-C; alkenyl, C;-Cs alkynyl, C;-Cs cycloalkyl, pheny®, C,-Cs alkoxy, phenoxy, C\-Css alkanoyl, aroyl, C:-Cs alkoxycarbonyl, C-Cs alkanoylo. xy, aminocarbonyloxy, C,-Cs alkylaminocarbonyloxy,

C)-Cs dialkylaminocarbonyloxy., aminocarbonyl, Cy-Cs alkyl aminocarbonyl, C-Cs dialkylaminocarbonyl, C;-Cs =alkanoylamino, C,-Cs alkoxyecarbonylamino, C;-Cs alkylsulfonylamino, C;-Cs alkyl aminosulfonyl, C,-Cs dialkylamminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, nitro, amino wherein the nitrogen atom is optionally independently mon-o- or di-substituted by C,-Cs alkyl; or ureido wherein either nitrogen atom is optionall=y independently substituted with C,-C; alkyl; or C,-Cs alkylthio wherein the sulfur atonm is optionally oxidized to a sulfoxide or sulfone, or atautomer, prodrug, solvate, or salt th_ereof.

A _mother aspect of the invention includes compounds of Formula (ID), wikherein:

R ' is thienyl, phenyl, naphthyl, dihydrobenzofuranyl, benz=ofuranyl, chromanyl, dihydroindolyl, indolyl, dihy~drobenzothienyl, benzothien_yl, benzodioxolanyl, benzoxazolyl, benzisoxazolyl, toenzpyrazolyl, benzimidazolyl , thienyl, quinoliny}, . pyridinyl, pyrimidinyl, or pyrazin_yl, each optionally independently substituted with one to three substituent groups, wherein each substituent group oefR! is independently C;-C; alkyl, C;-C; alkenyl, C;-Cs alkynyl, Ci-C; alkoxy, C;-C; alk=enyloxy, C-C; alkanoyl, C{-Cax alkoxycarbonyl, C;-C; alkanoyloxy, halogen, hydroxy, carboxy, cyano, triflucromeethyl, nitro, or C;-C; alkylthio wherein the sulfur ator is optionally oxidized to a sulfeoxide or sulfone, wherein each substituent grotip of R! is optionally independ-ently substituted with a substituent group selected firom methyl, methoxy, halogen, hydroxy, oxo, cyano,

heteroaryl, heterocyclyl, or amino wherein the nitwogen atom is optionally independently mono- or di-substituted by C;-Cs alkyl or aaryl;

R? and R® are each independently C;-C; alkyl, wherein one «or both are independently substituted with hydroxy, C,-Cs alkoxy;

R* is CHy;

Co R® is an imida=olyl, pyridyl, indolyl, azaindolyl, diazaindolyl, benzofuranyl, ’ 10 furanopyridinyl, furanopyrimidinyl, benzothienyl, thienopy/ridinyl, thienopyrimidinyl, benzoxazolyl, oxazolopyridinyl, benzothiazolyl, thiazolowpyridinyl, benzimidazolyl, imidazolopyridimyl, imidazolopyrimidinyl, imidazolopyridazinyl, imidazolopyrazinyl, quinolinyl, or isoquinolinyl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R’ is independently €C;-C; alkyl, C,-C; alkenyl, phenyl, C;-C3 alkoxy, methoxycarbonyl, aminocarbonyl, C;-C; alkylaminocarbonyl,

C1-C; dialkyEaminocarbonyl, heterocyclylcarbonyl, fluoxo, chloro, bromo, cyano, trifluoromethyl, or C;-C; alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or svalfone, wherein ea ch substituent group of R® is optionally independently substituted with a . substituent group selected from methyl, mecthox)y>, fluoro, chloro, bromo, ) trifluorome=thyl, heteroaryl, heterocyclyl, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C;-C;s alkyl or aryl; and

R® is C;-Cs alkyl, C;-Cs alkenyl, C3-Cs cycloalkyl, trifliaoromethyl, phenyl, Ci-Cs cycloalkyl-C,-C; alkyl, phenyl-C,-C; alkyl, phenyl-C,-C; hal oalkyl, C3~Cs cycloalkyl-C,-

C; alkenyl, phenyl-C;-C; alkenyl, each optionally independently substituted with one to three substituent groups,

wherein each substituent group of R® is independently C;-C3 alkyl, C,-C; alkenyl, C-Cs alkynyl, C,-C; alkoxy, aminocarbonyl, C,-C; allkylaminocarbonyl, Ci-Cs dialkylaminocarbonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, nitro, or Ci-

C; alkylthio wherein the sulfur atom is optionally oxidized tc a sulfoxide or sulfone, or a tautomer, prodrug, solvate, or salt thereof.

Yet another aspect of the inventiorm includes compounds of Formula (ID), wherein:

R! is thienyl, phenyl, naphthyl, pyridyl, chromanyl, dihydrobenzofur—anyl, or benzofuranyl, each ) optionally independently substituted with one or two substituent groups, wherein each substituent group of R! is independently metimyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, hyd roxy, trifluoromethyl, cyano, or C;-Cs alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;

R? and R? are each methyl wherein one or both are independently substituted with hydroxy or methoxy;

R* is CH;

R’> is a pyridyl, indolyl, az aindolyl, benzofuranyl, furanopoyridinyl, thienopyridinyl, benzoxazolyl, benzimidazoMyl, quinolinyl, or isoquinoliny=1 group, each optionally independently substituted with one to three substituent groups, wherein each substituerat group of R® is indepemndently methyl, phenyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminoaminocarboryl, morpbolinylcarbonyl, fluoro... chloro, bromo, cyano, or trifluoromethyl; and

R® is Ci-Cs alkyl, C5-Cs cycloalkyl, C;-Cs cycloalkylmethyl-, stxiflucromethyl, or benzyl, each optionally independently substituted with one to three sulostituent groups,

Co wherein each substituent group of R_® is independently methyl, metheoxy, fluoro, chloro, bromo, cyano, trifluoromethyl, or hydroxy, : 5 or a tautomer, prodrug, solvate, or salt thereof.

Yet another aspect of the invention includes compounds of Formula (ID), wimerein:

R! is phenyl, dihydrobenzofuranyl, or benzofuranyl, each optionally independently substituted with one to three substituent groups, n wherein each substituent group of R_! is independently C;-C; alkyl, C=,-C; alkenyl, C>-Cs

I alkynyl, C;-C; alkoxy, C;-C; alkeny/loxy, C;-C; alkanoyl, C,-C;3 alkenxycarbonyl, Ci-Cs alkanoyloxy, halogen, hydroxy, carboxy, cyano, triflucromethyd}, nitro, or C,-C; alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxidee or sulfone; and

R? and R? are each independently C;-C; alkyl each optionally independently substituted with hydroxy, Ci-C; alkoxy, or a tautomer, prodrug, solvate, or salt there of. : Representative compounds of Formula (ID) according to the invention are amappended hereto as

Table ID, where column A is the compotand name according to standard nomenclature and column B is the corresponding chemical struacture.

Preferred compounds of Formula (ID) include the following: 1,1,1-Trifluoro-5-methoxy-4-methyl-4-phen yl-2-quinolin4-ylmethylpentan-=2-ol; and 5,5,5-Trifluoro-2-methyl-2-phenyl-4-quinolin-4-ylmethylpentane-1,4-diol, or a tautomer, prodrug, solvate, or salt thereof.

The invention further provides methods of making a compound of Formula (ID).

R H

" +R (ID)

One method of making a compounds of Formula (ID) is via the iomtermediate aldehyde which is 5 shown below.

CN CN

Ht Bro NaHMDS SS

DMSO

Q 0

H

DIBAL A LAH, AS ———————— ad ———————

CH,Cl, THF

NaH —Q 1. 0, then Me,S — 0

MeOH-CH,C!

Mel x Ch H . DMF 2. p-TsOH/Acetonea

In another aspect of the invention, the compounds according to the invention are formulated into pharmaceutical compositions comprising an effecti_ve amount, preferably a pharmaceutically effective amount, of a compound according tos the invention or a tautomer, prodrug, solvate, or salt thereof, and a pharmaceutically acceptabl e excipient or carrier,

The invention also provides a method of modulating the glucoccorticoid receptor function in a patient, the method comprising administering to the patient an eff=ective amount of a compound according to the invention or a tautomer, prodrug, solvate, or salt athereof. . 15

The invention further provides a method of treating a disease-state= or condition mediated by the glucocorticoid receptor function in a patient in need of such treatment, the method comprising administering to the patient am effective amount of a pharmaceutically acceptable compound according to the invention or a- tautomer, prodrug, solvate, or salt thereof.

In addition, the invention also provides a method of treatin.g a disease-state or condition selected from: type II diabetess, obesity, cardiovascular diseases. , hypertension, arteriosclerosis, . neurological diseases, adrenal and pituitary tumors, and glaucorma, in a patient in need of such treatment, the method compmrising administering to the patient an effective amount of a pharmaceutically acceptable e=ompound according to the inve=ntion or a tautomer, prodrug, solvate, or salt thereof.

The invention provides a methaod of treating a disease character—ized by inflammatory, allergic, or proliferative processes, in a patient in need of such treatment, the method comprising administering to the patient am effective amount of a pharmac. eutically acceptable compound according to the invention or- a tautomer, prodrug, solvate, owr salt thereof. In a preferred embodiment of the invention, the disease characterized >y inflammatory, allergic, or proliferative processes is se=lected from: (i) lung diseasess; (ii) rheumatic diseases or autoimmune diseases or joint diseases; (iii) allergic diseasess; (iv) vasculitis diseases; (v) dermatological diseases; (vi) renal diseases; (vil) hepatic diseases; (viii) gastrointestinal diseases; (ix) proctological dis eases; (x) eye diseases; (xi) disea_scs of the ear, nose, and throat ) 20 (ENT) area; (xii) neurological diseases; (xiii) blood disease-s; (xiv) tumor diseases; (xv) endocrine diseases; (xvi) orgarm and tissue transplantations and gmraft-versus-host diseases; (xvii) severe states of shock; (xviii) substitution therapy; and (xix) pain of inflammatory genesis. In another preferred embodimen® of the invention, the disease characterized by inflammatory, allergic, or proliferative proce=sses is selected from: type I di=abetes, osteoarthritis, Guillain-

Barre syndrome, restenosis following percutaneous transliziminal coronary angioplasty,

Alzheimer disease, acute and chronic pain, atherosclerosis, repe_rfusion injury, bone resorption diseases, congestive heart failvare, myocardial infarction, thermaml injury, multiple organ injury secondary to trauma, acute pourulent meningitis, necrotizing enterocolitis, and syndromes associated with hemodialysis, leukopheresis, and granulocyte trarasfusion.

The invention further provides methods of treating the disease-sstates or conditions mentioned above, in a patient in need of such treatment, the method s comprising sequentially or simultaneously administering to the patient: (a) an effecti.ve amount of a pharmamceutically acceptable compound accomrding to the invention or a tautomeer, prodrug, solvate, or samlt thereof, and (b) a pharmaceutically acceptable glucocorticoid.

The invention further provides a method of assaying the glucocorticoid receptor furction in a sample, comprising: (a) co=ntacting the sample with a selected amount of a compound according to the invention or a tautorrrer, prodrug, solvate, or salt there=of; and (b) detecting the amount of the compound according to the invention or a tautomer, pro drug, solvate, or salt thexr—eof bound . to glucocorticoid receptor=s in the sample. In a preferred embodiment of the invention, the compound according to thme invention or a tautomer, prodrug, solvate, or salt thereof™ is labeled with a detectable marker szelected from: a radiolabel, fluoresscent tag, a chemiluminesscent tag, a chrormophore, and a spin label.

The invention also providlles a method of imaging the gluceocorticoid receptor distrillbution in a sample or patient, the m_ethod comprising: (a) contactingz the sample or administering to a patient a compound accor=ding to the invention or a tautomer, prodrug, solvate, or salt thereof kaving a detectable marke=r; (b) detecting the spatial distribution and amount of the compound according to the inventiomn or a tautomer, prodrug, solvate, or salt thereof having a detectable marker bound to glucocomticoid receptors in the sample or patient using an imaginge means to obtain an image; and (c)» displaying an image of the spatial distribution and amount of the compound according to the invention or a tautomer, prodraug, solvate, or salt thereof having a detectable marker bound =to glucocorticoid receptors in the sample. In a preferred emmbodiment of the invention, the im. aging means is selected from: radioscintigraphy, nuclea—r magnetic resonance imaging (MRI, computed tomography (CT scar), or positron emission teomography (PET). ’ The invention also provides a kit for the in vitro diagnostic determination of the glucocorticoid a receptor function in a san—ple, comprising: (a) a diagnosticamlly effective amount of a— compound according to the inventio=n or a tautomer, prodrug, solvate, or salt thereof; and (b) Minstructions for use of the diagnostic lit.

It is preferred that the compounds of Formula (1A), (IB), (IC), and (ID) exclude the compounds disclosed in UF _S. Patent Application Pub. No. 2004/0023 999.

Brief Descripp tion of the Tables

TableIA lists representative compounds of Formula (IAD;

Table IB lists representative compounds of Formula (IB)»;

Table IC lists representative compounds of Formula (IC; and

Table ID lists representative compounds of Formula (ID).

Detailed Des cription of the Invention

Definition of Terms and Conventions Used

Terms not specifically defined herein should be giverm the meanings that would be given to them by ones of skill in the art in light of the disclo sure and the context. As useed in the specification and appended claims, however, unless s—pecified to the contrary, the following terms have thme meaning indicated and the following con_ventions are adhered to.

A. Chemical Nomenclature, Terms, and Conventiomns

In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified pre«ceding the group, for example, C;-Cyo alky means an alkyl group or radicaml having 1 to 10 catbosn atoms. The term “lower” applied to any carbon-containing group meanss a group containing from 1 to 8 carbon atoms, as appropriate to &he group (i.e., a cyclic group mmmust have atleast 3 atoms to constitute a ring). In general, for gramups comprising two or more su dbgroups, the last naned group is the radical attachment point, for example, “alkylaryl” mmeans a monovalent xadical of the formula Alk-Ar-, while “arsylalkyl” means a monovalent readical of the formula _Ar-Alk- (where Alk is an alkyl group and Ar is an aryl group). Furthermore, the use of a tern designating a monovalent radical where = divalent radical is appropriate shall be construed toe designate the respective divalent radic al and vice versa. Unless owtherwise specified, conventional definitions of terms control anc conventional stable atom vale=nces are presumed an d achieved in all formulas and groups.

The terms “alkyl” or “alkyl group” mean a breanched or straight-chain satur ated aliphatic

A hydrocarbon monovalent radical. This term is exe=mplified by groups such as me=thyl, ethyl, n- - propyl, I-maethylethyl (isopropyl), n-butyl, n-penty~1, 1,1-dimethylethyl (ferz-butylD), and the like. . 5 It may be abbreviated “Alk”.

The terms “alkenyl” or “alkenyl group” mezan a branched or straight-chain aliphatic hydrocarbon monovalent radical containing at leasst one carbon-carbon double bomnd. This term is exemplified by groups such as ethenyl, propenyyl, n-butenyl, isobutenyl, 3-met=hyibut-2-enyl, n-pentenyl , heptenyl, octenyl, decenyl, and the likes.

The terms “alkynyl” or “alkynyl group” me an a branched or straight-chain aliphatic hydrocarbon monovalent radical containing at leasst one carbon-carbon triple bond. This term is exemplified by groups such as ethynyl, propynyel, n-butynyl, 2-butynyl, 3-methylbutynyl, 7- pentynyl, heptynyl, octynyl, decynyl, and the like.

The terms “‘alkylene” or “alkylene group” mean a branched or straight-chain satarated aliphatic hydrocarb on divalent radical having the specifi ed number of carbon atoms. This term is exemplified by groups such as methylene, ethyle=ne, propylene, n-butylene, aned the like, and may alterraatively and equivalently be denoted her-<in as -(alkyl)-.

The terms “alkenylene” or “alkenylene group” mean a branched or straight-echain aliphatic hydrocarbon divalent radical having the specifie=d number of carbon atoms ard at least one carbon-caxbon double bond. This term is exemplified by groups such zas ethenylene, propenyleme, n-butenylene, and the like, and maay alternatively and equivalen-tly be denoted herein as —(alkylenyl)-.

The termss “alkynylene” or “alkynylene group” mean a branched or straight-echain aliphatic hydrocart»on divalent radical containing at least one carbon-carbon triple bond . This term is exemplified by groups such as ethynylene, peropynylene, n-butynylene, 2-Ebutynylene, 3- methylbut ynylene, n-pentynylene, heptynylene, owctynylene, decynylene, and the= like, and may alternativesly and equivalently be denoted herein a_s -(alkynyl)-.

The terms “alk=oxy” or “alkoxy group” mean a monovalent radical of the formula AlkeQ-, where

Alk is an alky® group. This term is exemplified by groups such as methoxy, ethoxy, propoxy. isopropoxy, bumtoxy, sec-butoxy, tert-butoxy, pentoxy, and the like.

The terms “arwy/loxy”, “aryloxy group”, mean a monovalent radical of the formula AreQ-, where

Aris aryl. Thi_sterm is exemplified by groups such as phenoxy, naphthoxy, and the like.

The term “ox ©” means a double-bonded divalent oxygen radical of the formula (=O), for example, one example of an alkyl group substituted by an “oxo” would be a gromup of the formula Alk-C=(0)-Alk, wherein each Alk is an alkyl.

The terms “al kylcarbonyl”, “alkylcarbonyl group”, ‘“alkanoyl”, or “alkanoyl groups” mean a monovalent radical of the formula AlkC(O)-, where Alk is alkyl or hydrogen.

The terms “ar=ylcarbonyl”, “arylcarbonyl group”, “aroyl” or “aroyl group” mean a mmonovalent radical of the formula ArC(Q)-, where Ar is aryl.

The terms “acs” or “acyl group” mean a monovalent radical of the formula RC(O)-, vovhere R is a substituent seelected from hydrogen or an organic sub»stituent. Exemplary substituermts include . alkyl, aryl, ar—ylalkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroarylalkyl, and the like. As such, the termss comprise alkylcarbonyl groups and aryl carbonyl groups.

The terms “accylamine” or “acylamino group” mear a monovalent radical of thee formula

RC(O)N(R)-, wvbere each R is a substituent selected frosm hydrogen or a substituent greoup.

The terms “al koxycarbonyl” or “alkoxycarbonyl group” mean a monovalent radiccal of the formula AlKCD-C(O)-, where Alk is alkyl. Exemplary alkoxycarbonyl group s include methoxycarbomnyl, ethoxycarbonyl, tert-butyloxycarborayl, and the like.

The terms “allkylaminocarbonyloxy” or “alkylaminoc arbonyloxy group” mean a m_onovalent radical of the formula R;NC(O)O-, where each R is independently hydrogen or lower aalkyl.

The term “alkoxycarbonylamino” or “alkoxycarbonylamino group” mean a monovalent radical of the formula ROC(O)NH-, where R is lower alka,

The terms “alkylcarbonylamino” or “alkylcarbsonylamino group” or “alkan oylamino” or “alkanoyl amino groups” mean a monovalent radical of the formula AIKC(O)NH- , where Alk is alkyl. Exemplary alkylcarbonylamino groups inclwude acetamido (CH;C(O)NH-).

The term=s “alkylaminocarbonyloxy” or “alkylanminocarbonyloxy group” mean a monovalent radical of the formula AIKNHC(O)O-, where Alk i s alkyl.

The termss “amino” or “amino group” mean an -NEJ; group.

The term. s “alkylamino” or “alkylamino group” mean a monovalent radical cmf the formula (AI)NH—, where Alk is alkyl. Exemplary alkylamino groups include methylamino, ethylamirmo, propylamino, butylamino, fert-butylarmino, and the like.

The termss “dialkylamino” or “dialkylamino group>” mean a monovalent radical eof the formula (AIK)(AIK=)N-, where each Alk is independently al kyl. Exemplary dialkylamino groups include dimethylammino, methylethylamino, diethylamino_, dipropylamino, ethylpropylarmino, and the like.

The terms “substituted amino” or “substituted am=ino group” mean a monovalent: radical of the formula —NR;, where each R is independently am substituent selected from hysdrogen or the specified =substituents (but where both Rs cannot b e hydrogen). Exemplary substituents include alkyl, alk=anoyl, aryl, arylalkyl, cycloalkyl, heter=ocyclyl, heteroaryl, heteroarylealkyl, and the like.

The terms “alkoxycarbonylamino” or “alkoxyc arbonylamino group” mean =a monovalent radical of the formula AIkOC(O)NH-, where Alk i=s alkyl.

THe terms “ureido” or “ureido group™’ mean a monovalent radical of the formula R,NC(O)NH-, wEnere each R is independently hydro gen or alkyl.

The terms “halogen” or “halogen grosup” mean a fluoro, chloro, bromo, or iodo group.

Thhe term “halo” means one or mome hydrogen atoms of the group are replaced by halogen groups.

Thhe terms “haloalkyl” or “haloalicyl group” mean a branched or straight-chain saturated aliphatic hydrocarbon monovalent mradical, wherein one or more hycirogen atoms thereof are each independently replaced with haalogen atoms. This term is exemplified by groups such as chloromethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropyl, 2-iodobut yl, 1-chloro-2-bromo-3- fl uoropentyl, and the like.

The terms “sulfanyl”, “sulfanyl group”, “thioether”, or “thioether group” mean a divalent radical of the forrmula -S-.

The terms “alkylthio” or “alkylthio group” mean a monovalent radi-cal of the formula AlkS-, vwhere Alk is alkyl. Exemplamry groups include methylthio, ethylthio, z-propylthio, issopropylthio, n-butylthio, and the Ii ke. "Ihe terms “sulfonyl” or “sulfonyl group” mean a divalent radical of tine formula -SO,-.

The terms “sulfonylamino” or “sul Zfonylamino group” mean a divaleent radical of the formula -2S0,NR-, where R is a hydrogen or a substituent group.

T he terms “aminosulfonyl” or “a -minosulfonyl group” mean a monovalent radical of the feormmla NR,SO,-, where R is each independently a hydrogen or a submstituent group.

The terms “carbocycle” or “carboecyclic group” mean a stable aliphatic 3- to 15-membered monocyclic or polycyclic monovamlent or divalent radical consisti ng solely of carbon and mydrogen atoms which may comprisse one or more fused or bridged ri-mg(s), preferably a 5- to 7-

membered monocyclic or 7- to 10-membered bicyclic ring. Unless otherwise specified, the carbocycle may be attached at any carbon atom which results in a stable structure znd, if substituted, may be substituted at any suitable carbon aatom which results in a stable strmucture.

The term comporises cycloalkyl (including spiro cy-cloalkyl), cycloalkylene, cycloalkenyl, . 5 cycloalkenylene,. cycloalkynyl, and cycloalkynylene, armd the like.

The terms “cyc loalkyl” or “cycloalkyl group” mean. a stable aliphatic saturated 3- to 15- membered mon acyclic or polycyclic monovalent ramdical consisting solely of carbon and hydrogen atoms which may comprise one or more fuse«d or bridged ring(s), preferably a S-to 7- membered monacyclic or 7- to 10-membered bicycliac ring. Unless otherwise specifi=ed, the cycloalkyl ring wmay be attached at any carbon atom vwhich results in a stable structure and, if substituted, may= be substituted at any suitable carbon atom which results in a stable structure.

Exemplary cyc loalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, nortoornanyl, adamantyl, tetrahydronzaphthyl (tetralin), l-dec=alinyl, bicyclo[2.2.2]octanyl, 1-mneth yicyclopropyl, 2-methylcyclopen tyl, 2- methylcycloocty./], and the like.

The terms “cycloalkenyl” or “cycloalkenyl group” me=an a stable aliphatic 3- to 15-memubered monocyclic or polycyclic monovalent radical having at least one carbon-carbon double bond and consisting s olely of carbon and hydrogen atoms w—hich may comprise one or more fused or bridged ring(s), preferably a 5- to 7-membered monocyclic or 7- to 10-membered bicycl ic ring.

Unless otherwisse specified, the cycloalkenyl ring masy be attached at any carbon atom which i results in a stab Je structure and, if substituted, may bes substituted at any suitable carbo=n atom which results im a stable structure. Exemplary cycMoalkenyl groups include cyclope=ntenyl, cyclohexenyl, «<ycloheptenyl, cyclooctenyl, cycloncnenyl, cyclodecenyl, norbornerayl, 2- methylcyclopen-tenyl, 2-methiylcyclooctenyl, and the lilice,

The terms “cycRoalkynyl” or “‘cycloalkynyl group” mean a stable aliphatic 8- to 15-memmbered monocyclic or polycyclic monovalent radical having a least one carbon-carbon triple bond and consisting solely of carbon and hydrogen atoms whi ¢h may comprise one or more fi ised or bridged ring(s), preferably a 8- to 10-membered mon _ocyclic or 12- to 15-membered bicyclic ring. Unless ot-herwise specified, the cycloalkynyl ring may be attached at any carbo_n atom which results in a stable structures and, if substituted, may be sultostituted at any suitable carbon atom which results in a stable stricture. Exemplary cycloalkynyR groups include, cyclooctyny~1, cyclononynyl, cyclodecynyl, 2-m ethylcyclooctynyl, and the like.

The terms “cycloalkylene” or “cy/cloalkylene group” mean a statole saturated aliphatic 3- to 1=5- membered monocyclic or polycyclic divalent radical consisting =solely of carbon and hydrogen atoms which may comprise one or more fused or bridged rzing(s), preferably a 5- to ~7- membered monocyclic or 7- to 10-membered bicyclic ring. [Tuless otherwise specified, thine cycloalkyl ring may be attached at any carbon atom which results in a stable structure and, if substituted, may be substituted at any suitable carbon atom whiech results in a stable structure.

Exemplary cycloalkylene groups include cyclopentylene, and the like.

The terms “cycloalkenylene” or “cycloalkenylene group” mea-m a stable aliphatic 5- to 1=5- membered monocyclic or polycy=clic divalent radical having at l-east one carbon-carbon doubsle bond and consisting solely of czarbon and hydrogen atoms which may comprise one or mo-re fused or bridged ring(s), preferably a 5- to 7-membered monccyclic or 7- to 10-membered bicyclic ring. Unless otherwise specified, the cycloalkenylene= ring may be attached at ary carbon atom which results in a stable structure and, if substituslted, may be substituted at ary suitable carbon atom which restalts in a stable structure. Exemplary cycloalkenylene groups include cyclopentenylene, cyclohexenylene, cyclohepatenylene, cyclooctenylen_e, cyclononenylene, cyclodecenwlene, norbornenylene, 2-mmethylcyclopentenylene, 2- methylcyclooctenylene, and the lake.

The terms “cycloalkynylene” or- “cycloalkynylene group” mea—m a stable aliphatic 8- to 155- membered monocyclic or polycyclic divalent radical having at least one carbon-carbon trip_le bond and consisting solely of camrbon and hydrogen atoms which may comprise one or mome fused or bridged ring(s), preferably a 8- to 10-membered mono=cyclic or 12- to 15-membere=d bicyclic ring. Unless otherwise specified, the cycloalkynylene ring may be attached at army carbon atom which results in a sstable structure and, if substituted, may be substituted at army suitable carbon atom which results in a stable structure. Exemplary cycloalkynylene groupos include cyclooctynylene, cyclonomynylene, cyclodecynylene, 2-nethyleyclooctynylene, and thae like.

The terms “aryl” or “aryl group” mean an aromatic carbocyclic monovalent or divalent radical of from 6 to 14 carbon atoms having a single ring (e.g., phenyl or phermylene) or multiple condensed rings (e.g, naphthyl or anthranyl). Unless otherwise specified, tke aryl ring may be attached at any suitable carbon atom which results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structur—e. Exemplary aryl groups include phenyl, naphthyl, anthryl, phenanthryl, indanyl, indenyl, biplhenyl, and the like.

It may be abbreviated “Ar”.

The terms “heteroaryl” or “heteroaryl group” mean a stable aromatic 5— to 14-membered, monocyclic or polycyclic monovalent or divalent radical which may conmprise one or more fused or bridged ring(s), preferably a 5- to 7-membered monocyclic or A- to 10-membered bicyclic radical, having from one to four heteroatoms in the ring(s) independ ently selected from nitrogen, oxygen, and sulfur, wherein any sulfur heteroatoms may optionally be oxidized and any nitrogen heteroatom may optionally be oxidized or be quaternized. Unless otherwise specified, the heteroaryl ring may be attached at any suitable heteroatom or carbon atom which results in a stable structure and, if substituted, may be substituted at any suitable heteroatom or carbon atom which results in a stable structure. Exemplary and preferred “heteroaryls include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxamzolyl, isothiazolyl, 220 oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimmidinyl, pyrazinyl, triazinyl, indolizinyl, azaindolizinyl, indolyl, azaindolyl, diazaindoly=l, dihydroindolyl, dihydroazaindoyl, isoindolyl, azaisoindolyl, benzofuranyl, furanopyridinyl, furanopyrimidinyl, furanopyrazinyl, furanopyridazinyl, dihydrobenzofuranyl, dihycdrofuranopyridinyl, dibydrofuranopyrimidinyl, benzodioxolanyl, benzothienyl, thienopyridinyl, thienopyrimidinyl, thienopyrazinyl, thienopyridaziny1, dihydrobenzothienyl, dihyedrothienopyridinyl, dibydrothienopyrimidinyl, indazoly1, azaindazolyl, diazaindazolyl, benzimidazolyl, imidazopyridinyl, benzthiazolyl, thiazolopyridinyl, thiazolopyrimidin—y], benzoxazolyl, oxazolopyridinyl, oxazolopyrimidinyl, benzisoxazolyl, purinyl, chromammyl, azachromanyl, quinolizinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl , isoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, azacinnolirayl, phthalazinyl, azaphthalazinyl, quinazolinyl, azaquina=zolinyl, quinoxalinyl, azaquinoxalinayl, naphthyridinyl,

a WO 2005/0302213 PCT/ US2004/031009 ; dihydrona—phthyridinyl, tetrahydronaphthyridinyi, pteridinyl, carbazolyl, acriadinyl, phenazinyl, phenothia=ziny!, and phenoxazinyl, and the like. . The termss “heterocycle”, “heterocycle group”, “heterocyclyl”, or “heterocyclyl group” mean a stable nomm-aromatic 5- to 14-membered monoc=yclic or polycyclic, monovalerat or divalent, ring which mamy comprise one or more fused or beridged ring(s), preferably a S- to 7-membered monocyclmc or 7- to 10-membered bicyclic rim g, baving from one to three Ieteroatoms in the ring(s) immdependently selected from nitrogesn, oxygen, and sulfur, whmerein any sulfur heteroatorms may optionally be oxidized andl any nitrogen heteroatom nay optionally be oxidized or be quaternized. Unless otherwise sspecified, the heterocyclyl ringe may be attached at any suitable heteroatom or carbon atom which results in a stable structure sand, if substituted, may be su_bstituted at any suitable heteroatom o x carbon atom which results in_ a stable structure. oo Exemplar—y and preferred heterocycles imclude pymolinyl, pyrrolidi myl, pyrazolinyl, . pyrazolidi_nyl, piperidinyl, morpholinyl, thie<morpholinyl, piperazinyl, ®tetrahydropyranyl, ’ 15 tetrahydromthiopyranyl, tetrahydrofuranyl, hexalmydropyrimidinyl, hexahydropsyridazinyl, and the . like.

The term “compounds of Formula (I) and equivalent expressions are mmean to embrace compouncis of Formula (IA), compounds of Formula (IB), compounds of Formula (IC), and compouncis of Formula (ID), either individual ly, in some combination, or amll of them, as the context pe=rmits.

The term ‘compounds of the invention” and equivalent expressions are rxeant to embrace compounds of Formula (I) as herein described, including the tautomers, the prodrugs, the salts, particular] y the pharmaceutically acceptable salts, and the solvates and hydra ‘tes thereof, where the context so permits. In general and prefex-ably, the compounds of the invention and the formulas designating the compounds of the inv—ention are understood to only include the stable compoundls thereof and exclude unstable compe ounds, even if an unstable co-mpound might be ’ considerecd to be literally embraced by the compound formula. Similemrly, reference to : 30 intermedie=mtes, whether or not they themselves zare claimed, is meant to embrace their salts and solvates, vovhere the context so permits. For the sake of clarity, particular irastances when the context so permits are sometimes indicated in the text, but theese instances are purely illustmrative and it is not intended to exclude other instances when the context so permits.

The terms “optiomal” or “optionally” mean that the subsequently described evemnt or circumstances may” or may not occur, and that the descripstion includes instances where the event or circumstance occurs and instances in which it domes not. For example, “optionally substituted aryl” means that the aryl radical may or may not be substituted and theat the description include s both substituted aryl radicals and aryl raedicals having no substitution.

The terms “stable compound” or “stable structure’ mean a ceompound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation ito an efficacious therapeutic or diagnostic agent. For example, a compound which would h ave a “dangling valency’ or is a carbanion is not a compound contemplated by the invention.

The term “substituted” means that any one or more hydrogemms on an atom of a group or moiety, whether specifically designated or not, is replaced with a sel ection from the indicated grasup of substituents, provided that the atom’s normal valency is not exceeded and that the substi~tution results in a stable compound. If a bond to a substituent is sFaown to cross the bond connecting : two atoms in a ring, then such substituent may be bonded —to any atom on the ring. W_hen a substituent is listed without indicating the atom via which su-ch substituent is bonded to thae rest of the compound, then such substituent may be bonded via any atom in such substituent For example, when thee substituent is piperazinyl, piperidiny1, or tetrazolyl, unless specified otherwise, such piperazinyl, piperidinyl, or tetrazolyl group may be bonded to the rest Of the compound of the invention via any atom in such piperaziny~l, piperidinyl, or tetrazolyl group.

Generally, when amy substituent or group occurs more thamn one time in any constitue=nt or compound, its definition on each occurrence is independemt of its definition at every other occurrence. Thus, for example, if a group is shown to be su_bstituted with 0 to 2 R®, then. such group is optionally substituted with up to two R® groups ancl R® at each occurrence is sel ected independently fromx the defined list of possible R®. Such combinations of substituents a_nd/or variables, however, are permissible only if such combinations result in stable compounds.

In a specific embodiment, the term “about” or “approxima=tely” means within 20%, prefexably within 10%, and mo xe preferably within 5% of a given valuee or range.

The yield of each of the reactions described herein is expressed as a percentage of the theoretical yield. ’ B. Salt, Prodrug, Derivative, and Solvate Terms and Conventions

The terms “prodrug’ or “prodrug derivative” mean a covaleently-bonded derivative or carrer of the parent compound or active drug substance which undermsoes at least some biotransform ation prior to exhibiting its pharmacological effect(s). In generaml, such prodrugs have metabolically cleavable groups amd are rapidly transformed in vivo to yield the parent compound, for example, by hydrolysis in blood, and generally include est-ers and amide analogs of the pwarent compounds. The prodrug is formulated with the objecti=ves of improved chemical staboility, improved patient acceptance and compliance, improved bioavailability, prolonged duratieon of action, improved organ selectivity, improved formulatio-n (e.g., increased hydrosolubiility), and/or decreased sicle effects (e.g., toxicity). In general, pr—odrugs themselves have weak «or no biological activity and are stable under ordinary condition=s. Prodrugs can be readily pregpared from the parent commpounds using methods known in the= art, such as those described in A

Textbook of Drug Design and Development, Krogsgaarcl-Larsen and H. Bundgaard (eeds.),

Gordon & Breach, 1991, particularly Chapter 5: “Desigzgn and Applications of Prodrugs”™;

Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; _Prodrugs: Topical and Ocular Drug

Delivery, K.B. Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985, particularly pp. 309—396; Burger’s Medicinal Chenistry and Drug Discovery, 5th Ed., M. Wolff (ed.), John Wiley &= Sons, 1995, particularly Vol. I and pp. 172-178 and pp. 949-982; Pro-Drugs as Novel Deliver—y Systems, T. Higuchi and V. Stella (eds), Am. Chem. Soc., 1975; Bioreversible Carriers izn Drug Design, E.B. Roche «fed.),

Elsevier, 1987, each. of which is incorporated herein by reference in their entireties.

The term “pharmaceutically acceptable prodrug” as us-ed herein means a prodrug of a compound of the inwention which is, within the scope of scound medical judgment, suitabl_e for use in contact with he tissues of humans and lower anima 1s without undue toxicity, irritaation,

allergic ressponse, and the like, commensurate witha a reasonable benefit/risk ratio, and effective for their inwtended use, as well as the zwitterionic fosrms, where possible.

The term “salt” means an ionic form of the pare=nt compound or the product of the reaction between thme parent compound with a suitable acidll or base to make the acid sal t or base salt of the parent compound. Salts of the compounds of t-he present invention can be s=ynthesized from ] the parent: compounds which contain a basic cr acidic moiety by conven—tional chemical ’ methods. Generally, the salts are prepared by reamcting the free base or acid parent compound ) with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or basse in a suitable solvent or various combinations of solvents.

The term “pharmaceutically acceptable salt” mean s a salt of a compound of the Sinvention which is, within the scope of sound medical judgment, suitable for use in contact wisth the tissues of humans ard lower animals without undue toxicity, irritation, allergic response, and the like, commensumrate with a reasonable benefit/risk ratio_, generally water or oil-solubl_e or dispersible, and effective for their intended use. The tern includes pharmaceutically— acceptable acid addition saalts and pharmaceutically-acceptable base addition salts. As the compounds of the present invention are useful in both free base and salt form, in practice, the use of the salt form amounts tO use of the base form. Lists of suitable salts are found in, e.g., SMC. Birge ef al, J.

Pharm. ScE., 1977, 66, pp. 1-19, which is hereby irmcorporated by reference in its- entirety.

The term =‘pharmaceutically-acceptable acid addistion salt” means those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic ac=ids such as hydrochloric acid, hydrobromic acid, hydrooiedic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, =and the like, and organic ac-ids such as acetic acid, trichloroacetic -acid, trifluoroacetic acid, adimpic acid, alginic . acid, ascomrbic acid, aspartic acid, benzenesulfoni c acid, benzoic acid, 2-aceto Xybenzoic acid, ] butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, - digluconic acid, oo ethanesulfeonic acid, glutamic acid, glycolic acied, glycerophosphoric acid, Iemisulfic acid, : 30 heptanoic acid, hexanoic acid, formic acid, fsumaric acid, 2-hydroxyethazmesulfonic acid (isethionic acid), lactic acid, maleic acid, hydr—oxymaleic acid, malic acid_ malonic acid, mandelic acid, mesitylenesulfonic acid, metha nesulfonic acid, naphthalermesulfonic acid,

nicotinic acid , 2-naphthalenesulfonic acid, oxalic acic, pamoic acid, pectinic acid, phenzylacetic acid, 3-pheny~lpropionic acid, picric acid, pivalic ac id, propionic acid, pyruvic acid, Jpyruvic acid, salicylic acid, stearic acid, succinic acid, sulfa—nilic acid, tartaric acid, p-toluenessulfonic acid, undecan oic acid, and the like.

The term “phn.armaceutically-acceptable base additiorn salt” means those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise unclesirable, formed with inorganic bases ssuch as ammonia or hydroxide, carbonate, or bicarbonat € of ammonium or a metal cation suck as sodium, potassium, lithium, calcium, magnesium, i Ton, zinc, copper, manganese, aluminurm, and the like. Particularly prefemred are the ammonicam, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutic ally-acceptable organic nontoxic bases include salts of primary, secondamry, and tertiary amines, quaternary amine compounds, substituted amines including naturally occurring substituted amines, cyclic amines and basic ionm--exchange resins, such as methy~lamine, dimethylamirme, trimethylamine, ethylamine, dieth—ylamine, triethylamine, isopropy~lamine, tripropylamin_e, tributylamine, ethanolamine, diettmanolamine, 2-dimethylaminoethamol, 2- diethylaminoesthanol, dicyclohexylamine, lysine, ar=ginine, histidine, caffeine, hydralbamine, choline, betaine, ethylenediamine, glucosamine, mmethylglucamine, theobromine, gourines, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium comyppounds, tetracthylamomonium compounds, pyridine, NN-Slimethylaniline, N-methylpiperidi ne, N- methylmorph«oline, dicyclohexylamine, dibenzylammine, N,N-dibenzylphenethylami ne, 1- ephenamine, N,N’-dibenzylethylenediamine, polyanmnine resins, and the like. Particularly preferred organic nontoxic bases are isopropoylamine, diethylamine, ethanolamine, trimethylamirae, dicyclohexylamine, choline, and caffeine.

The term “somlvate” means a physical association o—f a compound with one or more solvent molecules or za complex of variable stoichiometry for—ued by a solute (for example, a cormpound of Formula (X)) and a solvent, for example, water, ethanol, or acetic acid. This pehysical association mmay involve varying degrees of ionic arad covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capamble of isolation, for example, wher one or more Solvent molecules are incorporated in the cr—ystal lattice of the crystalline sokid. In general, the solvents selected do not interfere with the= biological activity of the solute. SSolvates encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, etharmolates, methanolates, and the like.

The term “hyd-xate” means a solvate wherein the solv—ent molecule(s) is/are HO.

The compounsds of the present invention as discusssed below include the free= base or acid thereof, their s alts, solvates, and prodrugs and may irclude oxidized sulfur atoms or quaternized nitrogen ators in their structure, although not explicitly stated or shown, p articularly the pharmaceutica_lly acceptable forms thereof. Such forms, particularly the pharmaceutically acceptable forms, are intended to be embraced by the appended claims.

C. Isomer Terms and Conventions

The term “isommers” means compounds having the s ame number and kind of ato-ms, and hence the same mole= cular weight, but differing with respec=t to the arrangement or confi_guration of the atoms in space=. The term includes stereoisomers anc geometric isomers.

The terms “stesreoisomer” or “optical isomer” mean a stable isomer that has at 1 east one chiral i atom or restricted rotation giving rise to perpenclicular dissymmetric planes (e.g., certain biphenyls, all epes, and spiro compounds) and cean rotate plane-polarized ligght. Because asymmetric ce=nters and other chemical structure exi=st in the compounds of the irmvention which may give rise to stereoisomerism, the invention contemplates stercoisomers and mixtures thereof. The compounds of the invention and their =salts include asymmetric car bon atoms and may therefore- exist as single stereoisomers, racerxmates, and as mixtures of en_antiomers and diastereomers Typically, such compounds will be prepared as a racemic mixticre. If desired, however, sucha compounds can be prepared or isolateed as pure stereoisomers, i.e, as individual enantiomers owr diastereomers, or as stereoisomer-e=nriched mixtures. As discwssed in more detail below, Endividual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chir=a! centers or by preparation of mixtures of enantiomeric poroducts followed by separation or res olution, such as conversion £0 a mixture of . diastereomers followed by separation or recrystalliz=ation, chromatographic teclmniques, use of chiral resolvirag agents, or direct separation of th € enantiomers on chiral ch romatographic columns. Starting compounds of particular stereocheemistry are either commercially available or are made= by the methods described below and resolved by techniques well-known —in the art. oo The term ‘®epantiomers” means a pair of stereoisomers that are non-superimposalble mirror - 5 images of ezach other.

The terms —“diasterecisomers” or “diastereomers” mean optical isomers which are mot mirror images of e ach other.

The terms ‘racemic mixture” or “racemate” mean a mixture containing equal parts of ~ individual enantiomerss.

The term <‘non-racemic mixture” means a mixture containing unequal parts of individual enantiomerss.

The term “moeometrical isomer” means a stable isomer~ which results from restricted #freedom of rotation about double bonds (e.g, cis-2-butene and fraens-2-butene) or in a cyclic structure (e.g., cis-1,3-dickalorocyclobutane and frans-1,3-dichloroccyclobutane). Because cartoon-carbon : double (ole finic) bonds, C=N double bonds, cyclic structures, and the like may be pre=sent in the compoundss of the invention, the invention contemplates each of the various stable geometric isomers an d mixtures thereof resulting from the arrangement of substituents arcound these double bonds and in these cyclic structures. The sulbstituents and the isomers are designated using the cas/trans convention or using the E or Z sysstexn, wherein the term “E” me=ans higher order substituents on opposite sides of the double bond, and the term “Z” means hi gher order substituentss on the same side of the double bond. A tThoxough discussion of E and Z isomerism is provided in J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and _ Structure, 4th ed., Joan Wiley & Sons, 1992, which is hereby incorporated by reference in i=ts entirety.

Several of t=he following examples represent single E i soxmers, single Z isomers, and raixtures of

E/Z isomers. Determination of the E and Z isomers caan be done by analytical methcmds such as x-ray crystallography, "H-NMR, and >*C-NMR.

Some of the compounds of the invention can exist in more than one tautomeric form. AS mentioned above, tlhe compounds of the invention include all smach tautomers.

It is well-known ir the art that the biological and pharmacoleogical activity of a compound is sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit= strikingly different biological activity including differences in pharmacokinetic properties, including metaboli sm, protein binding, and the like, and pharmacological properties, includings the type of activity— displayed, the degree of activity, toxicity, Zand the like. Thus, one skilled ime the art will appreci_ate that one enantiomer may be more actives or may exhibit beneficial effectss when enriched relative to the other enantiomer or when sepa rated from the other enantiomer—

Additionally, one sskilled in the art would know how to separaxte, enrich, or selectively prepare= the enantiomers ofS the compounds of the invention from this disclosure and the knowledge off the prior art.

Thus, although tle racemic form of drug may be used, it is often less effective tharm administering an e=qual amount of enantiomerically pure drug; indeed, in some cases, one enantiomer may b e pharmacologically inactive and would merely serve as a simple diluent.

For example, although ibuprofen had been previously administered as a racemate, it has beera shown that only tEae S-isomer of ibuprofen is effective as arm anti-inflammatory agent (in thes case of ibuprofen, however, although the R-isomer is inactive=, it is converted in vivo to the S— isomer, thus, the r=apidity of action of the racemic form of the drug is less than that of the pure

S-isomer). Furthesrmore, the pharmacological activities of enantiomers may have distinc biological activity Por example, S-penicillamine is a therapeutic agent for chronic arthritis. while R-penicillanmine is toxic. Indeed, some purified enantXomers have advantages over thes racemates, as it has been reported that purified individual isomers have faster transdermal penetration rates ecompared to the racemic mixture. See WJ.S. Patent Nos. 5,114,946 andl 4,818,541.

Thus, if one enartiomer is pharmacologically more active , less toxic, or has a preferrecl disposition in the I>ody than the other enantiomer, it would be -therapeutically more beneficial to administer that en=antiomer preferentially. In this way, the pastient undergoing treatment woul be exposed to a lower total dose of the drug and to a lower dose of an enantiomer sthat is possibly toxic or an inhibitor of the other enantiomer.

Preparation of pure enant-iomers or mixtures of desired enantiomeric excess (ese) or enantiomeric purity are accomplished by one or more of the mamny methods of (a) separa=tion or resolution of enantiomers, or (b) enantioselective synthesis knov=vn to those of skill in the - art, or a combination thereof. Th ese resolution methods generally —rely on chiral recogniticon and include, for example, chrormatography using chiral stationary phases, enantioselectives host- guest complexation, resolution or synthesis using chiral auxiliaries, enantioselective syrathesis, enzymatic and nonenzymatic: kinetic resolution, or spontaneous enantioselective crystallization.

Such methods are disclosed. generally jn Chiral Separation Techniques: A Practical Apmproach (2nd Bd), G. Subramanian (ed), Wiley-VCH, 2000; T.E. Be esley and R.P.W. Scott, Chiral

Chromatography, John Wiley & Sons, 1999; and Satinder Ahuja, Chiral Separations by

Chromatography, Am. Cherm. Soc., 2000. Furthermore, there amze equally well-known n—cthods for the quantitation of enan_tiomeric excess or purity, for exan—ple, GC, HPLC, CE, or— NMR, and assignment of absolutes configuration and conformation, for example, CD/ORD_, X-ray crystallography, or NMR.

In general, all tautomeric foams and isomeric forms and mixturess, whether individual gesometric isomers or stereoisomers COI racemic or non-racemic mixtur—es, of a chemical struc=ture or compound is intended, unless the specific stereochemistry omr isomeric form is specifically indicated in the compound name or structure. Generally, one enantiomer is preferred, when a racemic mixtures is resolved.

D. Pharmaceutical Adxministration and Diagnostic amnd Treatment Ternmms and

Conventions

The term “patient” includes both human and non-human mamirals.

The term “effective amoumnt” means an amount of a compo-und according to the irwvention which, in the context of which it is administered or used, is -sufficient to achieve the desired effect or result. Dependimng on the context, the term effective amount may includ _e or be synonymous with a pharmaceutically effective amount or a diagnostically effective amount.

The tems “pharmaceutically effective amount™ or “therapeutically effective amount” means an amount of a compound according to the invemntion which, when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an armount would be sufficient to elicit the biological or medical response of a tissue, system, or patient that is sought by a researcher or clinician.

The zamount of a compound of according to the invention which constitutes a thesrapeutically effective amount will vary depending on suech factors as the compound and is biological activity, the composition used for administration, the time of administration, the route of admimistration, the rate of excretion of the compound, the duration of treatment. the type of disesmse-state or disorder being treated and i&s severity, drugs used in combination with or coincidentally with the compounds of the invesntion, and the age, body weight, gexneral health, sex, and diet of the patient. Such a theragpeutically effective amount can ber determined routi-nely by one of ordinary skill in the art having regard to their own knowledge, the prior art, and this disclosure.

The term “diagnostically effective amount” m_eans an amount of a compound acceording to the invemtion which, when used in a diagnostic method, apparatus, or assay, is sufficiesnt to achieve the clesired diagnostic effect or the desired biological activity necessary for time diagnostic methnod, apparatus, or assay. Such an amourt would be sufficient to elicit the "biological or medical response in a diagnostic method, app-aratus, or assay, which may include> a biological or maedical response in a patient or in a in vitro or in vivo tissue or system, that iss sought by a researcher or clinician. The amount of a compound according to the invention which constitutes a diagnostically effective amourmt will vary depending on such faactors as the compound and its biological activity, the dmagnostic method, apparatus, or assay used, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of administration, drugs and othe x compounds used in combination with or coincidentally -with the compounds of the invention, and, if a patient is the subject of the diagnostic administration, the age, body weight, general health, sex, and diet of the patient. Such a diagnostically effective amount can be determinedk routinely by one of ordinary skill in the art having regarcll to their own knowledge, the prior art, and this disclosure.

The term “rmodulate” means the ability of a ccompound to alter the funection of the o glucocorticoi«d receptor by, for example, binding to and stimulating or imohibiting the glucocorticoi«d receptor functional responses. : bh}

The term “modulator” in the context of describing compounds according to ~the invention means a compound that modulates the glucocorticoid receptor function. As suchh, modulators include, but zare not limited to, agonists, partial agonisfits, antagonists, and partial armtagonists.

The term “ag=onist” in the context of describing comp ounds according to the invemntion means 2 compound that, when bound to the glucocorticomid receptor, enhances or -increases the glucocorticoid receptor function. As such, agonists in_ clude partial agonists and fix 11 agonists.

The term “full agonist” in the context of describingg compounds according to the invention means a cormpound that evokes the maximal stimn 1latory response from the mslucocorticoid receptor, even when there are spare (unoccupied) glucocorticoid receptors present — "The term “p=artial agonist” in the context of describimng compounds according to the invention

EER means a compound that is unable to evoke the _maximal stimulatory respo-mse from the glucocorticoid receptor, even at concentrations sufficient to saturate the aglucocorticoid receptors pre=sent.

The term “zamntagonist” in the context of describing compounds according to the invention means a conmpound that directly or indirectly inhibitss or suppresses the glucocorticoid receptor function. Ass such, antagonists include partial antagoxists and full antagonists.

The term “fall antagonist” in the context of describi_ng compounds according to- the invention means a compound that evokes the maximal inhmbitory response from the _glucocorticoid receptor, eveen when there are spare (unoccupied) glucocorticoid receptors presente.

The term “partial antagonist” in the context of describing compounds acc ording to the invention meeans a compound that is unable to evoke= the maximal inhibitory response from the glucocorticoid receptor, even at concentrations s-ufficient to saturate the gluacocorticoid receptors pr-esent.

The terms eating” or “treatment” mean the treat-ment of a dlisease-state in a patient, and include: : (i) preventing the disease-state from occurring ir a patient, in particular, when such patient is gzenetically or otherwise predisposed to the disease-state but has neot yet been . diagnosed as having it; (ii) inhi biting or ameliorating the disease-state in a patient, i.e., arresting or slowing its } 10 deveelopment; or (iii) reliesving the disease-state in a patient, i.e., «causing regression or cure of the disease- : stat-e.

General S.-ynthetic Methods for Making Compounds of Formula (JA), Formula (TB),

Formula (MC), and Formula (ID)

The invent=ion also provides processes for making compounds of Formula (IA), F omula (IB),

Formula (I=C), and Formula (ID). In all schemes, 1anless specified otherwise, R! to R® in the formulas beslow shall have the meaning of R! to R® ir the Formula (I) of the inventi on described hereinabov—e; and where appropriate, R! to RS in the formulas below shall have thes meaning of

R! to R® in the Formula (IB), Formula (IC), or Formula (ID) of the invention described hereinabov—e. Intermediates used in the preparation. of compounds of the invention are either

Cs commercially available or readily prepared by methceds known to those skilled in thme art.

Optimum reaction conditions and reaction times may vary depending on the partici alar reactants used. Urnless otherwise specified, solvents, temperatures, pressures, and ot"her reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided ira the Experimental Examples section. Typically, reaction progress may te monitored : by thin la_yer chromatography (TLC), if desired, and intermediates and prodiicts may be purified by~ chromatography on silica gel and/or by reecrystallization.

Compoundlts of Formula (IA), Formula (IC), and Fommula (ID) may be prepared b=y the method outlined in Scheme I.

R\ Ho CF, Reduction RY HO CF Oxidati ve

NE —_— 2X on _—

R' R' Cleavamge oO

I mn

SP RSRM Roy oF rR? =! CF, - rR? R' RY R° v IA&ID epoxidation

Ry Q RSH or RSM rose

R rR’ CF, R \ IA&IC ’ Scheme I

AAs illustrated in Scheme I, an ester interrmediate of Formula (II), where R* is Me or Et, is . reduced with a suitable reducing agent, such as lithium aluminum hydride, in a suitable solvent, ssuch as THF or diethyl ether, to produce the 1,2-diol of Formula (II). Oxidawtive cleavage of 1 2-diols is well-known in the art and may be achieved with periodic acid or le=ad tetraacetate, or example, in a suitable solvent, such as methanol, to provide ketone (IV). Re _action of ketone

CIV) with a suitable organometallic reagent R°R*M, such as a Grignard reagent= (M is MgBr or

I=vigClI) or an organolithium reagent (M is L.1), in a suitable solvent such as THF or diethyl ether porovides the desired compound of Formula (I). Such organolithium reagests or Grignard r-eagents are well-known in the art, for example, Grignard reagents are easly prepared by reacting the corresponding halides (R’R*X_, where X is Br or Cl) with magne=sium metal in a ssuitable solvent, such as diethyl ether or THF, under anhydrous coxnditions. The aforementioned organolithium reagents are readily prepared by reacting the R*F=*H, where Ris Izeteroaryl, with alkyl lithium reagents stxch lithium diisopropylamide (LDAw) in a suitable ssolvent, such as diethyl ether or THF, under anhydrous conditions.

Alternatively, ketone (TV) is reacted with a suitable reagent to provide epoxides (V). Reaction of epoxide (V) with the desired R*H or R°2M (M is Na or Li), provides the dessired product of

Formula (I). The reaction may take place bry heating R’H and epoxide (V) in a suitable solvent s:uch as DMF, heating R’H and epoxide (V") together in a solvent in the presemce of a suitable base such as =sodium ethoxide in ethanol, or by reacting R°M and epoxicie (V) in suitable solvents such sas DMF or DMSO. Such organometallic reagents could be gemnerated by treating

RH with NaF, LiH, or other reagents or methods known by one of ordinary skill in the art, in tL suitable solvernts such as THF, DMF, or DMSO.

Scheme IT outMines another approach that may be used to obtain compounds oef Formula (IA). rR’ re

HO_ C F. =

FO = \ = a Rr?

R HO, CF. ' AE or Friedel—Crafis Cog + eee 0 0] vi vii 3 3

RHo_ cr, R R

R=eduction Oxidative CF,

OH Cleaavage vill IX

RRM

R® RHO CF,

Xe, cr, RSRM g-R°

X X X IA

X =H, |,Br, Cl

RZ=Me =r x

Scheme II

In Scheme IM, ethyl triflucropyruvate is reacted with a substituted allyl (Grignard to provide olefin (VI). Reaction of olefin (VI) with 2,3-dihysdrobenzofuran in the pre=sence of a suitable

Lewis acid smich as AlCl3, well-known in the art as the “Friedel-Crafts alkylation”, gives ester

(VID. Reduction of ester (VI) with a suitable redumcing agent such as lithium aluminum hydride (LAH) in a solvent such as THF provides 1,2-adiol (VII). Oxidative cleavage of 1,2- diol (VII) may be achieved with sodium periodate or lead tetraacetate, for instance in 2 suitable solvent, such as methanol, to provide ketone (IX). Reaction of ketone (IX) wvith a suitable halogen (Clz, Bry, or I) or halogenating reagermts such as N-bromosuccinirnide (&NBS), affords ketone (X). Treatment of ketones (IX) or (X) with a suitable organometallic reagent

RR*M, where M is Li or MgX and X is CL, Br, or I, provides the desired compound of Foamula (D), where RR! is an optionally substituted 2,3-dihydrotoenzofuranyl group and R! is a methyl group.

Compounds of Formula (IA) may also be prepared by time method outlined in Scheme IIL fo) H Q wos ig J + He os —_— econ, —_—

F.C” 0” “CF, i. Le

Xl

R 1a RRQ RR HO CF -— By == RSA, = NG 3 cuX R

Xi Iv 1A

Scheme II

In this approach, trifluoroacetic anhydride and N,0-dirmethythydroxylamine hydrochloricle are coupled under basic conditions to afford triflucroacetzmmide (XI) (Weinreb amide). Weinreb amide (XIp is reacted with a vinyl magnesium br-omide bearing R? and R® to afford : trifluoromethylenone intermediate (XII). Trifluoromcwthylenone intermediate (XII) is treated with an orgganocopper reagent, derived from a Grignard or organolithium reagent by treating with a copper salt, to afford 1,4-addition product (IV). This trifluoroketone intermediate ( IV) is reacted with an organometallic reagent R*R*M (as described in Scheme I) to afford the desired compound of Formula (A).

Compounds: of Formula (IA) where RR’ is an optionally substituted benzimidazol-2-ylnethyi group may ©e prepared by the procedure outlined in Scheme IV.

NH, 2 RO 1. Base PY EL

EtOAc

CH — Rt COH NH, 8 2. hydrolysis CF, \ XIN

Rr mR IC, —— WP

R' N R' N

CF, | CF, “H

Ho NH, 1A . Xv N (where RS-R¢ is ~~ S—cH,)

Lo N

H

Schemme IV

As illustra~ted in Scheme IV, trifluoromethylk=etone (IV) is reacted with ethyl acetate in the presence o—f a strong base such as lithium diisogpropylamide (LDA) in a sui—tsble solvent such as

THF. The= intermediate ester is hydrolyzed, feor example, by treatment with aqueous base, to provide ca_rboxylic acid intermediate (XIII). "This carboxylic acid intermediate (XIII) is then coupled w_ith an optionally substituted phenyl enediamine under standard coupling conditions known ira the art, for example, by ®reatment with 1-(3-dime=thylaminopropyl)-3- ethylcarbo diimide (EDC) in the presence of 1—hydroxybenzotriazole in a =suitable solvent such as NN-dirmethylformamide (DMF), to provide compound (XIV). Ring closure by methods known in the art, for example, acid catalyzed ring closure by treatment with polyphosphoric acid, provmdes the desired compound of Formula (IA). : Compouncls of Formula (IB) may be prepared by the procedure illustrated min Scheme V. . OH 2

SORTA PEE

R' R

R¥ “RS

XV XVI XVil

Me IR ©

HNR"R™ NT R8M — R R® ) —

Mel R™

Xw/ill

Me B® O Me Rho Rr

C) RSR4M _ 5

Me

XIX IB,R! = p-

Schemmne V

In Scher me V, substituted phenol (XV) is reacteed with an acryloyl chloride bearirag R* and rR? (XVI) im the presence of a suitable base, such a s triethylamine, to provide an intermediate ester which iss cyclized by treatment with a Lewis a«cid, such as aluminum trichloride, in a suitable solvent, such as carbon disulfide, to provide lasctone (XVII). Lactone (XVII) is tareated with a suitable amine HNR”R’”, such as morpholirae, such that in the resulting anmide (XVII), -NR¥R” ° will function as a leaving group in the subsequent reaction. The intermeediate phenol that forrms is protected, for example, by reactiora with methyl iodide in the presence of a suitable base suech as potassium hydroxide to form protected phenol (XVII), in this c-ase having a methoxsy group. Amide (XVII) is then reactecd with an organometallic reagent (FRM), such as a Grign=ard reagent (M is MgBr or MgCl) or a_n organolithium reagent (M is Li), in a suitable solvent, such as THF or diethyl ether, to prowide the ketone (XIX). Reaction <f the ketone (XIX) vevith R’R*M as described in the last step in Scheme I provides the desired compound of

Formule (IB) where R' is an optionally substitu_ted methoxyphenyl group.

In a mo-re general procedure, suitable for a vamriety of R!, one may use a method analogous to that des-cribed in Scheme III. As illustrated in_ Scheme VI, using a Weinreb amiede bearing R® one maZy employ the method described in Scheme III to prepare thie desired ketone (XX) and compoumnd of Formula (IB).

B55

. &R . H

NP + HC” ~0~ a RE N “cH, —

HCl CH, 3 3 3 6 x 6 — R RR — RY RY ’ Roux R xX IB

Scheme= VI

An alternat3ve method to prepare intermediate (IV”) in Schemes I, III, and IV, ass well as ketone (XX) in Sckaeme VI, is illustrated in Scheme VII. pis i Cond tl ¥ R'M , Condensation

R2 RS + ne JR BR —— a —— come OX

XXI| XX XX , R® rR?

R L ;

Ro Hydrolysis len Reduction

Decarboxylation co,Me

XXIV XXV

REIL CF,SIMe, /F- RET Oxidation RETR rR H R' CF, R' CF,

XXXVI XXVII Iv -

RET Oxidation RE rR’ R° R' R®

XXvill XX

Scheme VII

As illustrateed in Scheme VII, a ketone bearing R! and R? (XXI) is condensed with cyanoacetic acid ester (CXXII), where R’ is Me or Et, in a reaction known in the art as a Knoevenagel condensation to provide olefin (XXII). Reaction of olefin (XXII) with a sujtable } organometzmllic reagent such as R'M, where M is MgBr, MgCl, or Li, in thes presence of a copper salt, such as Cul, affords estesr (XXIV). Hydrolysis of ester (XXXIV) followed by the . concomitant decarboxylation of resualting acid in the presence of suitable reagent, such as ’ sodium chloride, and in a suitable solvent mixture, such as DMSO amnd water, gives the corresponding nitrile (XXV). Reduction of nitrile (XXV), for example, by treatment with a = 5 suitable reducing agent, such as diisobutylaluminum hydride (DIBAL), £n a suitable solvent such as dichloromethane, furnishes @ldehyde (X3XVI). Treatment of aldehyde (XXVI) with ‘ trimethyl(triflucromethyl)silane in the presence of a suitable fluoriCle source, such as tetrabutylammonium fluoride, provicles alcohol (XXVIII). Oxidation of alcohol (XXVII) by methods known in the art, such as treatment with the Dess-Martin periowdinane reagent, in 8 suitable solvent, such as dichlorometinane, gives ketone (IV).

Alternatively, aldehyde (XXXVI) is tre ated with a suitable organometallic reagent RM, suchas a

Grignard reagent (M is MgBr or Mg&CI) or an organolithium reagent (MC is Li), in a suitable solvent such as THF or diethyl ether to provide alcohol (XXVIII). Sub sequent oxidation of alcohol (XXVIII) by a method well-known in the art provides ketone (XX) - ) Additionally, ketone (XX) in Schenie VI may be prepared from ketone= (IV) as depicted in

Scheme VIIL

RR §

RZ,

Iv

Cleavage 2 s OH 2 3s

AD. Reduction NEI RR‘NH DOD -

R' * Rr’ OH — Rg! N"

XXI XXX XXX RT" otter | RM

RRQ REM ET Oxida § 2 9 ton R R

AN TR rR DSN

XXVi XXViil XX

Scheme VIII

WO» 2005/030213 P@CT/US2004/031009

Im Scheme VIII ketone (IV) is cleaved in the presence of a suitable base, such as NaOH, and in a suitable solvent mixture, such as a mixture of water and ethanol, to provide acid (XXIX)-

Acid (XXIX) is treated with a suitable amine HINR"R™, such as morpholine, such that

NR”R™ will function as a leaving growp in the subsequent reaction. ~The resulting amide (XXX), is then reacted with an organome tallic reagent (RM), such as a Grignard reagent (M is ™MgBr or MgCl) or an organolithium rea gent (M is Li), in a suitable solv—ent, such as THF or

Glliethy! ether, to provide ketone (XX). Alternatively, acid (XXIX) is tre=ated with a suitable reducing agent such as lithium aluminum hydride (1LAH) in a solvent s=uch as THF to give alcohol (XXX). Oxidation of alcohol (3&XXT) according to methods known by one of ordinary skills in the art, such as treatment with the Dess-Martin periodinane reagent, in a suitable solvent, such as dichloromethane, gives aldehyde (XX VT).

As previously illustrated in Scheme “WII, reaction of aldehyde (XX VI) with a suitable organometallic reagent RM (M is MgBr, MgCl, or Li), in a solvent such as THF or diethyl aether affords alcohol (XXVIII), which is oxidized to alcohol (XXVIII) oy a method, such as

Swern oxidation or treatment with the Dezss-Martin periodinane, provides ketone (XX). «Compounds of Formula (YA) where R*1R’ is an optionally substituted inedol-2-ylmethyl group may be synthesized by the procedure outlined in Scheme IX. rR’ oF R® R® OH

R2 (CH,),SO*t 2 Le 2

I NaF, > =" 2 ® DMSO 3 TBAF R CF,

Iv \ XXXi

R' rR’ , R® OH 3

Coupling ofp A Reduction of TAC x R

B+ CF, ‘ =CF, NF oF XXXII XXX]

RrR' 1) Protection 2) Cyclization ofp £7 3) Deprotecti ! ) Deprotection R CF, N (1A)

Scheme IX

As depicted in Scheme IX, reaction ©fketone (IV) with sulfur ylide in a suitable solvent, such as DMSO, provides epoxide (V). Opening of epoxide (V) with a sui_ table acetylide reagent, such as lithium trimethylsilylacetylid_e (M is Li) in a suitable solvent, sLach as DMSO, followed by deprotection with a suitable fluoride source in a suitable solvent, affords alkyne (XXXD)-

Treatment of alkyne (XXXI) with ax suitsble coupling partoer, such as optionally substituted aniline or nitrobenzene (X is OT, I or Br) in the presence of suitz=able catalysts, base and solvent (e.g., dichlorobis(triphenylpwhosphine)palladium (II), Cul, triethylamine, and DMF) provides alkyne (XXXII). Reductio-n of intermediate (XXXII) with a suitable metal reducing agent, such as iron, in a suitable solvent, such as acetic acid, affords aniline (CXXID.

Protection of aniline (XXXII) with a suitable protecting group, such as trifluoroacetyl is well- known in the art and may be achieved by treatment with trifluoroacetic anhydride in a suitable solvent, such as dichloromethane. Whe resulting intermediate is cyclizzed with a suitable base, such as 1,1,3,3-tetramethyl guanidimne, in a suitable solvent, such as methanol, provides the trifluoroacetyl-protected indole, whi ch undergoes an in sifu deprotection of the acyl group to afford compound of Formula (IA).

Additionally, compounds of Formul=a (IA) where RAR’ is an optionally substituted azaindol-2- yimethy! group may be prepared by she procedure illustrated in Scheme= X.

NP Propar gylation NP Coupling

R CF, —— ——— R oF Tay, 3 a JS

Iv XXX] be

VY wR

Ca. 5

XO an cyaizaton RET 7 | Nz

R CF. H Nps R CF, N 3 3

X00 | 1) Deprotection A) 2) Cyclization

Scheme X

Ketone (IV) is treated with a suit=able propargylating reagent, such as propargyl aluminum sesquibromide, in a suitable solverat, such as THF, to furnish alkyn € (XXXI). Reaction of homopropargyl alcohol (XXXT) with a suitable coupling partner, such as optionally substituted and protected amino pyridines, optionally substituted and protected amineo pyrimidines or optionally substituted and protected amino py=ridazines, wherein one or tw~o atoms selected from A, W”,Y, and Z are nitrogens and the remaining atoxms are carbons, Xis lorBrandPGis

H or BOC (tert-butoxycarboyl), in the presencce of suitable catalysts, base =and solvent (e.g. dichlorobiss(triphenylphosphine)palladium (II), Cul, triethylamine, and DMEF") provides alkyne (XXXIV). Alkyne (XXXIV), where PG is HI, is converted to the corresponding optionally protected @zaindole or diazaindole of Formula A) by treatment with the suifikable base such as potassium tert-butoxide, in a suitable solvent, such as N-methyl pyrrolidimnone (NMP). In addition, alkyne (XXXIV) containing a N-BOC group is cyclized with a suitable base, such as 1,8-diazab-icycle[5.4.0lundec-7-ene (DBU), in a suitable solvent mixture, such as a mixture of water and methanol, to give the desired product of Formula (IA). Alternatively, the N-BOC protecting group of alkyne (XXXIV) may be removed by treatment with a suistable acid, such as

HC], in a ssuitable solvent, such as ethyl acetate, to provide the corresponding amine salt, which is cyclizecl in the presence of potassium tert-butoxide in NMP to provide the compound of

Formula (AA).

Moreover,. compounds of Formula (I) where R_'is an optionally substituted amryl group may be converted by the sequence illustrated in Scherre XI to compounds of Formumi{a (I) where Rlis further optionally functionalized. rR, RAR OH rR. RAR OH rR

IA& IC Tet Bag X20 wv i»

R= &r

J owns couping /

R' RR’ OH =

RY

R* IA&IC

Rr on TF

I

Schemme XI

As outlinec in Scheme XI, compounds of Formula (I) where R'is an optionally substituted aryl group in which one of the substituents is a suitamble coupling group, sucha as Cl, Br, I, or OTE, may be tre ated with a suitable coupling partner, such as a boronic acid oxx a boronic ester, in a suitable somlvent or a mixture of solvents, such as amixture of DME, meth=anol, and DMF, in the presence Of a suitable catalyst, such as tetral=is(triphenylphosphine)pa’lladium (0), with an appropriate base, such as potassium carbonate, at a suitable tempemcature and under an appropriates atmospheric environment, such as amgon, to give compounds of Formula (I) where

R'is furthest optionally functionalized. Alternatively, compounds of Formula (I) where R' is an optionally substituted aryl group containing a suitable group, such as Cl, Br, I, or OTf, is converted ®o its corresponding boronic ester (X>=XXV) by reacting with an= appropriate coupling partner, suach as his(pinacolato)diboron, under a suitable condition, such eas heating at 100°C in

DME wvith potassium carbonate amnd in the pressence of [1,1’- bis(diphen-ylphosphino)ferrocene]dichloropalladi un (II). Subsequently, the boronic ester of formula (3=XXV) may be converted to compounds of Formula (I) where R! is optionally functionalized by treating with a suitable aryl hallide, and under a suitable, previously indicated, coupling condition. The choice between the two described methods depends on the commercial or synthetiac availability of the coupling partner, which is up to the discre=tion of one skilled in the art.

As illustrated in Scheme XII, compounds of Formula (IA) where R*R® i_s a cyano-substituted azaindol-2—ylmethyl or a cyano-substituted indokE-2-ylmethyl may be converted to a compound of Formula (IA) where RR’ is optionally functiomnalized.

-CN x=(_ =,

R' on

X= C, YN, or

Reducter_- reovig” Ny . " so oe , R' on N Da R' on N t) rr

Rr

Hydrolysls oH Reduction

Q re ~~

OH

< x va 1 N 1 N rR oH 2 R OH h

Amt «do | . Oxidation

Formestion fo) rR" 3 =0

Dat =a 1 1 N

R oH i R oH mew x= "Re

R

R' OH Y,

Scheme XII

Compounds of Iormula (IA) where R°R® is a cyano-ssubstituted azaindol-2-ylmethsyl (X is a nitrogen and Y 1 sa carbon, or X is a carbon and Y is a xaitrogen) or a cyano-substitute «d indol-2- ylmethyl (X andl Y are carbons), may be converted to the corresponding ketone by treatment with a suitable osrganometallic reagent such as R’M, wiere M is Mgl, MgBr, MgCl, «or Li, and

R’ is alkyl, cycleoalkyl, aryl, heteroaryl), or heterocyclyl . Reduction of the cyano group with a suitable reducing agent, such as boraneemethyl sulfide complex, in a suitable solvert such as

THF, gives a cormpound of Formula (IA) bearing a 1° a—mine moiety. Moreover, the compound of Formula (IA) bearing a cyano group may be treated v=vith an alcohol, such as metharol, in the presence of an acid catalyst, such as HCI, to afford the corresponding ester. The resulting ester may be hydroly==ed by treatment with a suitable base, ssuch as lithjum hydroxide, in =a suitable mixture of solvents, such as a mixture of THF, water, amnd methanol, to provide a conapound of

Formula (IA) containing za carboxylic acid moiety. The resultings carboxylic acid of Formula (IA) can be converted to zn amide using standard peptide coupling conditions known to one skilled in the art. This tsansformation may be affected by treatment with a suitable amine ’ HNR”R™ and a suitable activating reagent, such as 1,3-dicyclolmexylcarbodiimide (DCC), in the presence of a suitable base, such as N,N-diisopropylethyl amime, in an appropriate solvent, such as DMF or acetonitrile. Alternatively, the compound of Formula (IA) bearing an ester group may be reduced by treatment with a suitable reducing agert, such as lithium aluminum hydride (LAH), in a suitable solvent such as THF, to furnisha the corresponding alcohol.

Oxidation of the resulting alcohol with a suitable oxidizing age=nt, such as manganese (IV) oxide, in a suitable solvent, such as acetone, gives the desired compound of Formula (IA) containing an aldehyde group. Such aldehyde may be converted to the corresponding amine by a method well-known in tlie art as reductive amination. This func=tional group inter conversion may be performed by reaction of an aldehyde with a suitable ami ne HNR”R™” in the presence of a suitable reducing agent, such as sodium triacetoxyborohydr—ide, and an appropriate acid catalyst, such as acetic acid, in a suitable solvent, such as 1,2-dichleoroethane.

Compounds of Formula (ID) may be prepared according to the procedure shown in Scheme

X11.

Q oa he She Reduction PS

XXXVI pee XXXIX XL

Hi ~—q

Reduction Pn Mel oF Oxidative

NaH Cleavage

XL Xu — - . H

San ChSMe, | RE oF, dation

TBAF

XLII Xuv

W © 2005/030213 PCT /US2004/031009 - AN 0 H > Rm Ee : CF,

XLV

(ID) : Scheme XITI

In Scheme XIII, nitrile (XXXVI) is treated with allyl bromide in the pre sence of a suitable base, such as sodium bis(trimethylsilyl3amide (NaHMDS), in a suitable solvent, such as

DMSO, to provide the corresponding nitrile (XXXIX). Reduction of the nigrile (XXXIX) with a suitable reducing agent, such as DIBAL , in an appropriate solvent, such a_s dichloromethane, affords aldehyde (XL). Aldehyde (XL) iss further reduced by reacting with a suitable reducing agent, such as lithium aluminum hydrides (LAH), in a suitable solvent, such as THF, to give alcohol (XLI). Reaction of alcohol (XII) with methyl iodide, in the presences of a suitable base, such as sodium hydride (NaH), in an appropriate sol vent such as DMF, prowvides ether (XLII).

Ether (XLII) is converted to aldehyde (LI) by oxidative cleavage meth ods well-known in the art, such as treatment with ozone, Reamction of aldehyde (XLII) with a sweiitable nucleophilic trifluoromethylating reagent, such as trEmethyl(trifluoromethyl)silane, in the presence of a fluoride source, such as tetrabutylammeonium fluoride (TBAF), provides alcohol (XLIV).

Subsequent oxidation of alcohol (XLIV) with a suitable oxidizing reagent, such as Dess-Martin periodinane reagent, provides trifluoromethyl ketone (XLV). Reaction of ketone (XLV) with a - suitable organometallic reagent R°R*M, -where M is Li or MgX, and X iss CL, Br, or I, in a suitable solvent, such ag THF, furnishes time compound of Formula (ID).

In order that this invention may be more fully understood, the following Exam mples are set forth,

These Examples are for the purpose of illiastrating embodiments of this inveration, and are not to be construed as limiting the scope of thee invention in any way since, as recognized by one skilled in the art, particular reagents or ceonditions could be modified as ne eded for individual compounds. Thus, while the Examples illustrate the synthesis of certain compounds of the invention or intermediates that may be used to synthesize compounds according to the invention, all of the compounds disclosed herein may be made by one or more methods disclosed herein, as one of skill in the art- would appreciate. Starting mater-ials used are either

. commercially available or easily prepared from commercially available materiamls by those skilled in tine art.

Experimexatal Examples

Example 1: Syntheses of (3-Iodopyridin-4-yl)ecarbamic acid terr-butyl esteer and (4- iodopyridi n-3-yl)carbamic acid terf-butyl ester

Q

H Jy Jie J 7

N =N

The title products were prepared according to the porocedure described by T.A. Ke=lly ef al, J.

Org. Chem, 1995, 60, p. 1875.

Example 2 : Synthesis of (2-Bromopyridin-3-yl)ca_rbamic acid rerz-butyl ester

N._ Br COH H (0) = AS ~

CC —CL — (Xr

N Br N Br 2-bromo-3-—methylpyridine (25.0 mL, 213 mmol) was added to a solution of potassium permanganate (87.7 g, 555 mmol) in 800 mL of water and thie mixture was stirred under reflux.

After 5 hovars, 600 mL of water was distilled off amnd the remaining suspension vevas filtered.

The residue= was washed with two 50 mL portions o—f hot water and the combined filtrates were acidified wi th concentrated HCl. The white precipit=ate was filtered and dried in a vesacuum oven to give 26.8 g of 2-bromonicotinic acid (62% yield).

Diphenylph-osphorylazide was added to a solution of ~ 2-bromonicotinic acid (15.0 g, “74.0 mmol) and triethyl=amine (11.4 mL, 81.4 mmol) in 140 mI_, of anhydrous fert-butanol. T he reaction mixture wass stirred under reflux for 2 hours, cooled” to roorm temperature, and concentrated in vacuo. The= residue was dissolved in 150 mL of ethyl acetate and washed with thmree 50 mL portions of water, three 50 mL portions of saturated maqueous sodium bicarbonate, ard with two 50 mL portions of brine. The organic layer was dried Over magnesium sulfate- (MgSOy), filtered, and concentrated in vacuo. The residue crystallized upon standing to give 15.3 g of the title product (76% yield).

Example 3: Synthesis of 4-Amino-3-iodo-2-methylpwyridine and 4-Amino—3-iedo-6- methylpyridine

NO», NH, NH, NH ) x 0— Qo CC A

NT N N

. le} ) ot 5 A solution of 2-methy 1-4-nitropyridine-N-oxide (3.80 g, 24. 6 mmol) in 100 mL of amcetic acid

Co was slowly heated with iron powder (6.89 g, 124 mmol) in a large flask (caution: th_e reaction : becomes very exotherrmic upon turning brown). The resultitag slurry was heated for 2 hours at ’ ) 80°C. Excess acetic zacid was removed in vacuo, the residue was taken up in 20%=% aqueous : sodium hydroxide soliation, and 100 mL of chloroform (CIHCl;) was added and th _e mixture } 10 filtered through CELI"TE® filter aid. The aqueous phase was extracted with twos 200 mL portions of chloroform. The combined organic layers wee dried over magnesiurm sulfate, filtered, and concentra-#ed in vacua. The crude product (2.2 g, 83% yield) was use«d without further purification.

A solution of KI (1.96 g, 11.9 mmol) and I, (1.87 g, 7.36 mxmol) in 10 mL of water vewas added to a refluxing solutiora of the 2-methylpyridin-4-ylamine (1.00 g, 9.25 mmol) aned sodium carbonate (683 mg, 6.214 mmol) in 5 mL of water. The nmixture was heated at reflux for 2 hours, cooled to room temperature, and treated with 20 mI. of ethyl acetate (EtOAc). Phases were separated and the aqueous layer was extracted with thre=e 20 mL portions of ethy1 acetate.

The combined organic layers were washed with a saturated aqueous sodium timiosulfate (Na;S03) solution, dxied over magnesium sulfate, and concentrated in vacuo . Flash chromatography (30% ethyl acetate in hexanes to 100% ethyl acetate, gradient) of the resulting residue yielded 4-amin o-3-iodo-6-methylpyridine (first elut3ng: 226 mg, 11% yield) and 4- amino-3-iodo-2-methylpoyridine (second eluting: 116 mg; 5%6 yield).

Example 4: Synthesis Of 4-Amino-3-bromo-2,6-dimethylpy-ridine

NO, NH, NH,

OL — 0 — nN NT Nig lo}

A solution of 4-nitro-2,6-dimethylpyr-idine-N-oxide (11.0 g, 65.4 mmol) in 50 mL of acetic acid was treated with iron powder (21.8 g 390 mmol) in small portions —while the mixture was rapidly stirred and gradually heated to 50°C (caution: the reaction becoxrmes very exothermic at this temperature). After the exotherrm ceased, the mixture was heated for an additional hour at 80°C. The resulting solidified mixtur-e was treated with 50 mL of water zand the suspension was ) filtered through CELITE® filter aid. The filtrate was treated with ca. 200 mL of 6 N sodium hydroxide solution until the pH of the= solution was basic (>12). The resulting green suspension was extracted with three 300 mL pomtions of chloroform. The extracts were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo to give yell owish crystals (5.70 g, 71% yield).

A solution of 2,6-dimethylpyridin-4-=ylamine (2.00 g, 16.4 mmol) in 5 mL of acetic acid was treated dropwise with a solution of t»romine (0.84 mL, 16.3 mmol) in 22 mL of acetic acid at room temperature in a water bath oven a period of 10 minutes. After 1 how, the resulting slurry was treated with 40 mL of 20% sodium hydroxide solution and extract=ed with three 100 mL portions of dichloromethane (CH2Cls). The combined extracts were Clried over magnesium sulfate, filtered, and concentrated #7e vacuo. The resulting solid (stamrting material~desired product-dibromo byproduct (1:3:1)) was dissolved in 100 mL of hot hexamnes and hot filtered to remove the insoluble starting materiall. The filtrate was allowed to cool to room temperature, which gave the title product as fine white needles (1.30 g, 40% yield).

Example 5: Synthesis of 4-Amino-3-Tbrome-6-cyano-2-methylpyridine-

NO, NO , NH, NH,

QQ (— LX «> = — = 3 ZN NZ oN NZ n 4-Nitropicoline-N-oxide (10.0 g, 64.9 mmol) and dimethylsulfate (6.39 rxL, 64.5 mmol) were heated at 70°C for 6 hours under a nitrogen gas (N,) atmosphere. The dark brown mixture, which solidified upon cooling to room temperature was dissolved in 20 nal of water, cooled to

-10°C winile vigorously stirring, and treated dropwise with a solution of KCI (5.04 g, 77.4 mmol) ira 20 mL of water. The mixture was waumed to room temperature eovernight. The resulting black heterogeneous mixture was dissolwed in 50 ml. of ethyl acetate and 50 mL of water. “The phases were separated and the aqueous layer was extracted with two 50 mL

S portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (20% to 50% ethyl acetate in hexanes., gradient) afforded the product as a brown solid (2.80 g, 27% yield). 2-Cyanc-6-methyl-4-nitropyridine (1.9 g, 11.6 mxmol) in a mixture of 50 mL osf ethanol and 15 mL of ssaturated aqueous ammonium chloride (NEC) solution was heated wit¥h indium powder (7.00 g, 60.9 mmol) to 60°C for 3 days. 20 mL of water was then added, ard the slurry was ’ filtered through CELITE® filter aid and the pad was washed with methanol. The filtrate was concentrated in vacuo to remove volatile organics and extracted with three 2@0 mL portions of dichloromethane. The combined extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on SiO (30% ethyl acetate in hexanmes to 100% ethyl acetate, gradient) gave the product as a tan solid (C580 mg, 27% yield). 4-Amirn0-6-methylpyridine-2-carbonitrile was converted to the title produmct in 57% yield according to the procedure described for the preparation of 4-arrmino-3-bromo-2,6- dimeth-ylpyridine.

Example 6: Synthesis of 5-Amino-6-bromopyx-idine-2-carbonitrile

NH,

NN Br x

CN

5-Ami_mopyridine-2-carbonitrile (2.38 g, 20 mmol) was dissolved in 6 mL of : glacial acetic acid. : 25 A soltation of bromine (1 mL, 20 mmol) in 2.5 mL of glacial acetic acid w=as added dropwise : over a. period of 30 minutes while the room temgoerature was maintained with a water bath. The resulti_ng slurry was stirred for 1 hour at room temperature, treated with 50 xml of aqueous 20% sodiurm hydroxide solution and extracted with three 160 mL portions of dichmloromethane. The combined organic layers were dried over sodiurm sulfate (Na; SO.), filtered, amnd concentrated in vacuo. The residue was purified by crystallization frorm ethyl acetate-hexanes to give ZS-amino- 6-bromopyridine=-2-carbonitrile (1.42 g, 35% yield).

Example 7: Symthesis of (6-Cyano-4-iodopyridin-3-y/carbamic acid tert-butyl estex

CN

I —o" — \ 4 t

JK <> ~

I -— BY a HN >

LR SEES

(4-Xodopyridin-3 -yl)carbamic acid tert-butyl ester (3.2 g, 10 mmol) was dissolved in 130 mL of dimethoxyethane= at room temperature. m-Chloropero xybenzoic acid (77% by weight=, 3.36 g, 15 mmol) was added and the reaction was stirred overnight at room temperature. The= mixture was concentrateed in vacuo, redissolved in 400 mL. of ethyl acetate, and washed with two 200 mL portions of saturated sodium bicarbonate (NaXIC(,) solution. The phases were s-eparated and the aqueous layer was extracted with two 100 mL portions of ethyl acetate. The ceombined organic layers were washed with brine, dried o-ver magnesium sulfate, filtered, and concentrated in —vacuo. Crystallization from ethyl ace-tate-hexanes gave (4-iodo-1-oxy-pyridin- 3-yl)carbamic ac=id tert-butyl ester (2.65 g, 79% yield).

A mixture of (<%-iodo-1-oxypyridin-3-yl)carbamic acmd tert-butyl ester (2.65 g, 7.6 mmol), trimethylsilyl cyanide (4 mL, 30 mmol), triethylamin e (2.6 mL, 18.9 mmol), and 40 mL of anhydrous acetomitrile was heated at 90°C for 2.5 hours. The mixture was concenfitrated in vacuo, diluted with 500 mL of dichloromethane, and treated with saturated aqueous sodium carbonate (NaC ©) solution until the aqueous layer vwas basic. After phases were se=parated, the organic layer~ was washed with brine, dried over sodium sulfate, filtered, and concsentrated in vacuo. Chrommatography on SiO, (2:98 to 8:92 et-hyl acetate-hexanes, gradient) gave (6- cyano-4-iodopyradin-3-ylcarbamic acid tert-butyl ester (185 mg, 7% yield).

Example 8: Synthesis of (2-Cyano-3-iodopyridin-4-y X)carbamic acid zers-butyl estex—

HN K ~) 5

A Ii

PS 5 (3-Todopyridin-4-=yl)carbamic acid tert-butyl ester (3.2 gg, 10 mmol) was dissolved &n 100 mL of dimethoxyethane at room temperature. m-Chloroperox =ybenzoic acid (77% by we=ight, 3.36 g, 15 mmol) was added and the reaction was stired Oo ~vernight at room temper=ature. After removing the solvent in vacuo, the residue was disscslved in 400 mL of ethyl acetate and washed with two 200 mL portions of saturated aquecwus sodium bicarbonate solution. The phases were sepa—xated and the aqueous layer was extrac=ted with two 100 mL portions of ethyl acetate. The conmbined organic layers were washed wit=h brine, dried over magnessium sulfate, filtered, and conc entrated in vacuo. Crystallization from ethyl acetate-hexanes ga~ve (3-iodo-1- oxypyridin-4-yl)c=arbamic acid tert-butyl ester (1.95 g, 5 &3% yield).

A mixture of (3—iocdo-1-oxypyridin-4-yl)carbamic acid tert-butyl ester (1.95 g, 5.79 mmol), trimethylsilyl cycanide (3 mL, 23 mmol), and triethylar—mipe (2 mL, 14.5 mmol) in 30 mL of anhydrous acetortitrile was heated to reflux at 90°C For 2.5 hours. The solvesnt was then removed in vacuo. The residue was diluted with 500 ram 1 of dichloromethane anc treated with saturated aqueouss sodium carbonate solution until the aqueous layer was basic. The phases were separated ard the organic layer was washed with bmine, dried over sodium su 1fate, filtered, and concentrated in vacuo. Chromatography on SiO (2:98 to 8:92 ethyl ace=tate-hexanes, gradient) gave (2—cyano-3-iodopyridin-4-yljcarbamic aci_d tert-butyl ester (1.22 g, @®61% yield).

Example 9: Synthesis of 5-amino-6-bromo-2-methoxy= pyridine

POA

ZZ

HN

A stirred mixtur e of 2-methoxy-5-aminopyridine (10 g, 0.081 mol, 1.0 equivI® and sodium acetate (6.6 g, 0.0081 mol, 1.0 equiv) in 60 mL of acetic acid was treated dropwise with bromine (12.9 g, 0.081 muol, 1.0 equiv). After 20 minutes, the meaction mixture was pouzxed into 1000 mL of 10% aqueous sodium hydroxide solution and extmracted with three 250 mL portiomus of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered , and evaporated to dryness. Chromatography on SiO; (20% hexanes in dichloromethane) ga=ve 5- amino-6-bromo-2-methoxypyridine (6.5 g, 40% yield) as =a purple solid.

Example 10: Synthesis of (4-Iodo-6-phenylpyridin-3-yR)carbamic acid zerz-butyl ester

Ph oe be

Ch— CTL, Ye, on ) on’ J ° NZ ph © N” “Ph

A mixture of Pd(PPhs)s (354 mg, 1.58 mmol), 2-chloro--5-nitropyridine (5.00 g, 31.5 nmmol), and phenyKboronic acid (4.61 g, 37.8 mmol) was degas=sed and filled with nitrogen gas three times. The mixture was treated with 40 mL of DME aand aqueous 2 M potassium cartoonate (80.0 mmo) solution and heated to reflux. After 4 hous, the reaction mixture was cooled to room temprerature and diluted with 100 mL of ethyl ace=tate and 50 mL of water. The phases were separ ated and the aqueous layer was extracted with three 100 mL portions of ethyl acetate.

The combined organic layers were washed with 100 mL of brine, dried over magneesium sulfate, filtered, and concentrated in vacuo. Chromatogr=aphy on SiO; (0% to 50% ethyl acetate in hexanes, gradient) give 4.60 g of 5-nitro-2-phenylpyricline (73% yield).

A solution of 5-nitro-2-phenylpyridine (4.60 g, 23.0 mmol) and BOC anhydride (15.0 gz, 68.9 mmol) in a mixture of 25 mL of methanol and 25 ral of ethyl acetate was treated with } 20 palladium (10% on carbon, 500 mg). The resulting mixture was shaken under 50 —psi of hydrogen gas (1) at room temperature. After 18 hours, the mixture was diluted with 20 mL of dichloromethane, filtered through a pad of CELITE® filter aid, and concentrated in vacuoms. The resulting solid was triturated with ethyl acetate, filter-ed, and dried to give 5.54 g eof (6- phenylpyri din-3-yl)carbamic acid zerz-butyl ester as whitee solid (89% yield).

A solutionn of (6-phenylpyridin-3-yl)carbamic acid ferr—-butyl ester (5.54 g, 20.5 mmo}) and

TMEDA (6.49 mL, 43.0 mmol) in 100 mL of anhydrouss diethyl ether was treated with »=-Buli at -78°C. After 15 minutes at -78°C, the mixture wass warmed to -10°C and stirred —for an additional 3 hours. The reaction mixture was then coolewd to -78°C and a solution of iodirae in a mixture of 10 mL of THF and 100 mL of diethyl ether was added dropwise. After 2 heours at -78°C, the mixture was allowed to warm to 0°C and wass quenched with 400 mL of sawturated . aqueous ammonium chloride solution. The organic lamyer was washed with five 100 mL portions of saturated aqueous sodium thiosulfate. The commbined aqueous layers extracte=d with three 200 mL portions of ethyl acetate. The combired organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on SiO, (0% t=c 70% ethyl acetate in hexznes, gradient) afforded 900 mg of” the title product as yellow oil that solidified over time ( 11% yield).

Example 11: Synthessis of (4’-Iodo-3,4,5,6-tetrahydro-22H-[1,2’1bipyridinyl-5’-yl)car-bamic acid tert-butyl ester % i oN o®

QL, — ~ (A—

NT a ~~ 7) ~F be o_kN oH ro — Yo

N i$ N iQ 2-Chloro-5-nitropyridtine (10 g, 63.3 mmol) was dissolv=ed in 150 mL of THF. 20 mmL of piperidine was then added and the resulting mixture was stirred for 18 hours at room temperature. The reaction mixture with copious precipit=ate was then diluted with 200 mL of water and 100 mL off diethyl ether. The layers were theoroughly mixed and separated. The organic layer was drieed over sodium sulfate and concentrasted in vacuo. The bright yellover solid was redissolved in 35 mL of dichloromethane and, with v_igorous stirring, hexanes were added until the product begean to precipitate. The bright yellow solid was collected by filtratican and dried to afford 12.5 g «of 5°-nitro-3,4,5,6-tetrahydro-2H-[ 1,22’ ]bipyridinyl. 5°-Nitro-3,4,5,6-tetralm ydro-2H-[1,2’Jbipyridinyl (12.5 g, 6#0.4 mmol) was suspended in 125 mL of methanol in a Parr =shaker bottle and 16 g of di-tert-buty—Idicarbonate was added, follow=ed by 500 mg of platinum oxide. The resulting mixture was shalicen under 55 psi of hydrogen g-as for 2 hours, followed by stirring under argon overnight. After 16 hours, the mixture was fi ltered through a pad of diatomaceous earth and concentrated Zn vacuo. The crude residllue was triturated with hex=anes and filtered. Chromatography on silica gel (100% dichloromet=hane to 30% ethyl acetate in dichloromethane, gradient) provided 6.9 g (41.2% yield) of (34,5,6- tetrahydro-2£-[1,2 ’Jbipyridinyl-5’-yl)carbamic acid fert-butyl ester as a white solid.

The title product was prepared from (3,4,5,6-tetrahydro—24-[1,2’Jbipyridinyl-5’-yl)c=arbamic acid tert-butyl ester in the same manper as described in the preparation of (4—iodo-6- ’ phenylpyridin-3-yl_)carbamic acid tert-butyl ester.

Example 12: Synthesis of 4-[(tert-Butoxycarbonyllamino]-3-iodo-2-methoxypyridinme ~~ r 4-Amino-2-chlorogpyridine (15 g, 117 mmol, 1.0 equiv) was dissolved in 100 mL of WHF. A } solution of sodiurr1 methoxide in methanol (1.0 M, 234 mT, 234 mmol, 2.0 equiv) waas added and the resulting solution was refluxed for 16 hours. The reaction mixture was poured .into 500 ; 15 mL of a rapidly swing saturated sodium bicarbonate solution. 500 mL of ethyl acetate was added and the layers were separated. The organic layer was dried over sodium sulfate, decanted, and conecentrated in vacuo. Chromatography on SiO; (30% ethyl acetate in kexanes) provided the titled compound as a yellow solid (2.1 g). 4-amino-2-methoxzypyridine (2.1 g, 16.9 mmol, 1.0 equiv’) was dissolved in 35 mI. of ethyl acetate. BOC anhydride (5.4 g, 25.4 mmol, 1.5 equiv) was added and the resulting solu—tion was refluxed for 3 hovars. The reaction was cooled and concentrated in vacuo. The resi_due was triturated with 1000 mL of hexanes to give an off-white precipitate that was collected a_xnd dried under vacuum to geive the titled product (1.8 g).

A solution of 4-[(zert-butoxycarbonyl)amino]-2-methoxypsyridine (1.8 g, 8.03 mmol, 1. 0 equiv) in 100 mL of anhydrous diethyl ether was treated with 2.79 mL of N,AAN’N’- tetramethylethyleraediamine (18.5 mmol, 2.3 equiv) under an inert atmosphere. The mresulting solution was coole=d to -78°C, treated with n-Bulii (2.5 M, 7.2 mL, 18.0 mmol, 2.24 eq _uiv) and warmed to -7°C. The mreaction was stirred at -7°C to 0°C for 3 hours, cooled to -78°CC and

R treated with a solution o=f iodine (3.05 g, 12 mmol) in 30 mI. of anhydrous THF. The resulting mixture was stirred to rosom ternperature for 16 hours. 200 mM. of saturated ammonium chloride

Ce solution and 100 mL of~ diethyl ether were added. The phasees were separated and the or-ganic

CL 5 layer was washed with. 100 mL of sodium thiosulfate (108% aqueous solution), dried=. over sodium sulfate, decanteed, and concentrated in vacuo. (Chromatography on SiO; ( 100% dichloromethane to 5% methanol in dichloromethane, gradiemnt) provided the title product (650 mg, 23% yield) as a whi_ te wax.

Example 13: Synthesis of 5-[(tert-Butoxycarbonyl)amino]--~4-iodo-2-(isopropoxy)pyridiline es 0 or

A mixture of 2-chloro-S -nitropyridine (15 g, 95 mmol) and 28 mL of isopropyl! alcohol (366 mmol) in 100 mL of saxhydrous THF was stirred until thes solids dissolved. The res=ulting solution was cooled in =n ice bath and treated dropwise witkn potassium fers-butoxide (1 Min

THF, 115 mL, 115 mrxol) over 45 minutes. The reaction was quenched with 75 ml of saturated aqueous ammonium chloride solution and diluted vevith 100 mL of ethyl acetate . The phases were separated znd the organic layer was dried over= magnesium sulfate, filtered, and concentrated in vacuo. This residue was triturated witch hexanes and stirred at room temperature overnight. The mixture was filtered and the filt rate was concentrated in vacuo to yield 15.7 g of dark orarage oil that was used in the next step v=vithout further purification. 5-pitro-2-isopropoxypyr idine (15.7 g, 86 mmol) was dissolved in 125 mL of methanol and transferred to a Parr bottle. Palladium (10% on carbon, 1.5 7 g) and BOC anhydride (2 82 g, 129 mmol) were added. The resulting mixture was shaken on a Parr shaker under 50 —psi of hydrogen gas ovemight. The mixture was treated with 5 gg of CELITE® filter aid, fi ltered through a pad of CELI"TE® filter aid and concentrated in wwacuo. Chromatography on_ SiO, (hexanes-ethyl acetate (9:1)) yielded a pink solid (16.1 g=). This solid was dissolv—ed in dichloromethane, treatecd with hexanes, and filtered to give 135.7 g of the title product asa white solid.

A solution of 13.7 g of 5-[(tert-butoxycarbonyl)amin_o]-2-(isopropoxy)pyridine (54.3 mmol) and 18.1 mL of N,JNN ,N-tetramethylethylenediamine= (120 mmol) in 200 mL of ashydrous diethyl ether was cooled to -78°C and treated with r -BuLi (2.5 M in hexanes,.. 48 ml, 120 mmol) under an inert atmosphere. The mixture was placed in a -8°C bath foer 1 hour and allowed to slowly wrarm to room texmperature. After 4-0 minutes, the flask was ¢-ooled to -8°C and stirred for 4 hotnrs. The mixture was then cooled to -78°C, treated with a solu_tion of iodine

B (19.0 g, 75 mmol) im 100 mL of anhydrous THF, and the resulting mixture was stirred for 16 hours while allowing the bath to waxm to 11°C. The resaction mixture was poured into a rapidly stirring aqueous saturated ammonium chloride solutior (200 mL) and diluted wi—th 100 mL of water and 300 mL of diethyl ether. The phases wer € separated and the aqueous layer was extracted with 200 xxl of diethyl ether. The combine d organic layers were was=hed with two 200 ml, portions off sodium thiosulfate (10% aqueous solution), dried over so=dium sulfate, decanted, and concesntrated in vacuo. Chromatographs on SiO; (10% to 50% et"hyl acetate in hexanes, gradient) gzave the title product as an oil, whhich solidified on standingz (13 g, 63% yield).

Example 14: Synthesis of 4-Amino-3-bromopyridazimne and 4-Amino-S-bromeo pyridazine r

Ch RO — Nt PO:

B

50 mL of ammonia wvas condensed in a 200 mL, 3-necks flask equipped with dry iece condenser.

After the addition of” a crystal of Fe(NO,)s, potassium (<468 mg, 12.0 mmol) was aedded in small pieces at -78°C. The cooling bath vwas removed and thes intense dark blue mixtures was brought to a gentle reflux until a light grey slurry was obtained. After cooling to -78°C, 0 .35 mL (4.80 mmol) of pyridazinee was added and the mixture was stirred for 10 minutes. Solid KMnO, (2.65 g, 16.8 mmol) was added in small portions, thee cooling bath was remo—ved, and the mixture was stirred For 10 minutes. The reaction was carefully quenched with 1_.2 g of solid ammonium chloride. 20 mL of methanol was added amd the ammonia was left to evaporate in the hood. The black mixture was filtered through CELITE® filter aid, the filtrate was concentrated in vacuo, and the resulting black solid was purified on SiO, (100% CEIL,Cl, to 10%

MeOH in CH;Cl,, gradient) to yield pyr-idazin-4-ylamine as a brownish solid (380 mg; 83% yield).

B3romination of pyridazin-4-ylamine was performed in the same manner as for the preparation of 4-amino-3-bromo-2,6-dimethylpyridim e. Chromatography on SiO; (20% ethyl acetate in bmexanes to 100% ethyl acetate, gradient, followed by 2% methanol in ethyl acetate) yielded 4- ammino-3-bromopyridazine (first eluting: 15% yield) and 4-amino-5-bromopyridazine (second e=luting: 5% yield) as tan solids.

Example 15: Synthesis of 5-Amino-4-br-omopyrimidine 0 . HN PN HN ee : cl Br 2 solution of 5-amino-4,6-dichloropyrimmidine (5.0 g, 30.5 mmol) in 250 mI . of diethyl ether . vevas treated with sodium hydroxide solution (20.0 g, 0.50 mol, in 60 mL of water) and palladium (10% on carbon, 400 mg). Thee mixture was shaken at room temp-erature on a Parr sThaker under 50 psi of hydrogen gas for 220 hours. The mixture was filtered timrough CELITE® falter aid. The phases were separated anc the aqueous layer was extracted with three 100 mL portions of ethyl acetate. The combinec organic layers were dried over mamguesium sulfate, a faltered, and concentrated in vacuo. Coxystallization of the crude from ethhyl acetate gave p yrimidin-5-ylamine as white crystalline solid (2.8 g; 95% yield).

Beromination of pyrimidin-5-ylamine was performed in the same manner as for the preparation of 4-amino-3-bromo-2,6-dimethylpyridines. The resulting crude product (300 mg, 35% yield) w~as deemed pure and used without further- purification.

A lternatively, 5-amino-4-bromopyrimidirae can be synthesized according to the following procedure: A solution of 4,6-dichloro-5—aminopyrimidine (21 g, 128 mmol?) in 250 mL of

M1eOH was sequentially treated with ammonium formate (45 g, 714 mmol) and_ palladium (10% oma charcoal, 1 g, 0.943 mmol) at 0°C. Tiae mixture was stirred overnight at room temperature arad was filtered through CELITE® filter aid. The filtrate was concentrated ®o give a yellow solid. 100 mL of water and 250 mL of ethyl acetate were added. The organic phase was separated and the aqueous layer was extracted with eight ~250 mL portions of ethyl aczetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to yield off-white crystals (8.1 g, 67%).

A stirred solutiom of 5-aminopyrimidine (3.0 g, 31.5 moomol) in 150 mL of dichlromeethane and 30 mL of methariol was cooled to 0°C. Benzyltrimethyw/lammonium tribromide (13.5 g, 34.7 mmol) was added in portions over a period of 10 minutes. . Stirring was continued at <0°C for 15 minutes and at room temperature for 90 minutes. Theme reaction mixture was treated with aqueous sodium bicarbonate solution until the solution was pH 8. The organic layer was separated and aguieous layer was extracted with three 3-0 mL portions of ethyl acetate. The combined organics extracts were dried over sodium sulfate, filtered, and concentrate in vacuo.

An off-white solid (2.8 g; 51%) was obtained, which was —used without further purification.

Example 16: Syn thesis of 4-Amino-5-iodopyrimidine ( IN xX;

H,N N

A solution of 4-amninopyrimidine (0.970 g, [0.3 mmol) in 20 mL of acetic acid was treated with iodine monochloride (1.67 g, 10.3 mmol, 1.01 equiv), winch gave a copious precipi®ate of the

N-iodo intermediate. The resulting mixture was refluxed for 3 hours under argon and_ cooled to about 10°C with water bath. A precipitate formed that w=as collected and dried to pmovide the title compound as a yellowish solid (1.4 g, 62% yield).

Example 17: Synthesis of 2,2,2-Trifluoro-N-(4-iode-2-is opropylpyrimidin-5-yacetamide

Og, +0 Og, +-O

CNS CNP N o Ae

No A AY — re MN Na oN : SES Gl ¢

NH NH i aed TTT Re No A

SO

Ethylnitroeacetate (11.7 mL, 105 mmol) was added slowly to a stirred solution of dimethyl formamide dimethyl acetal (29.2 mL, 220 mmol). The resulting reddish mixture wems kept at room temyperature for 2 hours, heated in an oil bath at 100°C for 90 minutes, and cooled to room temperature. The mixture was concentrated in vacuo to remove volatile organicss and the resulting mresidue was heated at 60°C for 1 hour. A mreddish orange liquid was obtairmed (18 g, ~100% yi eld), which was used in the next step without purification.

To a stirred solution of 3-dimethylamino-2-nitroacryRic acid ethyl ester (3.8 g, 20 mmol) in 50 mL of amhydrous ethanol was added isopropyl ammidine hydrochloride (3.1 g, 225 mmol) followed by triethylamine (2.5 mL, 25 mmol). The resulting mixture was heated at S2¢°C for 6 hours. After cooling to room temperature, the mixtur € was concentrated ir vacuo and the crude was purified on SiO; (3% methanol in dichloromethane) to give 3.1 g of a brownish. oil (84% yield).

A suspen sion of 2-isopropyl-5-nitro-3H-pyrimidin-4—one (1.55 g, 8.5 mmol) and triesthylamine (1.4 mL, 10 mmol) in 10 mL of dichloromethane vas cooled in an ice bath. A seolution of phosphorus oxychloride (1.9 mL, 20 mmol) in 5 mL of dichloromethane was added sleowly over a period of 5 minutes, and the resulting mixture was stirred for 90 minutes. The= resulting mixture wvas diluted with dichloromethane, quench ed with ice, sequentially washed with a saturated sodium bicarbonate solution and water, dried over sodium sulfate, filtered, and concentreated in vacuo to give 0.7 g of brownish oil (41% yield), which was use d without further pvarification.

A stirred. solution of 4-chloro-2-isopropyl-5-nitropyrimidine (0.7 g, 3.5 mmol) in 10 mL of absolute zalcohol and 5 mL of glacial acetic acid was treated with iron powder and thme mixture was heated at 90°C for 20 minutes. After cooling &o room temperature, the reactio-n mixture was diluted with 200 mL of dichloromethane, sequaentially washed with a saturate=d sodium bicarbonate solution Zand water, dried over sodium sulfate, filtered, and concentrate=d in vacuo to give 450 mg of light brownish oil, which was used withoumt further purification (75=% yield).

A stirred mixture of 4&-chloro-2-isopropylpyrimidin-5-ylarnine (450 mg, 2.6 mmol) in 10 mL of a solution of HI (40% aqueous) was treated with Nal (1.97 g, 13.1 mmol). ~The resulting mixture was stirred at room temperature for 2 hours anc poured onto dichloron—ethane. The phases were separate]. The organic layer was washed wit-h aqueous sodium carbo~nate solution, aqueous sodium bisulfite solution, and water, dried over sodium sulfate, filtered, and concentrated in vacieo to give 600 mg of brownish oil, which was used wiathout further purification (87% yield).

A stirred solution of <4-iodo-2-isopropylpyrimidin-5-ylam ine (600 mg, 2.28 mmol) in 4 mL of anhydrous dichloromethane was treated with a solution of ~ trifluoroacetic anhydridee (0.43 mL, 3 mmol) in 2 mL of dichloromethane at room temperature . After 15 minutes, the mixture was concentrated in vacuo to give 0.8 g of brownish oil which solidified upon stancling and was used without purification (quantitative yield).

Example 18: Synthesis of 4-Bromo-6-phenylpyridazin-=3-ylamine rf

H,N Sy 4-Bromo-6-phenylpyriidazin-3-ylamine was prepared according to the procedure described in

M. Bourotte, N. Pellegrini, M. Schmitt, and J.-J. Bourguignon, Syn. Lett, 2003, 10, pp. 1482- 1484.

Example 19: Synthesis of (4-Todo-6-triffuoromethylpymridin-3-yl)carbamic acid ferr-butyl ester

A, ZN

PS "

A solution of 6-trifluoromethyiraicotinic acid (1.0 g, 5.23 mmob), diphenylphosplorylazide (1.36 mL, 6.3 mmol), and triethylamine (1.83 mL, 13.1 mmol) in M5 mL of anhyddirous tert- butanol was heated at reflux under nitrogen gas for 5 hours. The rea ction was cooleed to room temperature and concentrated jn vacuo. 150 mL of water was adcded and the mixture was extracted with two 150 mL portions of ethyl acetate. The combilined organic lawyers were washed with 150 mL of water, 15 O mL of saturated aqueous sodium bwicarbonate solut—ion, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude. mixture was purified on : SiO, (10% ethyl acetate in hexanes) to yield the title product (0.90 g, 6% yield).

A solution of (6-trifluoromethylpsyridin-3-yl)carbamic acid tert-butyl mester (0.90 g, 3.443 mmol) and NNN’ N’-tetramethylethyleriediamine (1.29 mL, 8.55 mmol) in 25 mL of a.whydrous diethyl ether was cooled to -78°«C under an argon atmosphere. Tle resulting mixture was treated dropwise with #-BuLi (2.5 M in hexanes, 3.42 mL, 8.55 mmoMR) over 5 minutess, and the mixture was allowed to warm to - 10°C, After 30 minutes, the mixture= was cooled to —78°C and asolution of I (1.14 g, 4.5 mmol) in 5 mL of anhydrous THF was add_ed rapidly. The resulting mixture was warmed to room texrmperature, stirred for 1 hour, and cquenched with S50 mL of water. The organic layer was dried over sodium sulfate, filtered, an_d concentrated an vacuo.

The crude mixture was purified ox SiO; (10% ethyl acetate in dichlomromethane) to aafford the title compound (150 mg, 11.3% yield).

Example 20: Synthesis of (4-Iodo»-2,6-dimethoxypyridin-3-yljcarba-mic acid zerz-bumtyl ester ~ ~

BE vet oO ) ZZ oo”

The title product was prepared froan 2,6-dimethoxynicotinic acid in th _e same manner as in the preparation of (4-iodo-6-trifluoromy ethylpyridin-3-yl)carbamic acid zere—butyl ester.

Example 21: Synthesis of (6-Chloro-4-iodopyridin-3-yl)carbamic ac=id fert-butyl est_er

’ 0

Tt lo) i 7 cl

The title product was prepared from 6-chloronicotinic acid in the same manner as in the ’ preparatiosn of (4-iodo-6-trifluoromethylpyridin-3-yl )carbamic acid tert-butyl ester.

Example 22: Synthesis of (2,6-Dichloro<4-iedopymridin-3-yl)carbamic acid ferr-bu_tyl ester +o oN

TN

0] i # Cl : The title product was prepared from 2,6-dichloromicotinic acid in the same manne=r as in the preparation of (4-icdo-6-trifiuoromethylpyridin-3-yX)carbamic acid zers-butyl ester.

Example 23: Synthesis of (4-Jodo-5-methylpyridi n-3-yl)carbamic acid zerz-butyl ester

Y

RAR

&] | =

The title product was prepared from 5-methylnicotinic acid in the same mannemr as in the preparation of (4-iodo-6-trifluoromethylpyridin-3 -yX)carbamic acid tert-butyl ester.

Example 24: Synthesis of (2-Fluore-4-iodopyridim-3-yl)carbamic acid tert-butyl eester

NE Co 0 | =

TWO 2005/030213 PCT/US2004/031009

The title product was prepareci from 2-fluoronicotinic acid ir the same manner as in time preparation of (4-iodo-6-trifluor<omethylpyridin-3-yl)carbamic acid tert-butyl ester.

Example 25: Synthesis of N-(4 —Bromo-2-iocdophenyl)b enzenessulfonamide

Ph 2 N_ 2 ~a” 0 — 0 — CF 0 0]

Br 1 Br i B )

A solution of 4-bromo-2-iodoaniline (8.5 g, 28.5 mmol) in 20 © mL of dichloromethane w-as sequentially treated with benzemesulfonyl chloride (15 mL, 1175 mmol) and triethylamine (25 mL, 179.6 mmol). After 4 days, the mixture was diluted witha 100 ml of saturated aquecwus sodium bicarbonate solution amd extracted with three 100 mL portions of ethyl acetate. T he combined organic layers were washed with 50 mL of brine, thr—ee 60 mL portions of saturated aqueous ammonium chloride solution, dried over magnesium sialfate, filtered, and concentraged in vacuo. The crude product was triturated with diethyl ether —to afford 5.74 g (35% yield) of

N,N-bisbenzenesulfonyl-(4-bro 1mo-2-iodoaniline).

A solution of tetrabutylammon jum fluoride (1 M in THF, 11 mM) in 30 mL of THF was treated with N,N-bisbenzenesulfonyl-(4-bromo-2-icdoaniline) (5.78 g, 10 mmol) in several portio-ns.

After 18 hours, the mixture waas diluted with of 40 mL of ethyl acetate and 40 mL of 1 N HCL

The phases were separated an_d the aqueous layer was extracted with two 40 mL portions. of ethyl acetate. The combined owrganic layers were washed with #wo 20 mL portions of 1 N HCC], two 20 mL portions of saturated aqueous sodium bicarbonate solution, 20 mL of brine, dried over magnesium sulfate, filtereed, and concentrated in vacuo to afford 3.95 g (90% yield) of the title compound as a solid, which was used without further purification.

Example 26: Synthesis of Triifluoromethanesulfonic a eid 3-fluoro-2-nitrophenyl ester 0 o=! =5 CF

CC OH 0 40 o -0 +2 IA

I | \. 1.

FO F © F ©

A solution of potassium tert-butoxide (1.23 g, 11 mmol) in 25 mL of anhydrous DMSO was stirred at room temperature for 30 minutes and treated with 1,3-difluoro—2-nitrobenzene (1.59 8 10 mmol). After 18 hours, the mixture was diluted with 150 mL of 1 T™ aqueous sulfuric acid and extracted with three 50 mL portions of diethyl ether. The combimmed organic layers were washed with water, dried over sodium sulfate, filtered, and concentrateca in vacuo. The residue was dissolved in 50 mL of trifluoroacetic acid. After 30 minutes at room temperature, the - mixture was concentrated in vacao, treated with 50 mL of 1 N aqueous sodium hydroxide, and extracted with three 30 mL portions of diethyl ether. The aqueous layer was acidified with 1 N aqueous sulfuric acid and extracted with two 50 mL portions of dichloromethane. The combined dichloromethane layexrs were washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.3 g of 3-fluoro-2-nitrophenol as oramnge oil (61% yield).

An solution of 3-fluoro-2-nitrophenol (1.13 g, 7.2 mmol) and pyridine (0.65 mL, 8 mmol) in 15 mL of anhydrous dichloromethane was cooled in an ice bath and tre=ated with a solution of triflic anhydride (1.33 mL, 7.9 xumol) in 3 mL of anhydrous dichlorormethane. After 4 hours, : the reaction mixture was diluted with 100 mL of dichloromethane, wwsashed with two 30 mL portions of saturated aqueous sodium bicarbonate, two 30 mL portions of 1 N aqueous sulfuric acid, and two 30 mL portions of water, dried over sodium sulfate, filte—xed, and concentrated in vacuo to give 2 g of the title product as a light brown oil (96% yield).

Example 27: Synthesis of Triffluoromethanesulfonic acid 4-cyano--2-methyl-6-nitrophenyl ester

OH lo} o = SY OY ol _CF, or — a. Om

NC N° or 5 NC a om

An ice-cold solution of 4-bromo-2-methylphenol (5.6 g, 30 mmol) amnd pyridine (6.1 mL, 75 mmol) in 50 mL of anhydrous dichloromethane was treated with a sowlution of acetyl chloride

(2.8 mL, 26 mmol) in 5 mL of anhydrous dichloromethane. After 2 hours, the reaction mixture was concentrated in vacuo. The resulting residue was treated wwith crushed ice, diluted with 150 mL of dichloromethane, washed with water, dried over sodium sulfate, filtered, =and concentrated in vacuo to give 6.9 g of 4-bromo-2-methylphe=nyl acetate as a light brown oil (quantitative yield).

A solution of 4-bromo-2-mmethylphenyl acetate (6.9 g, 30 mol) in 75 mL of anhydrous dimethyl acetamide was treated with zinc cyanide (3 g 25.6 mmol) and tetrakis(triphenylphosphire)palladium(0) (4.5 g, 3.9 mmol). “The reaction mixture was heated at 100°C for 2 hours, cooled to room temperature, and treated with 300 mL of cold water. ~The resulting precipitate was filtered, washed with water, and air dried. Chromatography on Ssi0» (100% dichloromethane) afforded 5.2 g of 4-cyano-2-methylphenyl acetate as a colorless oil (99% yield), which solidified on standing.

A stirred solution of 4-cy ano-2-methylphenyl acetate (5.2 g, 229.7 mmol) in 75 mL of metheanol was treated with a solution of potassium carbonate (30 mmo], 4.15 g) in 25 mL of water at room temperature. After 30 minutes, the mixture was concentrated in vacuo and treated winth 1

N sulfuric acid. The resulting precipitate was filtered, washed with water, and dried to give 3.1 g of 4-hydroxy-3-methylbenzonitrile as a white solid (78% yield).

A stirred solution of 4-hy-droxy-3-methylbenzonitrile (3.1 g, 23.3 mmol) in 60 mL of anhydrous acetonitrile was cooled to -30°C and treated with nitroniurm tetrafluoroborate (3.4 g, 25.6 mmol) in portions. Aftex 60 minutes, the reaction mixture waas diluted with 100 mL of waater.

The resulting light yellow precipitate was filtered, washed witta water, and dried to give 3.9 =gof - 25 4-hydroxy-3-methyl-5-nitrobenzonitrile (94% yield). 4-Hydroxy-3-methyl-5-ni trobenzonitrile was converted to th-e title product according to the procedure described for the preparation of trifluoromethanesul fonic acid 3-fluoro-2-nitrophenyl ester.

Example 28: Synthesis of 3-Fluero-6-methyl-2-nitrophenol oE Cy" =a —_ —_—

NO,

F F F

7 m”L of a hot solution of concentrated sulfuric acid in 21 mL of water —was added to 5-fluoro-2- metBhylphenylamine (5 g, 40 mmol). The mmixture was cooled in an ice bath for 30 minutes and treamted with a solution of sodium nitrite (3.38 g, 48 mmol) in 10 mL of water over a period of rinutes. After stirring at 0°C for 45 mminutes, the reaction was dilmited with 20 mL of cold watezr and treated with 0.3 g of urea. The r-esulting mixture was added t=o a stirred solution of 11 mL of concentrated sulfuric acid in 10 rmlL of water containing 15 g of anhydrous sodium sulfate at 130°C over 10 minutes. After an additional 5 minutes at “130°C, the reaction was allowved to cool to room temperature amnd was extracted with threse 100 mL portions of 10 dich loromethane. The combined organic I=ayers were washed with two 50 mL portions of water and concentrated in vacuo. The reddish oil was dissolved in 250 ml of diethyl ether and washed with three 50 mL portions of 10% aqueous sodium hydroxide. The combined aqueous sodiwmim hydroxide extracts were washed w=ith two 50 mL portions of iethyl ether. The basic layer— was acidified with 1 N aqueous FICl and extracted with three 100 ml. portions of dichMoromethane. The combined dichlomromethane layers were washed with two 50 mL porti ons of brine, dried over sodium sulfates, filtered, and concentrated in vacuo to give a light reddmsh liquid. The crude was purified oy chromatography on SiOx (10% ethyl acetate in hexammnes) to give 5 g of S-fluoro-2-methylphmenol as a Light brownish oil {99% yield).

A starred solution of 5-fluoro-2-methylph enol (640 mg, 5 mmol) im 20 mL of anhydrous acetownitrile was cooled to -30°C to -40°C ard treated with nitronium tetwrafluoroborate (740 mg, 5.5 ramol). After 45 minutes, the reaction mixture was diluted with 1060 mL of cold water and extraected with three 50 mL portions of dichloromethane. The combin_ed organic layers were washeed with three 25 mL portions of wateer, dried over sodium sulfate, and concentrated in vacuo to give a reddish crystalline solid. Chromatography over SiO _» (5% ethyl acetate in hexarmaes) gave 0.58 g of the title product as oright yellow solid (68% yiel_d).

The title compound was converted to the corresponding trifluosromethane sulfonate according tO oo the procedure described in Example 26.

Example 29: Synthesis of 4-Amino-3-fluoro-5-iodobenzonifrile

Br NC NC ! : QO, CL, CX ——— NH NH NH,

Th: ! Ao F PEN ps

A solution of 4-bromo-2—fluorophenylamine (10.9 g, 57.4 mmol) and pyridine (9.4 mL, 115 mmol) in 50 mL of anhydrous dichloromethane was treated with acetyl chloride (3.33 mL, 63.1 mmol) at 0°C. After 10 rminutes at 0°C and 10 minutes at rom temperature, the mixture wa=s concentrated in vacuo anc the residue was treated with 300 mmL of 1 N aqueous sulfuric acid.

The organic layer wass concentrated in vacuo to gmve 129 g of N-(4-bromo-2 - fluorophenyl)acetamide ass a light greyish solid (97% yield).

A solution of N-(4-brormno-2-fluorophenyl)acetamide (12.9 g, 55.4 mmol) in 125 mL of anhydrous dimethyl acetamide was heated in the presence of zinc cyanide (5.53 g, 47.1 mmol ) and tetrakis(triphenylphossphine)palladium (0) (5.2 g, 4.5 mmol) at 100°C for 3 hours. Thee mixture was diluted with 300 mL of cold water, the resultin_g solid was filtered, washed with water, and dried. The filtmrate was extracted with three 100 mM portions of ethyl acetate and thee combined extracts were cried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was corrmbined with the solid from the filtration. This combined material wa s filtered through a silica ge=1 column (100% dichloromethane feollowed by 100% ethyl acetate) teo give 8.5 g of N-(4-cyano-22-flucrophenyl)acetamide as a light ecream solid (86% yield).

A solution of sodium pertoorate (4.2 g, 27.3 mmols) and sodium tungstate (450 mg, 1.4 mmol) in a mixture of 20 mL of glacial acetic acid and 15 mL of acetic anhydride was treated with a solution of potassium iod=ide (2.3 g, 13.9 mmols) in 15 ml. o-f water. The mixture was treatead with 7.5 mL of concentrated sulfuric acid over 15 minutes. A suspension of N-(4-cyano-2_- fluorophenyl)acetamide (21.79 g, 10 mmols) in 15 mL of gla cial acetic acid was added to aned the resulting mixture was heated at 50°C. After 1 hour, the mmixture was poured into 300 mL o=f crushed ice and treated with 100 mL of a saturated solution eof sodium thiosulfate followed by 100 mL of a sodium bisufite solution. The mixture was extracted with three 100 mL portion_s of dichloromethane and the combined organic laye xs were washed with three 50 mL portions of sodium bicarbonate solution, three 50 mL portiomns of water, dried over sodiwam sulfate, and concentrated in vacuo to give a light brownish s olid. Chromatography on S30, (50% ethyl acetate in Thexanes) afforded 400 mg of the title prom duct as a light brownish solid (15% yield).

Co 5 : Example 30: Synthesis of 2-Fluoro-6-iodo-4-met—hylphenylamine ————

NH, NH,

F F

A solutiora of 2-fluoro-4-methylphenylamine (1.225 g, 10 mmol) in 5 mL of methanol was treated with a solution of iodine (1.27 g, § mmol) i_n a mixture of 25 mL of methanol and 3 mL of hydrogen peroxide over a period of 15 minute s at room temperature. Aftex 18 hours, the reaction nolixture was quenched with 30 mL of saturated aqueous sodium thiosulfate and extracted with three 50 mL portions of dichloromethane. The combined organic layers were washed with two 30 mL portions of saturated sodivmm bisulfite solution, three 50 mL portions of water, drieed over sodium sulfate, and copcentrate ir vacuo. Chromatography on SiO; (10% ethyl aceta te in hexanes) gave 1.1 g of the title pro<iluct as a light brownish oil (43% yield).

Example 31: Synthesis of 2-Ilodo-4-trifluoromet Imylphenylamine

F,Cu B ’

NH,

The title compound was prepared in the same mana er as indicated for the synthesis of 2-fluoro- 6-iodo-4-m_ethylphenylamine.

Example 322: Synthesis of 2-Iodo-4-nitrophenyla mine

NH,

The title commpound was prepared in the same manneer as indicated for the synthes is of 2-fluoro- 6-iodo-4-me=thylphenylamine.

Example 33: Synthesis of N-(4-Amine-3-iodopheryl)acetamide

H

TCC

NH,

The title compound was prepared in the same mann _er as indicated for the synthesis of 2-fluoro- 6-iodo-4—methylphenylamine.

Example: 34: Synthesis of 2-Ethyl-6-nitrophenol re oo oc

NO,

A solution of 2-ethylphenol (2.44 g, 20 mmol) in S30 mL of anhydrous acetonitri le was treated with nitronium tetrafluoroborate (2.93 g, 22 mmol s) in portions over a period off 5 minutes at 230°C to 40°C. After 20 minutes, the mixture wa=s quenched with ice, treated w—ith cold water and extr=acted with three 100 ml portions of dichloromethane. The combined eorganic layers were waashed with two 30 mL portions of wate=r, dried over sodium sulfate. filtered, and concentr-ated in vacuo. Chromatography on SiO; (C20% ethyl acetate in hexanes) gave 2.0 g of 2-ethyl-G-nitrophenol as a yellow oil (60% yield).

The title compound was converted to the correspont_ding trifluoromethane sulfonat=e according to the proce=dure described in Example 26.

Exampl-e 35: Synthesis of 2-Methyl-6-nitrophenol oe

NO,

The titles compound was prepared in the same marmner as indicated for the synthe=sis of 2-ethyl- 6-nitropIhenol and was converted to the corresponeiling trifluoromethane sulfonat-e according to the procedure described in Example 26.

Example 36: Synthesis of 4-Mode-3-(2,2,2-trifluoroacetylaminow)benzoic acid methyl ester 1 i \ \

C—O, JO JO 1 ON i HN I " 3

CFy (o]

A solution of 4-iodobenzoic excid methyl ester (5.24 g, 20.0 mmol) in sulfuric acid was treate=d with 1.43 mL of concentrated nitric acid in a dropwise fashion amt 0°C. After 5 hours at roomm temperature, the reaction mix@ure was heated to 40°C for 1 hour. The resulting orange soluticwn was added to 100 g of ice, treated with 200 mL of ethyl acetates, shaken for 30 minutes, amd filtered. The phases were sepwarated and the aqueous layer was extracted with 200 mL of ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate soluticen and brine, dried over magnesium sulfate, filtered, and concentrat-ed in vacuo. The residue was passed through a column of silica gel (100% ethyl acetate) to give 2.0 g of 4-jodo-3- nitrobenzoic acid methyl ester as a yellow solid (33% yield).

A solution of 4-iodo-3-nitrobe=nzoic acid methyl ester (2.0 g, 6.50 mmol) in 25 mL of absolute alcohol and 15 mL of glacial acetic acid was treated with iron powder (3.6 g, 65.0 mmol) an d the mixture was heated at 80% C. After 1 hour, the reaction mixtiire was filtered through a pa_d of silica, washed with ethanol, and concentrated in vacuo. Th_e residue was diluted with a solution of potassium carbonate and extracted with ethyl acetate. The combined organic layer—s were washed with brine, driec over sodium sulfate, filtered, and «concentrated in vacuo to give 1.6 g of 3-amino-4-iodobenzoic acid methyl ester as a white solid (88% yield).

A solution of 3-amino-4-iodobenzoic acid methyl ester (1.59 g=, 5.74 mmols) in 40 mL owf dichloromethane was reacted with trifluoroacetic anhydride {3 ml, 21 mmol) at room temperature. After 30 minutess, the reaction mixture was concentr—ated in vacuo and the residu-e was taken up in cold water, filltered, and dried to give 2.1 g of the title product as an off-whitee solid (quantitative yield).

Example 37: Synthesis of 2-Methyl-5-phenyl-1H-pyrrolo[2,3-cl pyridine a 2 roe — r — ~ or AN a

Ph Z HN Oo N

Te

Propyne (0.60 mL, 11_4 mmol) was condensed in a pressure tube at -78°C. A solution of (4- iodo-6-phenylpyridin-3-yl)carbamic acid tert-butyl ester (900 mg, 2.27 mmol) in 2 mL of

DMF, 6 mL of triethy/lamine, dichlorobis(triphenylphosphinee)palladium (I) (80.2 mg, 0.114 } 5 mmol), and Cul (43.0 mg, 0.227 mmol) were added, the tubes was sealed, and the mixture was stirred at room temperature overnight. The mixture was cooled to -78°C, the sealed tube was opened, and 20 mL Of ethyl acetate and 10 mL of saturasted aqueous ammonium chloride solution were added. The phases were separated and the aque-ous layer was extracted with three mL portions of ethyl acetate. The combined organic layers were dried over magnesium 10 sulfate, filtered, and concentrated in vacuo. The crude produect was purified on SiO; (0 to 40% ethyl acetate in hexanes, gradient) to give 670 mg of (C6-phenyl-4-prop-1-ynylpyridin-3- yl)carbamic acid terz-loutyl ester (96% yield). - A solution of (6-pheny/1-4-prop-1-ynylpyridin-3-yl)carbamic =acid tert-butyl ester (670 mg, 2.17 mmol) in a mixture of 33 mL of methanol and 11 ml of water was treated with DBU (2.0 mL, 13.4 mmol). The resulting mixture was heated at 60°C. After 24 hours, the mixture was concentrated in vacuo. 50 mL of water was added, the mixtur—e was sonicated, and the resulting

Lo . solid was filtered. The solid was dried over P.O; in vacuum ®&o give 450 mg of the title product as a yellow solid (99%G yield), which was used without further— purification.

Example 38: Synthesis of LH-Pyrrolo[3,2-b]pyridine

TTT A — 1)

TF 1

A mixture of (2-brommopyridin-3-yl)carbamic acid tert-butyl ester (1.09 mg, 4.00 mmol), (trimethylsilyl)acetylene (2.83 mL, 200 mmol), Cul (75.8 mg, 0400 mmol), and.

dichloro=bis(triphenylphosphine)palladium (II) (1 41 mg, 0.200 mmol) in a nomixture of 12 mL of triethylamine and 3.0 mL of anhydrous DMF were stirred at room temperatwure overnight. The reaction was diluted with 50 mL of diethyl ether and quenched with S@0 mL of saturated . aqueous ammonium chloride solution. The orga mic layer was washed with _20 mL of saturated aqueous ammonium chloride solution and the <ombined aqueous layers were extracted with three 20 mL portions of diethyl ether. The comtoined organic layers were thmen washed with 20 mL of brine, dried over magnesium sulfate, filtered, and concemntrated in vacuo.

Chromatography on SiO; (20% to 30% ethyl aceetate in hexanes, gradient) gave 500 mg of (2- trimethy~lsilanylethynylpyridin-3-yl)carbamic aci«d tert-butyl ester (43% yield).

A mixtare of (2-trimethylsilanylethynylpyridin—3-yl)carbamic acid ter-bu—tyl ester (500 mg, 1.72 mrxol) in 5 mL of THF was treated with TBAF (I M in THF, 10.3 ml) at room temperasture. The mixture was heated at reflux for 8 hours, cooled to room temperature, diluted with 100 mL of diethyl ether, and quenched with 100 mI of water. The aqueous layer was extracted with three 50 mL portions of diethyl ether, and the combined o-rganic layers were washed with 500 mL of brine, dried over magnesium sulfate, filtered, amnd concentrated ir vacuo. Chromatography on SiO; (100% CH,Clz to 10% MeOH in CH,Cl,, gradient) gave 160 mg of th_e title product as tan solid (79% yield). : 20 Exampl-e 39: Synthesis of 2-Methyl-LH-pyrrolo|2,3-c]pyridine 1 Le N - AN . | "r 0) a. ps & 0 "OK N id 0

Propyne (6.3 mL, 124 mmol) was condensed im. a pressure tube at -78°C. A solution of (3- iodopyriedin-4-yl)carbamic acid terz-butyl ester ("7.98 g, 24.9 mmol) in 15 mT of DMF, 60 mL of triethylamine, dichlorobis(triphenylphosphine®palladium (I) (877 mg, 1.25 mmol), and Cul (472 mg, 2.49 mmol) were added, and the tubes was sealed and stirred at room temperature overnight. 200 mL of ethyl acetate and 100 nil of saturated aqueous armmonium chloride solution were added, the phases were separated and the aqueous layer was e—xtracted with three 100 mL portions of ethyl acetate. The combine=d organic layers were driead over magnesium sulfate, Miltered, and concentrated in vacuo. Chromatography on SiO; (Z25% to 40% ethyl

] WO» 2005/030213 PCT/WS2004/031009 acetate in hexanes, gradient) afforde d 5.65 g of (3-prop-1-ynylpyridin-4-yl)c arbamic acid rert- butyl ester (98% yield). (3-Prop-1-ynylpyridin-4-yl)carbamics acid tert-butyl ester (5.65 g, 24.3 mmol) was treated with 30.4 mL of 4 M HCI in dioxane. The mixture was sonicated until the comapound completely dissolved. After 15 hours, the mixture was concentrated in vacuo. The resulting brown solid (4.10 g) was dissolved in 65 mL of 1-methyl-2-pyrrolidinone (NMP) and treated with zert-

BuOK (7.08 g, 63.2 mmol) at room temperature. After 18 hours, 300 mL o fethyl acetate and 300 mL of water were added. The phases were separated and the aqueous layer was extracted with five 100 mL portions of ethyl acetate. The combined organic layers were washed with two 20 mL portions of water, dried Over magnesium sulfate, filtered, and con centrated in vacuo.

Chromatography on SiO; (10% nmethanol in dichloromethane) yielded 2.85 g of the title . product as yellow solid (89% yield).

Lo 15 Example 40: Synthesis of 2,3-Dimethyl-LH-pyrrolo[2,3-c]pyridine - J

In a pressure tube, a solution of iodopyridine (1.80 g, 8.18 mmol) in 20 ml. of DMF was treated with 2-butyne (1.5 mL, 19.1 mmol), Pd(dppf),Cl;2CH,Cl; (357 mg, 0.4 38 mmol), lithium chloride (367 mg, 8.71 mmol), and sodium carbonate (1.82 g, 17.2 mmol). The tube was sealed and heated to 90°C. After 24 hours, the tube was cooled and opened. Th e resulting mixture was diluted with 20 mL of ethyl acetate and 20 mL of saturated aqueous axmmonium chloride solution. The phases were separated and the aqueous layer was extracted with three 50 mL portions of ethyl acetate. The cormbined organic layers were dried over mmagnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (CH:Cl; to 10% MeOH in CHCl, gradient) afforded the title product as a brown solid (520 mg, 77% yield).

Example 41: Synthesis of 2-Methy/1-5-methylsulfanyl-1H-indole

Br Br Se Sr

Feo, oN OU: I ©

N DMF N THE N EtOH, & N

To a solution of 5-bromo-=2-methyl-1H-indole (1.5 g, 7.14 mmol) in 10 mL of DMF was added 60% sodium hydride in mineral oil (189 mg, 7.9 mmol). Once “hydrogen gas evolution ceas ed, the mixture stirred for 10> minutes and was then treated with 1 mol (7.83 mmol) of benzene sulfonyl chloride. The reaction was monitored by TLC (ethyl aecetate-hexanes (5:95)) to afford a major new slightly less polar product than starting material. After 2 hours, the mixture vavas poured into 50 mL of satuarated aqueous ammonium chloride somlution and extracted with thmree 50 mL portions of ethyl acetate. The combined organic layers were washed with four 25 rmL portions of brine, dried ower magnesium sulfate, treated with activated carbon (NORIT ATM), ‘ 10 filtered through diatomaceous earth, and concentrated in vacuo. The residue was adsorbed orto ’ silica gel and chromatographed on silica el using ethyl acetate—hexanes (1:99, then 2:98, thmen 3:97) to afford 1.71 g (68.4% yield) of 1-benzenesulfonyl-5-b—romo-2-methyl-1H-indole ass a clear oil. )

To a chilled solution of 1-Tbenzenesulfonyl-5-bromo-2-methyl-1#4-indole (350 mg, 0.99 mmol) } in 4 mL of THF was addled 440 pL (1.10 mmol) of n-BuLi (2.5 M solution in hexane s), followed by dimethyl disulfide (100 pL, 1.11 mmol). The mixteire was stirred as it warmed to room temperature and was then quenched with ammonium chloride and extracted with three 15 mL portions of ethyl acetzate. The combined organic layers w-ere washed with three 15 nol portions of brine, dried ovesr magnesium sulfate, filtered, and concentrated in vacuo. The crus=de material was adsorbed onto silica gel and chromatographed on silica gel using ethyl acetatze- hexanes (1:99, then 2:98) to afford 156 mg (44.3% yield) of Ml -benzenesulfonyl-2-methyl- 5- methylsulfanyl-1 H-indole aus a clear oil. - . 25 To a solution of 1-benzenesulfonyl-2-methyl-5-methylsulfanyl-12-indole (156 mg, 0.45 mmol) in 10 mL of ethanol was added 10 mL of 10% aqueous sodium hydroxide solution. Tine mixture was warmed at reflux for 18 hours. The mixture was the=n diluted with 10 mL of brirme and extracted with three 20 mL portions of ethyl acetate. The c—ombined organic layers wemre washed with tw=o0 10 mL portions of 10% aqueous sodium hydroxide solution, two 20 ml portions of saturated aqueous ammonium chloride, two 220 mL portions of brine, dried ower magnesium sulfate, filtered, and concentrated in vacuo. Whe crude product was adsorbed orto silica gel and chmromatographed on silica gel using ethyl aw.cetate-hexanes (1:99, then 2:98, thmen 3:97, then 5:96) to afford 62 mg (71.2% yield) of 2-methyA-5-methylsulfanyl-1H-indole.

Example 42: Synthesis of 1-Benzenesulfonyl-2-methyl-S-phenyl-1H-indole (J) 8 pna(oH),

Ja Pd[Ph,P], ld ()

N 2M ag. Na,CO;4 \

A mixture o f 1-benzenesulfonyl-5-bromo-2-methyl-AL H-indole (810 mg, 2.31 mm-ol), phenylboronic =acid (850 mg, 6.97 mmol) and tetrakis(triphenylphosphine)palladium(0) (55 mug, 0.029 mmol) ira 20 mL of toluene, 10 mL of ethanol, an«d § mL of 2 M sodium carbonate —was warmed at reflux for 4 hours. The reaction was monitored by TLC (ethyl acetate-hexeanes (5:95), 2x deve=loped; and toluene-hexanes (1:1)) indicating a slightly more polar product. ~The mixture was comoled and diluted with 12% aqueous ammonium hydroxide solution and extracted with three 15 mmL portions of ethyl acetate. The combined organic layers were washed with three 15 ml portions of brine, dried over magnesium sulfate, filtered, and concentratecd in vacuo. The crude mixture was adsorbed onto silica gel and chromatographed on silica gel using ethyl acestate-hexanes (1:99, then 2:98, then 3:977) to afford 731 mg (91% yield) oef 1- benzenesulfon=yl-2-methyl-5-phenyl-1H-indole.

Removal of thee phenyl sulfonyl group as described in Excample 41 gave 2-methyl-5-phenyl—1H- indole.

Example 43%: Synthesis of 1-Benzenesulfonyl-22-methyl-1H-indole-S-sulfonic acid dimethylamidlle

UN

Br 1. n-Bul S=o then SO, / Ether/ THF /

N 2. NCS nN . oo then NH(Me), 0" 2 THF 2

To a chilled (-78°C) solution off 1-benzenesulfonyl-5-bromo-2-me=thyl-1H-indole (505 mg, 1.44 mmol) in 5 mL of diethy] ethesr and 2 mL of THF was added 650 pL (1.63 mmol) of »-BuLi (2.5 M solution in hexanes). ~The mixture was stirred of 10 mimnutes and then sulfur edioxide (80, gas was bubbled througgh the solution, resulting in a pmrecipitate. The mixtumre was warmed to room temperature and filtered to afford 468 mg of the lithium sulfonate=. This material was dissolved in 10 nal of THF and then N-chlorosuccimnimide (200 mg, 1.49 mmol) was added. The mixture was stirred for 15 minutes and then 4 m1. (8 mmol) of a 2 M ssolution of dimethylamine in THF was -added. The mixture was then stirr—ed for 1 hour and was diluted with saturated aqueous ammonaum chloride solution and extractec with three 10 mL porstions of ethyl acetate. The combined carganics were washed with three 1-0 mL portions of brinec, dried over magnesium sulfate, filtered, and concentrated in vacueo to afford 365 mg of 1- benzenesulfonyl-2-methyl-1 H-Endole-5-sulfonic acid dimethylami de.

CL 15 Removal of the phenylsulfonyl group as described in Example 4-1 gave 2-methyl-1H-in_dole-5- sulfonic acid dimethylamide.

Example 44: Synthesis of 4-(5-Chlore-2,3-dihydrobenzofuran-7-yl)-1,1,1-triflu:1oro-4- methylpentan-2-one . o Fa

CFy ~~ AL or + — 0 HO 0

F 3 Fa

Oo _~ —— oH

HO HO o

— He = on]

A solution of ethyl trifluor-opyruvate (124.84 g, 0.734 mol) in 2.0 L of THF was treated with methylallyl magnesium ch loride (0.5 M in THF, 1.90 L, 0.954 mol) over 4 hours while the internal temperature was Traintained below -60°C. The reaction mixture was allowed to reach room temperature overnight, concentrated in vacuo to remove THF, quenched with 1 L of saturated ammonium chloride solution, and extracted with three 1 L portions of diethyl ether. : The combined organic plmases were washed with 100 mL of bmrine, dried over magnesium

Lo sulfate, filtered, and concemirated in vacuo. Vacuum distillation ant 60 mmHg afforded 100.1 g of 2-hydroxy-4-methyl-2-txiflucromethylpent-4-enoic acid ethyl ester as a clear oil (b.p. 97°C- 103°C, 60% yield).

A solution of 2-hydroxy-=tmethyl-2-trifluoromethylpent-4-enoic acid ethyl ester (100 g, 442 mmol) and 2,3-dihydrobermzofuran (57.7 g, 480 mmol) in 500 mL of dichloroethane was treated with AICI; (87.8 g, 660 rmmol) while maintaining the internal te_mperature below 10°C. The reaction was allowed to w-am to room temperature overnight and quenched with 1 L of cold 1

N HCL The mixture was €hen extracted with three 1 L portions of ethyl acetate. The combined organic layers were washesd with 1 L of saturated aqueous sodiun— bicarbonate solution, 1 L of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residuc was purified on SiO; (10% diethyl ether in hexanes). The resulting s=clid was recrystallized in hot hexanes to afford 39.5 g of 4-(2,3-dihydrobenzofuran—7-yl)-2-hydroxy-4-methyl-2- trifluoromethylpentanoic zcid ethyl ester as a white solid (26% yie- 1d).

A suspension of LAH (4.52 g, 119 mmol) in 230 mL of THF wass treated with a solution of 4- (2,3-dihydrobenzofuran-7 —yl)-2-hydroxy-4-methyl-2-trifluorometlaylpentanoic acid ethyl ester (27.5 g, 79.4 mmol) in 40 mL of THF at 0°C over 30 minutes. After stirring overnight, the reaction was cooled to 0 °C, quenched with 3 mL of water, ane treated with 3 mL of 4 M sodium hydroxide solution. After 10 minutes, the mixture was t-reated with additional 18 mL portion of water and the wesulting mixture was warmed to room ®emperature for 4 hours. The mixture was filtered and the filter cake was washed with five 100- mL portions of diethyl ether.

The filtrate was concentrated in vacuo to give 24.0 g of 4-(2,3-dibydro®oenzofuran-7-yi)-4- methyl-2-trifluoromethylpentane-1,2-di ol as an oil (39% yield).

A solution of 4-(2,3-dihydrobenzofuram -7-y1)-4-methyl-2-triflucromethylpermtane-1,2-diol (24.0

S g 78.9 mmol) and NalO; (84.3 g, 39<4 mmol) in 360 mL of methanol was stirred at room temperature overnight. The resulting mixture was filtered through pad of CCELITE® filter aid and the filter cake was washed with three 100 mL portions of methanol. The filtrate was concentrated in vacuo, taken up in hexznes, filtered again, and concentratecd in vacuo to give 21.4 g of 4-(2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-omne as colorless oil (quantitative yield), which was used witlnout purification. } A solution of 4-(2,3-dihydrobenzofuram-7-yl)-1,1,1-triflucro-4-methylpentaan-2-cne (20.8 g, 76.2 mmol) in 200 mL of acetic acid was treated with a solution of chlorine gas (Cla) in acetic acid (prepared by bubbling chlorine gas izmato acetic acid, ~1.19 M). The reaction was monitored by 'H-NMR. The ratio of the startings material to product was determineed based on the integration of CH, signal of the respective ketones (starting material: § = 3.32 ppm; product: 3 = 3.32 ppm). The concentration of the C1; solution was recalculated based orm the NMR ratios and an additional portion of Cl, solutioxs was added (this process was repe ated until NMR showed the complete consumption of the starting material). The mixture wass quenched with 500 mL of water and solid sodium bicarlonate (~500 g) was added carefully~ during 1 hour.

The mixture was poured onto 500 mL off ethyl acetate. The phases were se parated and the aqueous layer was extracted with three 500 mL portions of ethyl acetate. The combined organic layers were washed with two 100 aml portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 23.4 g of the title product (quamntitative yield), which was used without purification. —Example 45: Synthesis of 4-(5-Clnloro-2,3-dihydrobenzofuran-7-yl)-M,1-diflaoro-4- mmethylpentan-2-one 0] rt joan 0 —_— be if ]

A mixture of magnesiun turnings (204 mg, 8.40 mmol) anmd trimethylsilyl chloride (2-13 mL, 16.8 mmol) in 10 mL of DMF was treated with 4-(5-chloro—2,3-dihydrobenzofuran-7-yM)-1,1,1- trifluoro-4-methylpentan—2-one (1.23 g, 4.00 mmol) in 10 mmL of DMF at 0°C. The reesulting mixture was stirred at rosom temperature overnight. The mi. xture was filtered and concentrated in vacuo. The residue w-as suspended in 20 mL of THF anad treated with TBAF (1 M mn THF, 4.0 mL) at room temperature. After 15 minutes, the reacwtion was quenched with 25 mL of saturated aqueous ammomnium chloride solution and diluted with 50 mL of diethyl ether. The phases were separated an«d the aqueous layer was extracted vith three 50 mL portions of diethyl ether, The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on SiO; (100% hexanes to 10%%6 diethyl ether in hexanes, gradient) afforded 550 mg of the title produmct (48% yield).

Example 46: Synthesis o»f 5-(5-Fluoro-2-methylphenyl)-2,-dimethylhexan-3-one

H

Sass van

F

F F

Sane Saat

Lo

F F

A solution of 1,1,1-triffuore-4-(5-fluoro-2-methylphenyl)-4-mmethylpentan-2-one (4.88 =, 18.6 mmol) was treated with scadium hydroxide solution (4 M in a. mixture of 30% water in esthanol, 40 mL) at room temperatwure. The mixture was heated to 80°C for 1 hour. After cooling to room temperature, the mixzture was diluted with 100 mL of wavater and extracted with threse 100 mL portions of diethyl eth er. The aqueous layer was treated with 150 mL of ethyl aceta-te and the resulting mixture was t-reated with 6 M HCI dropwise until the solution had a pH of 22. The phases were separated and the aqueous layer was extracted with three 100 mL portions off ethyl acetate. The combined «organic layers were dried over rmagnesium sulfate, filterecd, and concentrated in vacuo to yield 3.92 g of 3«(5-fluoro-2-methy~Iphenyl)-3-methylbutyric a cid as an oil, which solidified up on standing and was used without further purification (quantitative yield).

A mixture of 3-(5-fluoro-2-methylphenyl)-3-methylbutyric acid (3.80 g, W8.0 mmol) in 15 ml of dichloromethane was treated with SOC; (1.98 mL, 27.1 mmol) at 0°C~ After 30 minutes, 2 mixture of morpholine (2.36 mL, 27.1 mmol) and pyridine (4.4 mL, 54.2 mmol) in 10 mL of dichloromethane was added to the reaction mixture at 0°C. After an addi tional 90 minutes, 60 mL of 2 M aqueous HCI solution was added, phases were separated and tHhe aqueous layer was extracted with three 50 mL portions of dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated in vacuo to give =5.03 g of 3-(5-fluoro- 2-methylphenyl)-3-methyl-1-muorpholin-4-ylbutan-1-one as an oil, whic’h was used without further purification (quantitative yield).

A solution of 3-(5-fluoro-2-methylphenyl)-3-methyl-1-morpholin-4-ylbiatan-1-one (200 mg, 0.716 mmol) in 2 mL of THF was treated with i-PrLi (0.7 M in pentane-, 1.28 mL.) at -78°C.

The reaction mixture was stirred at -78°C for 1 hour, allowed to warm t=o room temperature, quenched with 1 mL of methanol and 5 mL of saturated aqueous ammoniwam chloride solution, and extracted with three 50 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Chrosmatography on SiO; (100% hexanes to 25% ethyl acetate in hexanes, gradient) afforded 80.4 romg of the title product (48% yield).

Example 47: Synthesis of 4-(3-[1,3]Dioxan-2-ylphenyl)-1,1,1-trifluorae—4-methylpentan-2- one

Ay oe —_— At

A solution of the Grignard reagent (generated from the reaction of 2-(3-bromophenyl)- [1,3]dioxane with magnesium turnings in THF, 0.25 M, 52.6 mL, 13.1 mmol) was treated with copper (I) iodide (2.5 g, 13.1 mmol) at 0°C. After 45 minutes, 1,1,1-trifluz oro-4-methylpent-3- en-2-one (2 g, 13.1 mmol) was added, and the reaction mixture was slowaly warmed to room temperature and stirred overnight. The mixture was quenched with. aqueous saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with aqueous saturated sodium chloride solution, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated with hexan=es and filtered. The filtrate was concentrated in vacuo to give 1.78 g of the crude product, which was used without purification.

Example 48: Synthesis of (1-Fluorosvinyl)dimethylphenylsilane

Tow ~ S

Cl —

Cr FONE J NN of

To a suspension of 4.4 g of lithium wire cut into small pieces in 200 mL of anhydrous THF stirred under argon and cooled on ices (internal temperature <10°C) wa-s added dimethylphenyl- chlorosilane in 5 ml portions over 1 hour. The deep red color of -the silyl lithium reagent appeared after approximately 0.75 Inour. The mixture was stirred ora ice for an additional 5 hours (internal temperature remained between 5°C and 10°C). The mixture was cooled on a dry ice/acetone bath and 1,1-diflucroeth—ylene was introduced by filling a balloon connected to the reaction mixture and the reagent cylinder using a three-way valve. Thae balloon was filled with 1,1-difluoroethylene and emptied into the reaction mixture 10 times. ~The mixture was allowed to warm to room temperature (effervescence observed, probabKy from unreacted 1,1- difluoroethylene). The mixture wass diluted with 200 mL of hexanes and filtered through a cotton wool plug. The filtrate wass washed with water, dried, filteared, and concentrated in vacuo. Four fractional distillations under vacuum through a Vigremmx column gave 4.6 g of product.

Example 49: Synthesis of 1-(1-EFFluorocyclopropyl)-3(4-fluoroplacnyl)-3-methylbutan-1- one jones oo

OH ——= — + F Sim

F LES

H H 0

Jonas onc JO ae

12 mL of a 2 M solution of oxalyl chloride in dichloromethane was diluted with 19 mL of dichloromethane and cooled on a dry ice/acetone bath. To this solution was added a dropwise a solution of 3.6 mL of DMSO in 16 mL of dichloromethane. Afier 10 minutes. a solution of 3- {4-fluorophenyl)-3-methylbutan-1-0l (3.6 g, 19.8 mmol) in 12 ml of dichleoromethane was added and the mixture was stirred for 15 minutes. 14 mL of triethylamine wass then added, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature and was quenched with water and diluted vvith hexanes. The organic layer— was separated, washed with water, dried, filtered, and concentrated in vacuo. The residue —was purified by chromatography over silica gel (eluent: hexan es to hexanes-dichloromethane (9:1), gradient) to give 1.2 g of 3-(4-flucrophenyl)-3-methylbutyxaldehyde as an oil.

To a mixture of 3-(4-fluorophenyl)-3-methaylbutyraldehyde (1.2 g, 6.6 nmmol) and (1- “fluorovinyl)methyldiphenylsilane in 5 mL of THF cooled on ice under nitrogen gas was added 1 mL of TBAFR (1 M in THF). The mixture waas allowed to warm to room tempmerature and left overnight. The solvent was evaporated and th e residue was taken up in hexanes. The hexane soluble material was fractionated over silica gel (eluent: hexanes to hexane=s-ethyl acetate ((98:2)) to give a fraction (3.1 g) containing silylated product along with othezr silanes. This

Fraction was dissolved in 5 mL of THF and 10 anL of TBAF solution (1 M in THEF) was added.

The mixture was left at room temperature for 20 minutes, diluted with hexanes-ethyl acetate, a.nd washed with water, dried, filtered, and concentrated in vacuo. Fractionation_ of the residue over silica gel (eluent: hexanes-ethyl acetate (99:1 to 9:1 gradient)) gave 1.73 g of the crude 2- fl uoro-5-(4-fluorophenyl)-5-methylhex-1-en-3-01 as an oil which was used withaout additional panification. ’

To the above crude 2-fluoro-5-(4-flucropheny®)-5-methylhex-1-en-3-0l (1.73 g—, 7.65 mmol) stirred under nitrogen gas and cooled on ice, wvas added diethyl zinc (1.1 M ir toluene, 8.0 m1). After 5 minutes, 1.0 mL of diiodomethane was added dropwise over 20 mi nutes and the maixture was stirred and allowed to come to room temperature and then stimrred at room texmperature for 4 days. 0.5 mL of water was th en added to the reaction mixture_, followed by i 30 etlnyl acetate. The resulting mixture was then filtered through diatomaceous earth and the solvent was removed in vacuo and the residue was fractionated over silica gel (hexanes-

dichloromet=hane (1:1) to dichloromethane gradient) to give 1-(1-fluorocyc lopropyh-3-(4- ) fluoropheny-1)-3-methylbutan-1-ol as an oil. 2.2 mL of a- 2 M solution of oxalyl chloride in di chloromethane was diluted vewith 2.5 mL of dichlorometlhane and cooled on dry ice/acetone bath. To this solution was addead a dropwise 2 solution of 0-.7 mL of DMSO in 2.5 mL of dichloroxnethane, After 10 minutes, a solution of the above crude 1-(1-fluorocyclopropyl)-3+(4—fluorophe=nyl)-3-methylbutan-1-ol (0.7.2 g, 3.0 mmol) in 2 mL of dichloromethane was added and the mixture was stirred for 15 minmutes. 4 mL of triethylamine was added, the cooling bath was removed, the mixture was allowed to warm to room temperature and was then quenched with wa ter and diluted with hexanes— The organic layer was separated, washed with water, dried, filtered, and concentrated in vacuc>. The residue was purified by chromatography over silica gel (eR uent: hexanes to hexanes-dic=hloromethane (4:1) gradient) to give 0.37 g of the title product as aan oil.

Example 5@): Synthesis of 1-(1-FIuorocyclo propyl)-3-(5-flnoro-2-metho-xyphenyl)-3- methylbutan—I1-one ~ ~ H — ae oo” G&G

F F F

~ ~ H

Ss F . Cr hg oo or

F F

~ H ~

San Sas

F F

To a solution off 6-fluoro-4,4-dimethylchroman-2-one fn 40 mL of DMSO was addesd a solution of 5.5 g of sodimum hydroxide in 5 mL of water over 5 minutes (an exothermic react=icn). After 20 minutes, methyl iodide (20 g) was added portionwi se over 15 minutes and the nixture was stirred at room temperature overnight. The mixture was diluted wwith hexanes, washed with water, dried, filtered, and concentrated in vacuo to give 12.4 g off the ester which was used without additional purification.

To a suspension of LAH (1.64 g) in 100 mL of THF stirred under argon was added dropwise over 30 minutes a solution of the above 3-(5-fluoro-2-methoxyph. €nyl)-3-methylbutyric acid methyl ester in 10 mL of THF (vigorous reaction). The mix ture was stirred at room temperature overnight. The reaction was diluted with 200 mL of diethyl ether and quenched by the addition of 3 ml of water (added cautiously) and 3 ml of acetic acid. The mixture was filtered through diatomaceous earth and washed through with diethy® ether. Evaporation of the solvent gave 10.8 g of 3-(5-fluoro-2-methoxyphenyl)-3-methylbuttan-1-o0l, which was used without additional purification.

A solution of 3-(5-fluoro-2-methoxyphenyl)-3-methylbutan-1-ol (3.3®0 g, 15.5 mmol) in 40 mL of dichloromethane was treated with pyridinium chlorochroma te (4.2 g, 19.5 mmol) portionwise over 5 minutes. The mixture was stirred for 3 hours , filtered through pad of

CELITE® filter aid and the pad was wash with hexanes. The filErate was concentrated iz

ES vacuo. Chromatography on SiO; (30% to 50% dichloromethane in he=xanes, gradient) gave 2.5 - g of 3~(5-Fluoro-2-methoxyphenyl)-3-methylbutyraldehyde as an oil (77% yield). : 20

To a solution of 3-(5-fluoro-2-methoxypheny!)-3-methylbutyraldehydZe (1.1 g, 5.2 mmol) and the above (1-fluorovinyl)dimethylphenylsilane (2.2 g, 12.2 mmol) in =S mL of THF was added 0.6 mL of tetrabutylammonium fluoride (1 M in THF) and the mix®Eure was stirred at room temperature overnight. TAC showed partial conversion to product. (Cesium fluoride (0.22 g) was added and the mixture was stirred at room temperature for 3 day—s. 2 mL of water and 2 mL of acetic acid were added and the mixture was warmed at 60°«C for 2 hours to effect desilylation of any silylated product. The mixture was diluted with etlnyl acetate, washed with water, dried, filtered and concentrated in vacuo. Fractionation of the= residue over silica gel (eluent: hexanes-dichloromethane (3:1 to 1:3 gradient) gave 0.798 g (5%9.5% yield) of 2-flucro- 5-(5-fluoro-2-methoxypherayl)-5-methylhex-1-en-3-01 as an oil whiach was used without additional purification. 7 203

Tc 2-fluoro-5-(5-fluoro-2-methoxypherayl)-5-methylhex-1-en-3-ol, stirre=d under nitrogen gas amd cooled on ice, was added 8.0 mL o»f diethyl zinc (1.1 M in toluene). After 5 minutes, 1.0 mK of diiodomethane was added dropwise over 20 minutes, and the mixture was stirred and alB owed to come to room temperature amd then stirred at room temperature= for 2 days. Then 0.5 mi of water was added, followed by ethyl acetate, and the mixture was filtered through di=atomaceous earth. The product was concentrated in vacuo and the reszidue was fractionated over silica gel (hexanes-dichloromethane= (1:1) to dichloromethane, gradie—mt) to give 0.8 g of 1- (1—fluorocyclopropyl)-3-(5-fluoro-2-methhoxyphenyl)-3-methylbutan-1-0l =as an oil which was use=d without additional purification. 6 ral of a 2 M solution of oxalyl chl oride in dichloromethane was dmluted with 5 mL of dic_hioromethane and cooled on dry ice/ acetone bath. To this solution was added dropwise a solwution of 1.5 mL of DMSO in 5 mL off dichloromethane. After 10 minumies, a solution of the cru-de 1-(1-fluorocyclopropyl)-3-(5-fluo xo-2-methoxyphenyl)-3-methylbustan-1-ol (0.8 g, 3 mnomaol) in 4 mL of dichloromethane was added and the mixture was stirre=d for 15 minutes. 4 mL of triethylamine was added, the cooling bath was removed, and the r—eaction mixture was allowed to warm to room temperature, cjuenched with water, and diluted with hexanes. The organic layer was separated, washed with water, dried, filtered, and concenwtrated in vacuo. The residue was purified by chromatography over silica gel (eluent: hexan=es to hexanes-ethyl acetate (10:1), gradient) to give 0.68 g o=f the title product as an oil whic-h was used without addtional purification.

Exa-mple 51: Synthesis of 1,1,1-Triflaomro-4-(5-methanesulfonyl-2,3-dih=ydrobenzofaran-7- yl)-a#-methylpentan-2-one \ o=%°

A stuned solution of 1,1,l-trifluoro-4-maethyl-4-(5-methylsulfanyl-2,3-dilmydrobenzofuran-7- yDpe-ntan-2-one (5.3 g, 16.7 mmol) in acetonitrile was slowly added a solutmion of NalO, (10.7 g 50 mmol) in 70 mL of water. After 10 minutes, RuCl; (50 mg, 0.24 mn ol) was added and the stirring was continued at room temperaeture for 30 minutes. The mixtures was concentrated in vacuo, and €he resulting greyish solid was filtered, =washed with water, and dried to give 5.4 g of the title proaduct, which was used without further praarification (93% yield).

Example 52: Synthesis of 1,1,1-Trifluoro-4-(2-methmoxy-5-methylsulfanylphenyl)-a8- methylpentan—2-one ~~ fF, -~ (5 Pb{OAC), or,

HO —_—

OH

8 ~

To a solution of 4-(2-methoxy-5-methylsulfanylpheenyl)-4-methyl-2-trifluoromethy _pentane- 1,2-diol (1.5 g=, 5.3 mmol) in 25 mL of methanol was added 2.4 g of lead (IV) acetate (Pb(OAc)s) ancl the reaction mixture was stirred until _TLC indicated the reaction was c=omplete, : 10 after several hours. The reaction mixture was then filteered through a bed of diatomaceous earth and the filtrate ~was concentrated in vacuo to afford 1.1 2 g (83.8% yield) of 1,1,1-triflueoro-4-(2- methoxy-5-methhylsulfanylphenyl)-4-methylpentan-2-o-ne.

Example 53: Synthesis of 4-(2-Benzylox—y-5-fer-butylphenyl)-1,1,1-trif Juoro-4- methylpentan-22-one

H JP

H

: A= ACH, LIAM, ad + — —_— .

H so CO

Benzwyi bromide Dess—Martin op -— er - perioc—linane

Aucglone -—

Sf oP

Dewss-Martin

TAF CF, pewriodinane CF, er 2 28

To a chailled solution of 4-fert-butylphenol (15 g, 1.00 mmol) and 11.12 mL of 3-rethylbut-2- enoyl cEaloride in 200 mL of diethyl ether at 0°CC was added 13.9 mL of trietlnylamine by addition funnel. The reaction mixture was warmed to room temperature and stirre=d until TLC indicated the reaction was complete. The reaction mixture was then filter—ed through diatomac=eous earth, and the diethyl ether layer was washed two times with water, \ovashed with brine, dried over magnesium sulfate, and concentrated in vacuo to leave 23 g of 3-nmethylbut-2- enoic acid 4-fert-butylphenyl ester as a brown oil that partially crystallized upon stax ding.

To a solvation of 3-methylbut-2-enoic acid 4-ter-but-yiphenyl ester (23 g, 99 mmol) mn 50 mL of carbon disulfide (CS,) was added 19.8 g of alumiraum chloride (AICl;) portionwi=se over the course of 1 hour, a very exothermic reaction. After stirring for several hours, TLC -showed the reaction wwvas complete. The reaction mixture was concentrated under a stream of ni trogen gas, and the residue poured over ice and extracted with ethyl acetate. The organics were combined, dried ove=r magnesium sulfate, and concentrated in wacuo. The residue was purifie=d on silica pad (0% ®o 5% ethyl acetate-hexanes) to give 8.1 g of 6-tert-butyl-4,4-dimethylchro man-2-one as an oil.

To a chilled suspension of 1.99 g of LAH in 60 mL of THF at 0°C was added a solmution of 6- tert-butyl—4,4-dimethylchroman-2-one (8.1 g, 34.9 mmol) in 10 mL of THF by addition funnel.

The reaction mixture was warmed to room temperature and stirred until TLC indicated the reaction w-as complete. After 1 hour, the reaction mi=xture was cooled in ice bath anc carefully quenched with a minimum amount of water. The reaction mixture was then dried over magnesium sulfate and filtered through diatomaceous earth. The filtrate was conce=ntrated in . 25 vacuo, the residue was taken up in hexanes, and the solids isolated by filtration to affeord 5 g of ; 4-tert-buty~1-2-(3-hydroxy-1,1-dimethylpropyl)phenol.

To a solution of 4-tert-butyl-2-(3-hydroxy-1,1-dimethylgpropyl)phenol (2 g, 8.5 mmol) and 1.1 mL benzyl bromide in 10 mL of DMF was added 1.75 _g of potassium carbonate (CX,CO;) and bl the reaction mixture stirred at room temperature until TLC indicated that the re=action was complete. Aftemr stirring overnight, the reaction mixture wwas diluted with ice and exwtracted with diethyl ether. The organics were combined, washed foux times with water, washed with brine, dried over magnesium sulfate, and concentrated in vecicuo. The residue was purified on

COMBIFLASH-® apparatus (0% to 30% ethyl acetamte-hexanes) to give 1.7 _g of 3-(2- benzyloxy-5-ter &-butylphenyl)-3-methylbutan-1-ol as an il.

To a solution of 3-(2-benzyloxy-5-tert-butylphenyl)-3-me=thylbutan-1-0l (1.7 g, 5.2 ramol) in 20 mL of dichloromethane was added 3.27 g of Dess-Martirm periodinane and reaction s tirred until

TLC indicated t“he reaction was complete. After 2 howurs, the reaction mixture vewas passed through a pad Of silica, eluting with 5% ethyl acetate=-hexanes to afford 1.67 g& of 3-(2- benzyloxy-5-tert—butylphenyl)-3-methylbutyraldehyde as an oil. 3-(2-Benzyloxy-5-ert-butylphenyl)-3-methylbutyraldehycde was converted to 4-(2-b enzyloxy- 5-tert-butylpheny-1)-1,1,1-trifluoro4-methylpentan-2-one using similar procedure=s as in

Example 4 of U.S . Patent Application Pub. No. 2004/0023 999.

Example 54: Synthesis of 4-(2-Benzyloxy-S—isopropylphenyl)-1,1,1-tri_fluoro-4- methylpentan-2-One

F

I =n 4-(2-Benzyloxy-5-msopropylphenyl)-1,1,1-trifluoro-4-methy=Ipentan-2-one was prepared from 4- : isopropylphenol in the same manner as described in the synthesis of 4-(2-benzylox=y-S-tert- butylphenyl)-1,1,1--trifluoro-4-methylpentan-2-one.

Example 55: Symthesis of 7-(4,4,4-Trifluoro-3-hydrox=y-3-hydroxymethyl-1,1-dimmethyl- butyl)-2,3-dihydroMbenzofuran-S-sulfonic acid dimethyl ammide o X 0 Xe [o) [o}

Br 9, o al Oo - Fal - FC } - 01% 0* 1% . ANG AN

Co A solution of 5-bromo-7-[2-(2,2-dimethyl-4-triflucrometinyl-[1,3)dioxolan-4-yl)-1,1- oe dimethylethyl]-2,3-dihydrobesnzofuran (4.0 g, 9.4 mmol) in 8 mL of THF was treated with n- : 5 BuLi (2.5 M in hexanes, 4.2 mL, 10.5 ramol) at -78°C. After 15 mimnutes, an excess of SO; gas

To was bubbled into the mixture and the reaction was monitored fom the disappearance of the starting material. Next, the reaction mixture was concentrated unde=r a stream of nitrogen gas, diluted with THF, and treated with N-chlorosuccinimide (1.48 g, 11. 1 mmol). The mixture was stirred for 15 minutes and divided into three equal portions. A stock solution of sulfonyl chloride (1/3 of the mixture) in 8 mL of THF was treated with dimet=hylamine (2 M in THF, 10 mL, 20 mmol). After 30 minutes, the mixture was diluted with 20 mL of saturated aqueous ammonium chloride solution and extracted with three 10 mL porti=ons of ethyl acetate. The combined organic layers were washed with three 10 mL portions of saturated aqueous ammonium chloride solution, two 10 mL portions of brine, dried over magnesium sulfate, ’ 15 filtered, and concentrated in vacuo. The crude material was purified on silica gel (3% to 30% i ethyl acetate in hexanes, gradient) to afford 1.18 g (83% yield) of 7-[2-(2,2-dimethyl-4- trifluoromethyl-{ 1,3]dioxolan-4-yl)-1,1-dimethyl-ethyl}-2,3-dihydrobesnzofuran-5-sulfonic acid ) dimethylamide, which was usexd without further purification.

A mixture of 1.18 g (2.61 mrmol) of 7-{2-(2,2-dimethyl-4-triftuorom_ethyi-[1,3)dioxolan-4-yl)- 1,1-dimethyl-ethyl]-2,3-dihydrobenzofuran-5-sulfonic acid dimethylaamide and 303 mg (1.59 mmol) of p-toluenesulfonic acid monohydrate in 20 mL of methanol was warmed at reflux for 3 days. The mixture was them cooled and diluted with 15 mL of s aturated aqueous sodium

WED 2005/030213 PCT T/US2004/031009 bicarbonate and extracted with three 15 xnL portions of ethyl acetate. The combined organic layers were washed with two 15 mL portions of saturated aqueous sodiunm bicarbonate, two 15 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with ether to afford 845 mg (78% yield) of the title compound as a white solid. 7-(4,4,4-Trifluoro-3-hydroxy-3-hydroxymaethyl-1,1-dimethyl-butyl)-2,3-dibmydrobenzofuran-5- sulfonic acid dimethylamide was converted to the corresponding trifluoromethyl ketone according to the method disclosed in U.S. Patent Application Pub. No. 200~4/0029932, which is hereby incorporated by reference.

Example 56: Synthesis of 7-(4,4,4-Trifluoro-3-hydroxy-3-Eaydroxymethyl-1,1- dimethylbutyl)-2,3-dihydrobenzofuran-S-sulfonic acid amide

H OH

' F.C

Se 0” i) ~ 0

HTH

7-(4,4,4-Trifluoro-3-hydroxy-3-hydroxymethyl-1, 1-dimethylbutyl)-2, 3-dihycirobenzofuran-5- sulfonic acid amide was prepared from S5-bromo-7-[2-(2,2-dimethyM-4-trifluoromethyl- (1,3)dioxolan-4-y1)-1,1-dimethylethyl]-2,3 ~dihydrobenzofuran in the same manner as in the preparation of 7-(4,4 ,4-trifluoro-3-hydroxy-3-hydroxymethyl-1,1-climethylbutyl)-2,3- dihydrobenzofuran-S-sulfonic acid dimethylamide. ’ Example 57: Synthesis of 7-(4,4,4-Trifluoro-1,1-dimethy=]-3-oxobutyl)-2,3- dihydrobenzofuran-S-sulfonic acid 1-dimethylaminometh~(E)-ylideneamimde fas oF, (ema 0“1=0 070 - Ne

H H 3

AN

A solution of 7-(4,4,4-tr-ifluoro-1,1-dimethyl-3-oxobutyl)-2,3-=dihydrobenzofuran-5-sulformic acid amide (870 mg, 2.477 mmol) in 30 mL of dichlorometinane was reacted with N,aN- dimethylforamide dimethyl acetal (580 mg, 4.86 mmol). After 30 minutes, the mixture w—as concentrated in vacuo to dryness. The resulting solid was trite rated with diethyl ether amd collected to afford 950 mg ofthe title compound (94% yield).

Example 58: Synthesis of ~1,1-Difluoro-4-(5-methanesulfonyl-2. ,3-dihydrobenzofuran-7-y_1)- 4-methylpentan-2-one

F F

: Fo gH ~S8 “To l

To a solution of 1 ,l-diffuoro-4-methyl-4-(5-methylsulfa nyl-2,3-dihydrobenzofuran—7- yl)pentan-2-one (840 mg, 2 .8 mmol) in 12 mL of MeCN and 4 ma 1 of water was added soditeam periodate (1.79 g, 8.4 mmol) followed by a crystal of ruthenivumn (IIT) chloride hydrate. T he reaction was monitored by TLC until the thiol ether was no longzer evident. After 1 hour, t=he reaction was concentrated # z vacuo, diluted with water, and extr=acted with ethyl acetate. T “he combined organic layers weare dried over magnesium sulfate, treated with carbon, filtered, a-md concentrated in vacuo to afford 910 mg (98% yield) of the title comupound as a white solid.

Example 59: Synthesis of <3-Methoxy-3-methyl-3-phenylbutyramldehyde

CN NaHMDS on = DIBAL >E=

Sh + BA — Shi oon

H NaH —~Q 1. 0,, then Me,S -

LIAM, > Mel a MeOH-CH, CL, Ph

THE DMF 2. p-TsOH/Acetone

To a solution of =2-phenylpropionitrile (4.04 g, 30.79 mmmol) in 40 mL of DMSO was aclded 34 mL (34 mmol) off a 1 M solution of sodium bis(trimethyR silyl)amide (NaHMDS) in THE= over a minute period. After 10 minutes, allyl bromide (6 n=l, 69.33 mmol) was added dmropwise 5 (exothermic). Tbe mixture was cooled with an ice-waater bath. The mixture stirred for 20 minutes, becomirg a solid mass. An additional 20 ml. 0 DMSO was added. After 10 rminutes, the mixture was diluted with 200 mL of ammonium chl-oride and extracted with three 100 mL portions of ethyl acetate. The combined organic layers vavere washed with six 75 mI. por—tions of brine, dried over magnesium sulfate, filtered, and concemtrated in vacuo to afford 5.25 g (99.5% yield) of 2-metinyl-2-phenylpent-4-enenitrile as yellow oil which was used without further purification.

To a solution of 2-methyl-2-phenylpent-4-cnenitrile (C525 g, 30.65 mmol) in 150 mL of dichloromethane= was added a 1 M solution of diisobutsylaluminum hydride (DIBAL) &38 ml, 38 mmol} in dichloromethane over a 15 minute period. The reaction was monitored toy TLC; after 1 hour, TL_C (ethyl acetate-hexanes (1:9)) indicasted a slightly less polar produact. The reaction was powured into ice-cold 1 N aqueous HCl and the dichloromethane layer se=parated.

The aqueous waas extracted with two 50 mL portionss of dichloromethane. The combined organic layers wavere washed with 50 mL of brine, twos 50 mL portions of saturated aqueous sodium bicarbo=nate, 50 mL of brine, dried over magnesium sulfate, filtered through diatomaceous ezarth, and concentrated in vacuo to affo-rd 4.6 g (86.1% yield) of 2-nmethyl-2- phenylpent-4-en.al which was used without further purifi cation.

To a solution o-f 2-methyl-2-phenylpent-4-enal (4.6 g, 26.4 mmol) in 100 mL of THF was added of lithiurm aluminum hydride (LAH) (2.6 g, 6 8.51 mmol) in several portioras. The mixture stirred f=or 3 hours at room temperature and was then refluxed for 2 hours. The reaction was monitored by TLC with ethyl acetate-he—xanes (1:9) indicating a new more polar product.

The reacstion was cooled and the excess LAE was cautiously quennched vith water dropwise.

The mixture was then diluted with 1 N aqueowus HCI and extracted with 100 mL of hexanes and two 100 mL portions of ethyl acetate. The ¢ ombined organic layers were washed with 50 mL of 1 N aqueous HCl, two 50 mL portions off brine, two 50 mL portions eof saturated aqueous sodium Tbicarbonate, 50 mL of brine, dried o ver magnesium sulfate, filtereed, and concentrated in vacucs. The crude material was chromatcographed on silica gel using hexanes to load the sample :and then eluting with 1% to 15% ethyl acetate-hexanes to affor-d 3.2 g (68.8) of 2- methyl-22-phenylpent-4-en-1-ol.

To a soMution of 2-methyl-2-phenylpent-4-em.-1-ol (3.2 g, 18.15 mmol) in 17 mL of DMF was added scodium hydride (1.25 g, 31.25 mmol, €50% in mineral oil). The mixcture was stirred until foaming ceased and then methyl iodide (6 mI, 96 mmol) was added. Aftemr 2 hours, the mixture was que=nched with 50 mL of saturated aqueous ammonium chloride solution and extracted with thee 50 mL portions of ethyl acetate. "®he combined organic Layers ~were washed with 30 mL of s aturated aqueous ammonium chlorides solution, five 25 mL portion. s of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3.4 g (98.4% yield) of (1- methox=ymethyl-1-methylbut-3-enyl)benzene which was used without furthmer purification.

To a chmilled (-78°C) solution of (1-methoxy~methyl-1-methylbut-3-enyl)b-enzene (1.67 g, 8.77 mmol) in methanol-dichloromethane was toubbled ozone gas until the solution turned blue.

The exc=ess ozone was then purged from the mixture with oxygen and the=n dimethyl sulfide (5 mL, 68 mmol) was added and the mixtur-e was warmed to rooin temperature and stirred overnig_ht, The mixture was then concentrated in vacuo to remove the ex cess dimethyl sulfide and dilcated with 20 mL of ammonium chloricde and extracted with three 155 mL portions of ethyl acetate. The combined organic layers were washed with three 15 xnL powrtions of brine, dried over magnesium sulfate, filtered, and cwoncentrated in vacuo to afford an oil which corresponded to the dimethyl acetal by H-NMR. The crude product was cliluted with 40 mL of acetone . and p-TsOH (300 mg, 1.57 mmol} was added and the muixture= was stirred at room temperamture for 2 hours. The reaction was m_onitored by "H-NMR and indicated the presence of aldehyde and dimethyl acetal. The reaction was refluxed for 4 howrs aned monitored by TLC (ethyl =acetate-hexanes (1:9)) and then cooled and diluted with saturamted aqueous sodium bicarbonate solution and extracted with three 15 mL portions of ethyl acetate. The combined : organic layers were washed with two 10 mL portions of saturated aqueous sodium bicarbonate solution, two 10 mL portion s of brine, dried over magnesium sulfate, fil tered, and concentrated ’ in vacuo to afford 1.45 g (85.9% yield) of 4-methoxy-3-methyl-3-phenyl butyraldehyde. 4-Methoxy-3-methyl-3-phernylbutyraldehyde was converted to 1,1,1—trifluoro-5-methoxy-4- methyl-4-phenylpentan-2-orme as described previously in Examples 26 of U.S. Patent

Application Pub. No. 2004/0023999.

EB 10 Example 60: Synthesis of 1 -Benzo[1,3]dioxol-4-ylethanone ee Ee Ho (C0, YORE ; pi Wo _Med X if ~ NE 00 — a 3

THF CH,CL, -78°C 60°C

To a solution of benzo[ 1,3]clioxole-4-carbaldehyde (10 g, 66.7 mmol) irs 200 mL THF at -78°C was added, via addition fumnel, 43.7 mL of a 1.6 M MeLi solution in diethyl ether. The reaction was slowly warmed to room temperature and stirred overnight. A TLC of an aliquot showed reaction was complete. The reaction was then cooled to -78& °C and quenched with saturated aqueous ammonium chloride and concentrated in vacuo. The residue was then extracted with ethyl acetate. The organics were combined, dried over ¥nagnesium sulfate, and concentrated in vacuo to give 11 g (99.4% yield) of 1-benzof1,3]dioxol—4-ylethanol as a brown oil that crystallized upon standing, :

To a solution of 1-benzo[1 ,3]dioxol-4-ylethanol (11 g, 66.3 mmol) ime 100 mL of THF was added 17.26 g of manganesse dioxide (MnQO,) in one portion and reaction was monitored by

TLC. After several hours, TLC showed some product but significamt alcohol left. More manganese dioxide was added and the solution stirred. TLC then showed mostly product but a significant amount of alcokol. The reaction mixture was then filtered through a bed of diatomaceous earth and the filtrate was concentrated in vacuo to give an oil that mostly crystallized on standing. To 9.24 mL of a solution of oxalyl clmloride in 120 mL of dichloromethane at -60°C was added a solution of 15 mL of DMSO in 20 ml of dichloromethane. After 10 xninutes, a solution of above alcohol/ketones mixture (53 mmol) in

20 mL of dichloromethane was added, followed 15 minutes later by 44.3 mL of triethylamine —

The reaction was allowed to slow=ly warm to room temperature oveemight. The reaction mixtures was then poured onto ice and the organic layer was washed with fave 100 mL portions of water , then brine, and then dried over m -agnesium sulfate. The organics ~were concentrated in vacuo tS leave tan solids and the solids we=re triturated with hexanes, collected by filtration, and dried to give 9.33 g (85.8% yield) of 1-bemnzo[1,3]dioxol-4-ylethanone. 1-Benzo[1,31dioxol-4-ylethanones was converted to 4-benzo[l,3 ldioxol-4-yl-1,1,1-trifluoro-4 - methylpentan-2-one according to Example 26 of U.S. Pamtent Application Pub. Now. 2004/0023999.

Example 61: Synthesis of 2-Bliydroxy-4-methyl-4-phenyl-2-tmrifluoromethylhexanoic acied ethyl esters 1) NaHMDS DIBAL (rt AIO LOA

DMSO oN———> —+._o —_—

CN ——— NUN ~~ = = Fy

A . 1) H;S0,

NO Hone o / TAF oo > + CF—§ —_— 2)HC! IN me OH h HOH MN "J

To a solution of 2-phenylpropioritrile (5 g, 38 mmol) in 50 mL of DMSO was added 42 mL of 1 M THF solution of sodium bis(trimethylsilyl)amide (NaHMADS). After 15 minutes, time reaction was cooled to 0°C ancl 4.6 mL of ethyl iodide was a dded. The reaction was the=n stirred for 30 minutes. As TLC showed the reaction was compwlete, the reaction mixture was poured into water and extracted with diethyl ether. The organicss were combined, washed forar times with water, washed with twrine, dried over magnesium sulf ate, and concentrated in vaciaeo to give 6.1 g of 2-methyl-2-phen ylbutyronitrile as an oil.

To a solution of 2-methyl-=2-phenylbutyronitrile (6.1 g, 38.3 mmol) in 50 mL of dichloromethane at room temper=ature was added 57 mL of 1 M IDIBAL in dichloromethane v—ia syringe. The reaction was stirr-ed for 30 minutes, at which tinme TLC of aliquot showed tine

: reaction was complete. The reaction mixture was carefully poured into B00 mL of 1 N HCI and the layers were separated. The organics were concentrated in vacuo amnd taken up in diethyl ether, combined with the aqueous layer, and extracted with diethyl eth er. The organics were then combined, dried over magnesium sulfate, and concentrated in va=cuo. The residue was purified on silica gel column (0% to 2% ethyl acetate in hexanes) to giwwe 4.2 g of 2-methyl-2- . phenylbutyraldehyde as colorless oil.

To a solution of (diethoxyphosphoryl)ethoxyacetic acid ethyl ester (7.4 £, 27.6 mmol) in 30 mL of THF, at 0°C, was added 16 mL of 1.8 M LDA in heptane/THF/ethy dbenzene. The reaction mixture was stirred for 30 minutes and then a solution of 2-methyl-2-phmenylbutyraldehyde (4.2 g, 25.9 mmol) in 30 mL of THF was added dropwise by syringe. Thae reaction mixture was then warmed to room temperature, quenched with saturated aqueovs ammonium chloride solution, and extracted with diethyl ether. The organics were combined , dried over magnesium sulfate and concentrated in vacuo to give 8.3 g of a 2:1 mixture of £ andl Z isomers of 2-ethoxy- 4-methyl-4-phenylhex-2-enoic acid ethyl ester as orange oil. : To a solution of 2-ethoxy-4-methyl-4 -phenylhex-2-enoic acid ethyl estemr (8.3 g, 30 mmol) in 25 . mL of HOAc was added 116.5 mL of aqueous 1 M sulfuric acid solutiom. The reaction mixture ' was stirred at room temperature for several hours. As TLC showed n_o reaction, the reaction mixture was placed in a 100°C oil bath and stirred overnight. As TLC wmvas then inconclusive, 2 mL more aqueous | M sulfuric acid and 20 mL of HOAc were added. «After 1 hour, TLC of an aliquot showed major olefin isomer (more polar spot) consumed amnd minor isomer spot ’ remaining (product may co-spot with minor isomer). The reaction mix ture was then cooled to . room temperature and extracted with diethyl ether. Organics were comtoined, washed with four portions of water, washed with brine, dried over magnesium sulfate, aned concentrated in vacuo to afford 2.5 g of an orange oil. "H-NMR showed 1:1 mixture of mincor isomer and aldehyde.

The aqueous layer was extracted with ethyl acetate and the ethyl acetate extracts were combined, dried over magnesium sulfate, and concentrated in vacuo tao leave a brown liquid. 'H-NMR showed significant ethyl acetate and HOAc and desired produmct as the ketoacid. The

Kketoacid solution was taken up in 200 mL of ethanol, treated with 1 om] of concentrated HC], and heated to reflux overnight. TLC then showed a new, less polar spo t. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residvme was then diluted with water and extracted with diethyR ether. The organics were combined... dried over magnesium sulfate, and concentrated in vacuo to leave 4.3 g of 4-methyl-2-oxom-4-phenylhexanoic acid ethyl ester as an orange oil.

To a solution of 4-methyl-2-0xo —4-phenylhexanoic acid ethyl ester (4.23 g, 17.3 mmol) and 3.6 nL of triflucromethyltrimethylsilane in 50 mL of THF was added 1.5 mL (0.1 equiv) of { M

TBAF solution and reaction stirred at room temperature until the ket—oester was shown to be consumed by TLC, about 30 mimutes. The remainder of the TBAF (1 7.5 mL) was then added and the reaction mixture stirred for 1 hour. TLC then showed the reac=tion was complete. The reaction mixture was concentrated in vacuo, the residue diluted with 1 N HCI and extracted with diethyl ether. The organics were combined, dried over rmmagnesium sulfate, and concentrated in vacuo to leave a brown oil. The oil was taken up in hexanes (cloudy appearance), activated charcoal was added, and the resulting solution filtered through diatomaceous earth and concentrated in vacuo to leave 3.8 g (83% ymield) of a diastereomeric mixture of 2-hydroxy-4-methyl—4-phenyl-2-trifinoromethylhexanoic acid ethyl esters as a light green oil.

The diastereomeric mixture of esters was converted to the correspondirag trifluoromethyl ketone according to Example 1 of U.S. FPatent Application Pub. No. 2004/002=3999.

Example 62: Synthesis of 1,1, 1-Trifluoro-4-(2-methoxy-5-methylp_henyl)-4-methylpentan- 2-one ~~ ~ Ny 0 + PN 0 “ae I. 1.2 bramosthemrn Sa & ELO

To a yellow solution of 4-methylanisole (20 g, 183.5 mmol) and 1.7 mL of concentrated sulfuric acid was added 19.17 mL of 3-chloro-2-methylpropene b—y addition funnel. The reaction became warm and turned dark purple. After 20 minutes, so_1ids began to precipitate. : TLC of an aliquot showed some starting anisole left and a new, slightl=y less polar spot forming.

The reaction mixture was stirred overnight and TLC then showed that the reaction was complete. The reaction mixture was poured onto ice and extracted with diethyl ether. The organics were ~combined, dried over magnesium sul fate, and concentrated in vacuo to leave an oil. The residume was taken up in hexanes, cooled to -78°C, and the solids collecte=d by filtration to give 14 g of 2-(2-chloro-1,1-dimethylethyl)- 1 --smethoxy-4-methylbenzene ass an oil upon warming. The filtrate was concentrated in vacuo to give 15.5 g of a 4:1 mixture eof product and starting anisole=.

To a suspensicon of magnesium turnings (1.87 g) Wn 30 mL of anhydrous diethmyl ether under argon in a wawter bath was added 1.62 mL of dibreomoethane slowly by syringe= such that the internal reaction temperature did not go above= 27°C. A solution of 2—(2-chloro-1,1- dimethylethyl)es-1-methoxy-4-methylbenzene (4 g, 18.9 mmol) and additional exlibromoetbane (1.62 mL) in 2-0 mL of diethy! ether was added by a_ddition funnel] at a rate that keept the internal temperature beslow 25°C. The reaction mixture be=came green and a fine precSipitate formed.

After 1 hour, —the reaction mixture was cooled to ~ 78°C; solids clumped on the bottom of the reaction mixtumre and stirring was stopped. A solut=ion of 3.98 mL of trifluoroacetic anhydride in4 mL of diethyl ether was added to the reaction mixture by addition funnel while swirling the reaction mixtuare by hand. The reaction mixture wa s then warmed to room temperature, stirring resumed abovee 40°C. TLC of an aliquot showed anew slightly more polar spwot and starting material. The reaction mixture was then poured orato cold 1 N HCI and extracte=d with diethyl ether. The org=zanics were combined, dried over ma. gnesium sulfate, and concent—rated in vacuo.

The residue was purified on silica gel column (0% to 5% ethyl acetate-hexaness) to give 1.7 g (41% yield) o f 1,1,1-triffuoro-4-(2-methoxy-5-metihylphenyl)-4-methylpentan-2—one as a clear oil.

Example 63: Synthesis of 1,1,1-Trifluoro-4-(2-me=thoxy-3,5-dimethylphenyl)—4- methylpentarm-2-one ’ ~ o (Ca

The title product was prepared from 1-methoxy-2,4-dimethylbenzerme according to the same procedure described in the synthesis of 1,1,1-trifluoro-4-(2-me®hoxy-5-methylphenyl)-4- methylpentan-2-one. . 5 Example 64: Synthesis of 1,1,1-Trifluoro-4-(5-methoxyy-2,4-dimethylphenyl)-4- methylpentan-2-one

Jonas 0

The title product was prepared from 1-methoxy-2,4-dimethylbenzerne according to the same procedure described in the synthesis of 1,1,l-trifluoro-4-(2-me thoxy-5-methylphenyl)-4- methylpentan-2-one.

Example 65: 4-(2-benzyloxy-5-methylsulfanylphenyl)-1,1,1-trif Juoro-4-methylpentan-2- one or H (CoC,

Cr Ho gyBul > DMSO Or

THF NEt; 2) (MeS), s

Br N Ss.

Oo H (CoC),

DMSO Cr _ Sat Dus Hen

S, S.

To a solution of 3-(2-benzyloxy-5-bromophenyl)-3-methylbutan-1-ol (3 g, 8.6 mmol) in 50 mL : of THF at -78°C was added 7.56 mL of n-BuLi (2.5 M solution in hexanes) and the reaction mixture was stirred for 10 minutes. Then 1.55 mL of dimethyldis—ulfide was added and the reaction mixture was warmed to room temperature. After 20 min ates, TLC showed a new, slightly more polar spot (major) with very little else. The reaction mmixture was then quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether. The organics were combined, dried over magnesium sulfate, and co neentrated in vacuo to 2.84 g of 3-(2-benzyloxy-5-methylsulfanylphenyl)-3-methylbutan-1-ol as= an oil.

To a solution of 1.57 mL of Oxalyl chloride in 15 mL of dichlomromethane at -60°C was adde«d a solution of 2.55 mL of DMS® in 5 mL of dichloromethane. A_fier 10 minutes, a solution of 3- oe (2-benzyloxy-5-methylsulfan ylphenyl)-3-methylbutan-1-ol (2.834 g, 8.9 mmol) in 5 mL of dichloromethane was added solids quickly precipitated), follo—wed 15 minutes later by 7.5 lL triethylamine and the reaction mixture became very thick with solids. The reaction mixture was then warmed to room texruperature and monitored by TLC. After 1 hour, TLC of an aliquot showed reaction was complete, so water was added to the resaction mixture and the resulting layers were separated. The aqueous layer was washed with dichloromethane and the orgammics were combined, washed four times with water, washed witTh brine, dried over magnesium sulfate, and concentrated in v>acuo to afford a yellow oil. The r—esidue was purified on SiO, (0% to 10% ethyl acetate-hexcanes) to give 2.2 g (78.7% yield) of 3-(2-benzyloxy—-5- methylsulfanylphenyl)-3-methylbutyraldehyde as a colorless il that slowly crystallized upon standing. 3-(2-Benzyloxy-5-methylsul fanylphenyl)-3-methylbutyraldehysde was converted to 4-—(2- benzyloxy-5-methylsulfanylpohenyl)-1,1,1-triflucro-4-methylpemntan-2-ol as in Example 26 of

U.S. Patent Application Pub. No. 2004/0023999. 4-(2-Benzyloxy-5-methylsul #anylphenyl)-1,1,1-trifluoro-4-metlhylpentan-2-ol was oxidized to ’ 4-(2-benzyloxy-5-methylsulfanylphenyl)-1,1,1-trifluoro-4-mettrylpentan-2-one using Swem conditions as above.

Example 66: Synthesis of 1,1,1-Trifluoro-4-rmethyl-4-(5-pyrimidin-5-yl-2,3- dihydrobenzofuran-7-yl)pe mtan-2-one )

. rE

FF

[o] 0 ——

Br : Ne

To a mixture of 4-(5-bromo-2,3-dihydrobenzofuraan-7-yl)-1,1,1-triflucro-4-metlhylpentan-2-one (1.00 g.. 2.8 mmol), pyrimidine-5-boronic acid (529 mg, 4.3 mmol) and potasssium carbonate (787 mge) in a sealed tube was added 20 mL of TMeOH-DME-DMF (3:2:1). . After stirring at room tesmperature for 10 minutes, tetrakis(tripbaenylphosphine)palladium(0) (329 mg) was added mand the reaction mixture was heated at 120°C for 40 minutes. After <ooling to room temperamture, the crude mixture was filtered througzh a cotton plug with the aid of ethyl acetate.

The filtrate was concentrated in vacuo to remove most of the methanol, redissolved in 160 mL of ethyl acetate, and washed with 80 mL of aqueawus 1 N sodium hydroxide sol ution, 80 mL of water, amnd BO mL of brine respectively. The organic phase was dried over an hydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatog—_raphy with 20% to 30% ethyl acetate-hexanes afforded 620 mg (62% yield) of the title compoun d.

Example 67: Synthesis of 5-{7-[1,1-Dimetlayl-2-(2-trifluoromethyloxir anyl)ethyl]-2,3- dihydreobenzofuran-5-yl}pyrimidine o FF FF ° _ lo]

ZN =

Na N Na -N

To a solution of 1,1,1-trifluoro4-methyl-4&-(5-pyrimidin-5-y1-2,3-dihyd-xobenzofuran-7- ybhpentzan-2-one (620 mg, 1.8 mmol) in § mL of eanhydrous DMSO-THF (1:1) was added 2.64 mL of &a trimethylsulfoxonium ylide solution (stock solution prepared by reacti_on of NaH (242 mg, 604 dispersion in mineral oil) with trimeth-yisulfoxonium iodide (1.33 a, 6.0 mmol) in 7.50 mi of anhydrous DMSO for 30 minutes) dx-opwise over 5 minutes. After stirring for 2 hour at room temperature, the reaction mixture waas poured into 40 mL of wat-er and extracted with diesthyl ether (200 mL total volume). The «combined organic phases we=re washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 651 mg (99% yield) of the title compound as a pale yellow oil which was used without further purification.

Example 68: Synthesis of 5-Chloro-7-[1,1-dimethyl-2-(2-trifluorepmethyloxiranylethyl}- 2,3-dihydrobenzofuran

Fy 0 Fs + | 0 o + 3 > & cl

To a solution of trimethylsulfoxorxium iodide (343 mg, 1.56 mmol) in 3 mL of anhydrous

DMSO was treated with NaH (602% in mineral oil, 66.0 mg, 1.65 mmmol) in portions and the mixture was stirred at room temperature for 30 minutes. The mix@ure was transferred to 2 solution of 4-(5-chloro-2,3-dihydro benzofuran-7-y1)-1,1,1-triffuoro-4—methylpentan-2-one (400 mg, 1.30 mmol) in 1 mL of anhydrous DMSO over 5 minutes and tthe resulting mixture was stirred overnight. The mixture w-as quenched with water and extmracted with three 20 mL portions of ethyl acetate. The combined organic layers were washed with two 5 mL portions of 1S water, dried over magnesium sulfate, filtered, and concentrated in vacazio to afford 380 mg (91% yield) of the title product as a yellow oil. The crude product was s-ufficiently pure and used without further purification.

Example 69: Synthesis of 7-(1,1-Dimethyl-2-(2-trifluoro -methyloxiranylethyl]-5- 2€ methylsulfanyl-2,3-dihydrobenzo furan _-S _S

To a suspension of trimethylsulfo=onium iodide (1.36 g, 6.1 mmol) in 7.7 mL of anhydrous

DMSO was added sedium hydride (60% dispersion in mineral oil, 246 mg). The resulting solution was stirred at room temperature for 30 minutes and was shen added dropwise to a 2 5 solution of 1,1,1-trifluoro-4-methyr1-4-(5-methylsulfanyl-2,3-dihydroWbenzofuran-7-yl)pentan-2~ one (1.63 g, 6.2 mmol) in 6.5 mL of anhydrous DMSO. After 2 ho~urs, 100 mL of water was added and_ the resulting mixture was extracted ~with three 100 mL portions of diethyl ether. The combined organic phases were washed twice with water, aqueous satur—ated sodium chloride solution, Clried over magnesium sulfate, filterasd, and concentrated in vaezuo to afford the title compound, 1.64 g (95% yield) which was used without further purificatiom.

Example 70: Synthesis of 7-[1,1-D®imethyl-2-(2-trifluoromet-hyloxiranylethyi]-5- methaneszulfonyl-2,3-dihydrobenzofuran

GE — SR 8 520 ¢)

To a scolution of 7-[1,1-dimethyl-2-(2-trif Tuoromethyloxiranyl)ethyl]—5-methylsul fanyl-2,3- . 10 dihydrobe=nzofuran (535 mg, 1.9 mmol) in 30 ml. of acetonitrile and 10 n=l. of water was added sodium pweriodate (1.03 g, 4.8 mmol) follow ed by ruthenium (III) chloeride (1 mg). After 2 hours, thee reaction mixture was diluted with water and extracted with ethyl acetate. The combinecd organic phases were dried over rmagnesium sulfate, filtered, and concentrated in vacuo to afford the title compound as a tan solid, 568 mg (95% yield) which was used without further prarification.

Example= 71: Synthesis of 6-(5-Chloro-2,=3-dihydrebenzofuran-7-yl )-4-difluoromethyl-6- methylhept-1-yn-4-ol

F H = .

Fo F

Cl a Aluminumm foil (108 mg, 4.00 mmol) and merecuric chloride (ca. 1 mg, 0.€01 mmol) in 3.5 mL of anhydroums THF were vigorously stirred for 20 minutes. Propargyl brommide (80% in toluene, 0.45 mL, 4.00 mmol) was added slowly (the reaction mixture became warm) and the resulting mixture >was stirred at 40°C for 1 hour. Thine dark gray propargyl alu minum sesquibromide solution was added to a solution of 4-(5-chhloro-2,3-dihydrobenzofura n-7-yl)-1,1-difluoro-4- methylpe=ntan-2-one (380 mg, 1.32 mmol) in 10 mL of anhydrous THF =at 0°C and the reaction was allowwed to slowly warmed to room temperature and stirred overnizght. The mixture was concentrated in vacuo, quenclmed with ice and water, and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to give 420 mg of the title product as an oil (97% yield), which was used without further purification.

S

Example 72: Synthesis of 6—(3-[1,3]Dioxan-2-ylpheny))-6-methyl-=t-triflucromethylhept-1- yn-4-0l 0 Fs

RE Ah” «OH

Aluminum amalgam was prepared from aluminum foil (1.16 g, 1 4.4 mmol) and mercuric chloride (12 mg, catalytic ammount) in 20 mL of anhydrous THF by vigorously stirring the mixture at room temperature for 1 hour under an argon atmosphere— A solution of propargyl bromide (4.80 mL, 80 wt.% in toluene, 43.1 mmol) in 25 mL of ammhydrous THF was slowly added to a stirred suspension maintaining a temperature of 30°C—40°C, and after addition, stirring at 40°C was continued until a dark gray solution was ob€ained (ca. 1 bour). The propargyl aluminum sesquib>romide solution was added to a solution of 4-(3-[1,3]dioxan-2- yipheny})-1,1,1-trifluoro-4-m ethylpentan-2-one (5.6 g, 14.2 mmol) in 100 mL of anhydrous diethyl ether at -78°C. The reaction mixture was stirred at this tenperature for 3 hours, and then was allowed to warm to room temperature, at which time it wass stirred for 12 hours. The reaction mixture was then p»oured into 20 mL of ice-water and emxtracted with four 30 mL portions of diethyl ether. Th. e combined extracts were washed with 220 mL of brine, dried over magnesium sulfate, and concentrated in vacuo. Chromatography om silica gel (100% hexanes to 40% ethyl acetate in hexames, gradient) afforded 2.5 g of the title compound as an oil (50% yield).

Example 73: Synthesis of &6-(5-Methanesulfonyl-2,3-dihydroben=zofuran-7-yl)-6-methyl-4- triflnoromethylhept-1-yn-4—ol " SZ oF, Z4

I

=? 0=g=0

40 mL of anhydrous THF was added to a mixture of aluminum foil (1.25 g, 4.6 mmol) amd mercuric chloride (100 mg, 0.37 mmol). The resulting mix=ture was vigorously stirred fox 1 . hour, cooled in an dice bath, and treated with propargyl bromide (80% by wt. solution in toluemne, 62.9 mmol, 7 mL). The reaction mixture was stirred at 0°C feor 1 hour and at room temperature for 30 minutes.

A solution of 1,1,1-trifluoro4-(5 -methanesulformyl-2,3-dihydrobenzofuran-7-yi) -4- methylpentan-2-orze (5.4 g, 15.4 mmol) in a mixture of 10 rl of anhydrous diethyl ether zand mL of anhydrous THF was treated with the organoalumin um reagent at -78°C. After 1 hour 10 at -78°C and 1 hour at room temperature, the reaction mix=ture was quenched with saturated ammonium chloride solution and diluted with water. The aqueous layer was extracted with three 100 mL portions of ethyl acetate. The combined orgammic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vactedo to give 6.3 g of the title product as a solid, which wwas used without further purification (quanwtitative yield).

Example 74: Synthesis of {4-16-(3-[1,3] Dioxan-2—ylphenyl)4-hydroxy-6-methy 1-4- trifluoromethylh ept-1-ynyljpyridin-3-yl} carbamic acid te=rt-butyl ester

Z

)

SUSY Fe SY 9c)

OH OH

A mixture of 6-(3-[1,3]dioxan-2-ylphenyl)-6-methyl-4-trifhiaoromethylhept-1-yn-4-ol (300 mg, 0.84 mmol), (4—iodopyridin-3-yl)carbamic acid tert-but=yl ester (270 mg, 0.84 mmol), ’ bis(triphenylphosphine)palladium(Il) chloride catalyst (29. 6 mg, 0.04 mmol) and copper= () iodide (16 mg, 0. 08 mmol) in 4 mL of anhydrous triethylamine and [ mL of anhydrous TMF was stirred at room temperature for 12 hours. The reactioma mixture was then diluted with 30 mL of diethyl eth er and washed with 20 mL of aqueous satmurated ammonium chloride sohmtion and 20 mL of brime. The organic layer was dried over magnesium sulfate and concentrate=d in vacuo. Column chromatography over silica gel with hexane=s-ethyl acetate (5:1 to 1:1) provided 250 mg of the title compound as a foam (54% yield).

Example 75: Syn thesis of N-{4-[6(5-Chloro-2,3-dihydr=obenzofuran-7-yl)-4-hydroxy-eb- methyl-4-trifluoromethylhept-1-ynyl]-2-isopropylpyrimidilin-5-y1}-2,2,2-trifluoroacetamicle 1 _

Nea 1 = 5. OY — »

Na 3 eo “ X a cr

A mixture of chlorodihydrobenzofuran alkyne (185 mg, 0.53 3 mmol), iodopyrimidine (144 ng, 04 mmol), copper £y) iodide ©.5 mg, 0.05 mmol), amd dichlorobis(tripheny ylphosphine)palladium (ID (17.5 mg, 0.0825 mmol) io 0.8 ml of anhydrous acetonitrile and 0.25 mL of anhydrous triethylamine was stirred at room temperature. Aftex hour, LC-MS indicated mo starting alkyne but showed a major peak at M+H = 578 corresponding to the desired compound and a minor peak for the dimer at MAH = 691. The crude reaction mixture was purified by silica gel colunmn chromatography eluting witla a gradient of 0%-25% ethyl acetate in hexanes to give the title compound as 2 brownish oil, (M20 mg, 52% yield), ME+H = 577.

Example 76: Synthesis of 6-(5-Fluoro-2-methylphe=nyl)-1-(3-fluoro-2-nitrophenyIye-6- methyl-4-trifiuoremethylhept-1-yn-4-ol r A) = =

Ears

F F

A mixture of trifloromethanesulfonic acid 3-flucro-2-nitrcphenyl ester (149 mg, 0.52 mm-ol), dichlorobis(triphemnyiphosphine)palladium (II) (20 mg, 0.0228 mmol), copper (D iodide (14 mg, 0.074 mmol), tetarabutyl ammonium iodide (200 mg, 0.554 mmol), 0.25 ml of anhydr ous triethylamine, 0.5 ml of anhydrous acetonitrile, and 0.5 mL of anhydrous tetrahydrofuran was stirred at room termperature for 30 minutes. The resulting nixture was treated with 6-(5-flucoro- 2-methylphenyl)-G-methyl-4-trifluoromethylhept-1-yn-4-ol (145 mg, 0.48 mmol) and stirread at room temperature for 18 hours. The crude product was purified by chromatography on S=i0;

(50% hexanes in dichloromethzane) to give 96 mg of the title product. as light yellow oil, (45% yield).

Example 77: Synthesis of 4—[¢-Aydroxy-6-(5-methanesulfonyl-2 _3-dikydrobenzofuran-7- yI)-6-methyl-4-triflucromethy=lhept-1-ynyl]-3-methyl-S-nitrobenzomnitrile

CN

0] H

PZ Q OH g ~ =

CF, ® NO,

CF, 0=]=0

R 0=§=°

A mixture of trifluoromethanessulfonic acid 4-cyano-2-methyl-6-nitrophenyl ester (217 mg, 0.7 mmol), dichlorobis(triphenylptosphine)palladium (II) (24.6 mg, 0.03 5 mmol), copper (I) iodide ) (13.3 mg, 0.7 mmol), and 6-(5-methanesulfonyl-2,3-dihydroberazofuran-7-yl)-6-methyl-4- tifluoromethylhept-1-yn-4-ol 273 mg, 0.7 mmol) in a mixture of 0.8 mL of anhydrous toluene and 0.3 mL of anhydrous triethmylamine was heated in a microwave at= 60°C for 10 minutes. The reaction mixture was applied t-o a column of SiO; (50% ethyl acetate in hexanes) to give 165 . mg of the title product as a lighat yellow oil (43% yield).

Example 78: Synthesis of 2-(1-Benzenesulfonyl-5-bromo-1.ai-indol-2-ylmethyl)-4-(5- chloro-2,3-dihydrobenzofura_n-7-yl)-1,1,1-trifluoro-4-methylpent=an-2-ol

Br

F. H Q F

C2 Neg?® *q ()

OCR

1 oo

A mixture of 6-(5-chloro-2,3—dihydrobenzofuran-7-yl)-6-methyl-4-tarifluoromethylhept-1-yn-4- ol (170 mg, 0.49 mmol), N-(4—bromo-2-iodophenyl)benzenesulfonarmide (220 mg, 0.50 mmol), dichlorobis(triphenylphosphine=)palladium (I) (20 mg, 0.03 mmol), and copper (I) iodide (10 mg, 0.05 mmol) in 1 mL of DMF and 0.7 mL of triethylamine was ~warmed at 70°C. After 45 minutes, the mixture was coeled and diluted with 7 mL of satumated aqueous ammonium chloride solution and extracte=d with three 7 mL portions of ethy-1 acetate. The combined

- oxganic layers were washed with two 7 ml p-ortions of saturated aqueous ammonium chloride solution, four 7 mL portions of brine, dried osver magnesium sulfate, filtered ard concentrated : ir1 vacuo. The crude residue was purified orm silica gel eluting with ethyl acet-ate-hexanes (0- - 3. 0% gradient) to afford 126 mg (39% yield) o fthe title compound.

Fxample 79: Synthesis of 4-(3-[1,3] dio>xan-2-ylphenyl)-1,1,1-triftuoro-4—methyl-2-(1H- pPyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2—ol = N —

F. x F N

SUES Fc: No BU Js

OH OH

"To a solution of {4-[6-(3-[1,3]dioxan-2-ylp henyl)-4-hydroxy-6-methyl-4-triflmzoromethylhept- 1 -ynyllpyridin-3-yl} carbamic acid tert-butyl ester (250 mg, 0.46 mmol) in 5 =nl of methanol- ~water (4:1) was added DBU (0.7 mL, 4.6 mormol) and the reaction mixture heat=ed to 65°C for 2 hour. The solution was concentrated in vacuo and the product precipitated from water. The ~yorecipitation was filtered and dried to give 1776 mg of the title compound as a white solid (86% yield).

Example 80: Synthesis of 4-(5-Chloro~2 3-dihydrobenzofuran-7-yl}-1,1, 1-trifluore-2-(2- isopropyl-SH-pyrrolo[3,2-d]pyrimidin-6-yMmethyl)-4-methylpentan-2-ol

L ge

ZN . J NN

CF, eo CF, N a CF/ 5

To a solution of N-{4-[6-(5-chloro-2 ,3-dihydrobenzofuran-7-yl)-4-hydmroxy-6-methyl-4- trifluoromethylhept-1-ynyl]-2-isopropylpyriz nidin-5-yl}-2,2,2-trifluoroacetamisde (58 mg, 0.1 mmol) in 1 mL of anhydrous dioxane was added tetramethylguanidine (0.05 ml, 0.4 mmol) : and the reaction mixture stirred and heated in oil bath maintained at 10=0°C for 1 hour.

Purification by preparative TLC over silica gel eluting with 5% methanol in dichloromethane provided the title compound as a light cream. colored solid, (25 mg, 52% yield) M+H = 482.

Claims (46)

We Claim:

1. A compound of Formula (IA) 3 R H R* RYT 1 R CF, @ wherein; R' isan aryl or heteroaryl group, each optionally independently substitutec with one to three substituent groups, wherein each substituent group of R! is independently C,-Cs alkyl, C;—Cs alkenyl, C5-Cs allcynyl, C;-Cg cycloalkyl, heterocyclyl, aryl, heteroaryl, Ci;-C—s alkoxy, C,-Cs alkenyloxy, C,-Cs alkynylox y, aryloxy, acyl, C,-Cs alkoxycarbonyl, C=;-Cs alkanoyloxy, C1-Cs alkanoyl, aroyl, aminocarbonyl, alkylaminocarbonyl, diallecylaminocarbonyl, aminocarbonyloxy, C:-Cs alkcylaminocarbonyloxy, C;-Cs dialkylamincacarbonyloxy, Cy- Cs alkanoylamino, C;-Cs alkoxycarbonylamino, C;-C; allkylsulfonylamino, aminosulfonyl, C)-Cs alkylaminosulfonyl, C,-Cs dialkylaminosialfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, or ammino wherein the nitrogen atom is optionally independently mono- or di-substituted toy C;-Cs alkyl or aryl; or ureido wherein either nitrogen atom is optionally independently substituted with C,-Cs alkyl; or C,-Cs alkylthio wherein the sulfur atom is optiona_lly oxidized to a sulfoxide or sulfone, wherein each substituent group of R! is optionally independently substituted with one to three substituent groups selected from methyl, methoxy, hmalogen, hydroxy, Ox0, cyano, heteroaryl, heterocyclyl, or amino wherein the ritrogen atom is optionally independently 1mono- or di-substituted by C,-Cs alkyl or aryl; or ureido ‘wherein either nitrogen atom is optionally independently substituted with C;-Cs alkyl;

R? and RR? are each independently hydrogen or Ci-Cs alkyl, or R? anmd R® together with the carbon atom they are commonly attached to form a C;-Cg spiro cy=cloalkyl ring; R* is C-Cs alkyl, C,-Cs alkenyl, or C,-Cs a_lkynyl, each optionally in_dependently substituted witch one to three substituent groups,

w~herein each substituent group of R* is independently C;-C; a lkyl, hydroxy, halogen,

ar-nino, or oxo; and R’ is a heteroaryl group optionally independently substituted with cone to three substituent

Zro=ups, wherein each substituent group of R® iss independently C;-Cs alkyl, C,-C; alkenyl, C>-Cs al kynyl, C;-Cg cycloalkyl, heterocws«lyl, aryl, heteroaryl, C;-Cs alkoxy, C,-Cs aI kenyloxy, C,-Cs alkynyloxy, aryloxy—, acyl, C;-Cs alkoxycarbomyl, C,-Cs alkanoyloxy, hesterocyclylcarbonyl, aroyl aminocarb-onyl, alkkylaminocarbonyl_, dialkylaminocarbonyl, arninocarbonyloxy, C;-Cs alkylaminoc arbonyloxy, C,-Cs dialkyBaminocarbonyloxy, Ci- C 5s alkanoylamino, C;-Cs alkox—ycarbonylamino, C,-Cs alkylsulfonylamino, : arminosulfonyl, C;-Cs alkylaminosu~lfonyl, C;-Cs dialkylarminosulfonyl, halogen, h=ydroxy, carboxy, cyano, trifluoromet=hyl, trifluoromethoxy, tri —fluoromethylthio, nitro, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted bsy Ci-Cs alkyl; or ureido wherein emither nitrogen atom is opotionally independently substituted with C,-Cs alkyl; or Ci-Cs alkylthio wherein the sialfur atom is optionally oxidized to a sulfoxide or sulfone,

wherein each substituent group of R® is optionally indepen dently substituted with one to three substituent groups sele~cted from C;-C; alkyl, C; -C; alkoxy, acyl, C;-C; silanyloxy, C\-C; alkoxycarbonyl, carboxy, halogen, Iydroxy, oxo, cyano, heteroaryl, heterocyclyl, or smirao wherein the nitrogen atom is optionally independently mono- or di-substittated by C;-Cs alkyl or aaryl; or ureido wherein either nitrogen atom is optionally independently substitutced with C;-Cs alkyl, or trifluoromethyl,

or a tautomer, prodrug, solvate, or salt thereof.

2. The compound of Formula (TA) according to claim 1, wherein: R' is phenyl, naphthyl, dihydirobenzofuranyl, benzofuranyl, chrom=anyl, dihydroindolyl, indolyl, dihydrobenzothienyl, benzothienyl, benzodioxolanyl, dihydrobenzoxazolyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzimidazolyl, thienyl, quinolinyl, pyridinyl, pyrimidinyl, or pyrazinyl, each optionally independently= substituted with one to three substituent groups, wherein each substituent group of R! is independently C;-Cs alkyl... C.-C; alkenyl, Cr-Cs alkynyl, C;-C; alkoxy, C,—C; alkenyloxy, C,-C; alkanoyl, C;-C; amlkoxycarbonyl, C;-C; alkanoyloxy, halogen, hy-droxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, or C;-C; alkylthio wherein the sulfur atom is optionally oxiclized to a sulfoxide or sulfone, wherein each substituent group of R! is optionally independermtly substituted with a substituent group selected from methyl, methoxy, halogen, hyedroxy, oxo, cyano, or amino; R? and R? are each independently hydrogen or C,-C; alkyl, or R? and R’ together with the carbon atom they are commonly attached to form a C;-Cs spiro cycleoalkyl ring; R*is CH;; and R’ is an imidazolyl, pyridyl, indolyl, azaindolyl, diazaincolyl, benzofuranyl, furanopyridiny], furanopy rimidinyl, imidazolopyrimidinyl, mimidazolopyridazinyl, - imidazolopyrazinyl, benzothienyl, thienopyridinyl, thienopyrimidin yl, thienopyridazinyl, benzoxazolyl, oxazolopyridinyl, benzothiazolyl, thiazolopyridimyl, benzimidazolyl, imidazolopyridinyl, quinolimyl, or isoquinolinyl group, each opti_onally independently substituted with one to three substituent groups,

wherein each substituent group of R® is independently C;-C= alkyl, C,-C; alkenyl, phenyl, hydroxy, C;-C; alkoxy, methoxycarbonyl, a-minocarbonyl, Ci-C; } alkylaminocarbonyl, C,-C; dialkylaminocarbonyl, heterocyclylc arbonyl, fluoro, chloro, bromo, oxo, cyano, trifluoromethyl, or C,-C; alkylthio wher-ein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of R® is optionally independ -ently substituted with a substituent group selected from methyl, methoxy, fl—uoro, chloro, bromo, trifluoromethyl, hydroxy, cyano, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by Ci-Cs alkyl or aryl or a tautomer, prodrug, solvate, or salt thereof.

3. The compound of Formula (IA) according to claim 1, wherein: : R! is phenyl, naphthyl, pyridyl, cbromanyl, dihydrobenzofuranyl, or benzofuranyl, each optionally independently substituted with one or two substituent g=roups, wherein each substituent group of R! is independently methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, hydroxy, trifluoromethyl, triflucromethoxy, cyano, or C;-Cs alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, R® and R? are each independently methyl, or R* and R® together with tlhe carbon atom they are commonly attached to form a spiro cyclopropyl ring; R* is CH,; and R* is a pyridyl, indolyl, azaindolyl, diazaindolyl, benzofumranyl, furanopyridinyl, thienopyridinyl, benzoxazolyl, benzimidazolyl, quinolinyl, or iseoquinolinyl group, each optionally independently substituted with one to three substitnent groups,

wherein each substituent group of IR’ is independently methwl, phenyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylamiinocarbonyl, mosrpholinylcarbonyl, fluoro, chloro, bromo, cyano, or trifluoromethy®, hydroxyl, cyano, or amino wherein the nitrogen atormm is optionally independently n—ono- or di- substituted by C;-Cs alkyl or aryl or a tautomaer, prodrug, solvate, or salt thereof.

4. The compound of Formula (1A) according to clamim 1, wherein R? and R® together with the carbon atom they are commonly attached to form a C3-Cg spiro cycloalkyl ring.

S. The compound of Formula (IA) according teo claim 1, wherein R? and IR} are each independemtly hydrogen or C,-Cs alkyl.

6. The cormpound of Formula (IA) according to clairn 1, wherein: R! is phenyl, dihydrobenzofuranyl, or benzcofiranyl, each optionally in dependently substituted with one to three substituent groupss, wherein each substituent group of R! is independently C,-C; alkyl, C,-C3 alZkenyl, C>-Cs alleynyl, C-C; alkoxy, C,-C; alkenyloxy, C; -C; alkanoyl, C;-C; alkoxycartoonyl, C;-Cs allcanoyloxy, halogen, hydroxy, carboxy, cyano, trifluoromethyl, nitro, or Ci-C; alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sul fone; and R?and R® are each independently hydrogen or Cy-C; alkyl, or a tautomner, prodrug, solvate, or salt thereof.

7. The cormpound of Formula (IA) according to clairm 1, wherein:

W” 0 2005/030213 P=CT/US2004/031009 R* is a pyridyl, indolyl, azaindolyl, diazaindolyl, benzofur anyl, furanopyridinyl, thienopyridinyl, benzoxazoly~1, benzimidazolyl, quinolinyl, or iscquinolinyl group, each optionally independently subsstituted with one to three substituent gzgroups, or a tautomer, prodrug, solvate, or salt thereof.

8. The compound of Formula (YA) according to claim 1, wherein: R' is thienyl, phenyl, naphthyl, dihydrobenzofuranyl, ben=ofuranyl, chromanyl, dihydroindolyl, indolyl, dihydrobenzothienyl, benzothieenyl, benzodioxolyl, dihydrobenzoxazolyl, benzowxazolyl, benzisoxazolyl, benzpyramzolyl, benzimidazolyl, thienyl, quinolinyl, pyridinyk, pyrimidinyl, or pyrazinyl, each opptionally independently substituted with one to three substituent groups, wherein each substituent greoup of R! is independently C;-C; alk—yl, C,-C; alkenyl, C>-Cs alkynyl, C,-C; alkoxy, C,-C; alkenyloxy, C;-Cs alkanoyl, C;-C= alkoxycarbonyl, C;-Cs alkanoyloxy, aryl, hetero aryl, halogen, hydroxy, carboxy, cyano, heterocyclyl, trifluoromethyl, trifluoromesthoxy, nitro, aminosulfonyl, dialkyelaminosulfonyl, amino ’ wherein the nitrogen atom i s optionally independently mono- or di-substituted by C;-Cs E alkyl or aryl; or ureido wwwherein either nitrogen atom is opotionally independently substituted with C;-Cs alky~], or C;-C; alkylthio wherein the stalfur atom is optionally oxidized to a sulfoxide or sialfone, wherein each substituent group of R! is optionally indepenmdently substituted with one or two substituent groups selected from methyl, metheoxy, halogen, hydroxy, oxo, cyano, morpholinyl, or amino wherein the nitrogen atom is optionally independently mono- or «li-substituted by C,-Cs alkyl; R? and R® are each independently hydrogen or C;-C; alkyl, or R? anad R? together with the carbon atom they are commonly attached to form a C;-Cg spiro cycloalkyl ring; R*is CHy; and

R® is an imidazolyl, pyridyl, indolyl, indazolyl, azaindolyl, dRiazaindolyl, benzofuranyl, furanopyridiny]l, furanopyrimidinyl, imidazolopyrimidinyws, imidazolopyridazinyl, imidazolopyrazinyl, benzorthienyl, thienopyridinyl, thienopyrimmidinyl, thienopyridazinyl, benzoxazolyl, oxazolopywidinyl, benzothiazolyl, thiazolopoyridinyl, benzimidazolyl, imidazolopyridinyl, quinolinyl, or isoquinclinyl group, eacin optionally independently substituted with one to three substituent groups, wherein each substituent group of R® is independently C=,-Cs alkyl, C,-Cs alkenyl, phenyl, heteroaryl, heterocyclyl, acyl, dialkylaminossulfonyl, C;-C; alkoxy, . methoxycarbonyl, axninocarbonyl, C-Ca alkyMaminocarbonyl, CG, _ dialkylaminocarbonyl, heterocyclylcarbonyl, hydroxy, oxwo, fluoro, chloro, bromo, cyano, trifluoromethyl, amino wherein the nitrogen atom i_s optionally independently mono- or di-substituted by C;-Cs alkyl or aryl; or ureido whe=rein either nitrogen atom is optionally independently substituted with C;-Cs alkyl; or C-Cs alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substitiient group of R’ is optionally inde=pendently substituted with one or two substituent groups selected from methyl, metlmoxy, fluoro, chloro, bromo, oxo, trifluoromethyl, hydroxy, cyano, morpholinyl, pyrr-olidinyl, or amino wherein the nitrogen atom is optionally independently mono- or d=i-substituted by C,-C; alkyl or aryl, or a tautomer, prodrug, solvate, or salt thereof.

9. The compound of Formula (IA) according to claim 1, wherein: R! is thienyl, phenyl, naphthyl, pyridyl, chromanyl, benzodioxolyl, dihydrobenzofuranyl, or benzofuranyl, each optiomally independently substituted wimth one or two substituent groups,

wherein each substituent group of R! is independently methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, hydroxy, trifluoromethyl, trifluoromesthoxy, morpholinylmethyl, dimethylaminomethyl, aminosulfonyl, dimethylaminosulfeonyl, phenyl, pyrimidinyl, : pyridinyl, thiemyl, naphthalenyl, morpholinyl, piperidinyl, cyano, or C,-C; alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of R! is optionally independently substituted with ’ one or two groups selected from cyano, chloro, bromo, or fluoro; R? and R3 are each independently methyl or ethyl, or R* and R® toszether with the carbon atom they are commomly attached to form a spiro cyclopropyl ring; R* is CH,; and R® is a pyridyl, indolyl, azaindolyl, diazaindolyl, benzo-furanyl, thienopyridazinyl, furanopyridinyl, thienopyridinyl, benzoxazolyl, benzimraidazolyl, quinolinyl, or isoquinolinyl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R® is independently methyl, phenyl, methoxy, ethoxy, isopropoxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, morpholinylcarbonyl, morpholirayl, piperidinyl, phenoxy, pyrrolidinyl, acetyl, pivaloyl, ethylcarbonyl, isopropylcarbonyl, pyridinyl, pyrimidiny], trifluoromethyl, fluoro, chloro, bromo, hydroxy, cyano, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C;-Cs alkyl or aryl or trifluoromethy1, wherein each substituent group of R® is optionally ind ependently substituted with one or two substituent groups selected from cyano, halogen, methyl, dimethylamino, morpholiny1, pyrrolidinyl, or piperidinyl, or a tautomer, prodrug, solvate, or salt thereof.

10. The «compound of Formula (IA) accordingz to claim 1, wherein: R' is phenyl, dihydrobenzofuranyl, or benzofuranyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of Rliss independently Cy-C; alkyl, C2--Cs alkenyl, Cr-Cs alkynyl, C;-C; alkoxy, C,-C; alkenylo~xy, C;-C; alkanoyl, C1-C3 alko-xycarbonyl, Ci-Cs a 1kanoyloxy, halogen, hydroxy, carbo=y, cyano, trifluoromethyl, nitr<o, aryl, heteroaryl, Ineterocyclyl, or C,-C; alkylthio whemrein the sulfur atom is optionally oxidized to a sulfoxide or sulfone; and R? and R_3 are each independently hydrogen or C;-C; alkyl, or a tautomer, prodrug, solvate, or salt thereof.

. 11. The compound of Formula (JA) accordings to claim 1, wherein: R® is a pyridyl, indolyl, azaindolyl, diazaindolyl, benzofuranyl, thienopyridazinyl fur-anopyridinyl, thienopyridinyl, be=nzoxazolyl, benzimidazolyl, quinolinyl, or iso quinoliny! group, each optionally independently substituted with one to three subostituent groups, or a tautomer, prodrug, solvate, or salt thereof.

12. A plaarmaceutical composition comprising an effective amount of a compound according to one of cL aims | to 11, or a tautomer, prodrugs, solvate, or salt thereof, and =a pharmaceutically acceptable excipient or carrier.

13. A cosxnpound of Formula (IB)

R® OH AL oR RR 1, aR R R (IB) wherein: R! is an axyl or heteroaryl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of Rlis indegpendently C,-Cs alkyl, C2-Cs allikenyl, C>-Cs alkyrayl, C;-C; cycloalkyl, heterocyclyl, aryl, heteroaryl, C;-Cs; alkoxy, C:-Cs alkerayloxy, Co-Cs alkynyloxy, aryloxy, acyl CC; alkoxycarbonyl, C;-Cs amlkanoyloxy, C\-C5s alkanoyl, aroyl, aminocarbonys]l, C;-Cs alkylaminocarborayl, C;-Cs dialk—ylaminocarbonyl, aminocarbonyloxy, C,-Cs alkylaminocarbonyloxy, C;-Cs dialk—ylaminocarbonyloxy, C;-Cs alkanoyla-mino, C;-Cs alkoxycarbonylarmino, C;-Cs alkyl sulfonylamino, aminosulfonyl, Ci-Cs alkylaminosulfonyll, Ci-Cs dialk=ylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, triflu_oromethoxy, nitro, or arnino wherein th e nitrogen atom is optionally independently mono- or di-substituted by C,-C;s alkyl or ars]; or ureido wherein either nitrcgen atom is optiosnally independently substituted with C-Cs alkyl; or C;-Cs alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxcide or sulfone, wherein each substituent group of R! is optionally independently subsstituted with ore to three substituent groups selected from methyl, methoxy, haloge=n, hydroxy, 0><0, cyano, heteroaryl, heterocyclyl, or amino wherein the nitrogeen atom is optionally independently mono- or di-substituted by C;-Cs alkyl or ary=l; or ureido whherein either nitrogen atom is optionally independently substituted with C;-Cs alkyl; R? and R? are each independently C,-Cs alkyl;

R' is C;-Cs alkyl, C,-Cs alkenyl, or C-CCs alkynyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R* is independently C,-Cs alkyl, hydroxy, halogen, amino, or 0xo; i R’ is a heteroaryl group optionally indeependently substituted with one to three substituent groups, wherein each substituent group of =’ is independently C;-Cs alkyl, C=-Cs alkenyl, C2-Cs alkynyl, C3-C; cycloalkyl, heterocyclyl, aryl, heteroaryl, C;-C; alkoxy, Cz-Cs alkenyloxy, C;-C; alkynyloxy, aryl=oxy, acyl, C;-Cs alkoxycarbonyl, CC -Cs alkanoyloxy, aminocarbonyl, alkylaminocarbonsyl, dialkylaminocarbonyl, aminoc arbonyloxy, Ci-Cs alkylaminocarbonyloxy, C;-Cs diadkylaminocarbonyloxy, C;-Cs alkaanoylamino, C;-Cs alkoxycarbonylamino, Ci-Cs alkylsulfonylamino, aminossulfonyl, Ci1-Cs alkylaminosulfonyl, C,-Cs dialkyl aminosulfonyl, halogen, hydroxy~, carboxy, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, mitro, or ammino wherein the nitrogen atom is optionally indepe=ndently mono- or di-substituted Wy C,-Cs alkyl; or ureido wherein either nitrogen atorm is optionally independently subsstituted with C;-Cs alkyl; or C;-C; alkylthio wherein thme sulfur atom is optionally oxidize=d to a sulfoxide or sulfone, wherein each substituent group of R® is optionally independently substituted with one to three substituent groups selected from C;-C; alkyl, C;-C= alkoxy, halogen, hydroxy, oxo, cyano, heteroaryl, heterocyclyl, or amino wherein tle nitrogen atom is optionally independently mono— or di-substituted by C;-Cs alkyl or aryl; or ureido wherein either nitrogen atom is optionally independently substituted with C;-Cs alkyl, or trifluoromethyl, R°® is hydrogen, C;-C; alkyl, C,-Cy alkeenyl, C>-Cg alkynyl, carbocycle, heterocyclyl, aryl, heteroaryl, carbocycle-C,-Cy alkyl, amryl-C;-Cs alkyl, aryl-C;-Cs haloa_Tkyl, heterocyclyl- C-C; alkyl, carboxy, alkoxycarbonyw] heteroaryl-C;-Cj alkyl, carbocy—cle-C,-Cg alkenyl,

aryl-C;-Cy alkenyl, heterocyclyl-C,-Cg alkenyl, or heteroar—yl-C,-Cy alkenyl, each optionally independently suabstituted with one to three substituent groups,

wherein each substituent group of R® is independently C,-Cs allyl, C,-Cs alkenyl, C;-Cs alkynyl, C;-Cs cycloalkyl, phenyl, C;-Cs alkoxy, phenoxy, C;-€C; alkanoyl, aroyl, C;-Cs alkoxycarbonyl, C;-Cs alkanoyloxy, aminocarbonyloxy, C;-Cs alkylaminocarbonyloxy, C,-C;s dialkylaminocarbonyloxy, aminocarbonyl, C,-Cs alk—ylaminocarbonyl, C;-Cs dialkylaminocarbonyl, C,-Cs alkanoylamino, C;-Cs alkox ycarbonylamino, C;-Cs alkylsulfonylamino, C;-C; alkylaminosulfonyl, C;-Cs dialkyl aminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, nitro, amino wlherein the nitrogen atom . is optionally independently mono- or di-substituted by C;-Cs alkyl; or ureido wherein either nitrogen atom is optionally independently substituted wilith C;-Cs alkyl; or C,-Cs Co alkylthio wherein the sulfur atom is optionally oxidized to a sul foxide or sulfone, wherein RS cannot be trifluoromethyl, . or a tautomer, prodrug, solvate, ox salt thereof.

El

14. The compound of Formula (IB) according to claim 13, wherein:

R' is thienyl, phenyl, dihydrobenzofuranyl, benzofuranyl, dRihydroindolyl, indolyl, dihydrobenzothienyl, benzothienyl, benzodioxolanyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzimidazolyl, quinolinyl, pyridinyl, pyrimidi-nyl, or pyrazinyl, each optionally independently substituted with one to three substituent groups,

wherein each substituent group of R! is independently C;-Cs allyl, Cp-C5 alkenyl, C,-C; alkynyl, C,-C; alkoxy, C2 -C; alkenyloxy, Ci-C; alkanoyl, C;-C 5 alkoxycarbonyl, C;-C; } alkanoyloxy, halogen, hydroxy, carboxy, cyano, trifluoromethyl, mitro, or C;-C, alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of R! is optionally independllently substituted with a substituent group selected from methyl, methoxy, halogem, hydroxy, oxo, cyano,

Wa 2005/030213 PaCT/US2004/031009 heteroaryl, heterocyclyl, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C;-Cs alkyl or aryl;

R? and R? are each independently C,-C; alkyl;

R* is CHy;

R® is a pyridyl, indolyl, azaindolyl, oenzofuranyl, furanylpyridinyM, imidazolopyridinyl, imidazolopyrimidinyl, ~ imidazolopoyridazinyl, imidazolopyraz=inyl, benzothienyl, thienopyridinyl, benzoxazolyl, toenzothiazolyl, benzimidazo1yl, quinolinyl, or isoquinolinyl group, each optionally independently substituted with one to three substituent groups,

wherein each substituent group o f R® is independently C;-Cs alkyl, C,-C3 alkenyl, phenyl, hydroxyl, oxo, C;-C; alkoxy, methoxycarbonyl, a minocarbonyl, Ci-G; alkylaminocarbonyl, C;-C; dialkyl=aminocarbonyl, heterocyclylca—rbonyl, fluoro, chloro, bromo, cyano, trifluoromethyl, or C-C; alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of R® is optionally independemntly substituted with a substituent group selected frorm methyl, methoxy, fluoro, chloro, bromo, cyano, trifluoromethyl; heteroaryl, heterocyclyl, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C;-Cs alksyl or aryl and

Ré is C;-Cs alkyl, C-Cs alkenyl, C;-C=¢ cycloalkyl, phenyl, C3-Cs ¢ ycloalkyl-C-Cs alkyl, phenyl-C;-Cs alkyl, phenyl-C;-C; haloalkyl, C3-Cs cycloalkyl-C,-CC;5 alkenyl, phenyl-C,- C; alkenyl, each optionally independently substituted with one to three substituent groups,

wherein each substituent group of ER is independently C,-C3 alkyl, C,-C; alkenyl, C;-C; alkynyl, C;-C; alkoxy, amirocarbonyl, C;-C; alkylarmninocarbonyl, C;-C;

dialkylaminocarbonyl, halogen , hydroxy, carboxy, cyano, trifluoxomethyl, nitro, or Ci- C; alkylthio wherein the sulfur atom is optionally oxidized to a sumlfoxide or sulfone, or a tautomer, prodrug, solvate, or salt thereof. )

15. The compound of Formula (IB) ac<cording to claim 13, wherein: ' R! is thiemyl, phenyl, pyridyl, dilhydrobenzofuranyl, or benzofuraanyl, each optionally independently substituted with ome or two substituent groups, wherein each substituent group» of R! is independently methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, hydroxy, trifluoromethyl, cyano; or C;-C=s alkylthio wherein the sulfur atom is optionally oxidizzed to a sulfoxide or sulfone; R? and R? are each methyl; R* is CHy; . R® is a pyridyl, indolyl, azaindolyl, diazaindolyl, benzofix ranyl, benzoxazolyl, benzimidazolyl, quinolinyl, or isoquinolinyl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R’ is independenstly methyl, phenyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, di methylaminocarbonyl, morpholinylcarbonyl, hydroxy, oxo, fluoro, chloro, cyano, or triflmuoromethyl; and R® is C;-Cs alkyl, C3-Cs cycloalkyl, C;-Cs cycloalkylmethyl-, or be=nzyl, each optionally independently substituted with ore to three substituent groups, wherein each substituent group of R® is independently methyl, methoxy, fluoro, chloro, bromo, cyano, trifluoromethyl, <r hydroxy,

or a tautomer, prodrug, s«olvate, or salt thereof.

16. The compound of Formula (IB) according to claim 135, wherein: R! is thienyl, phenyl, dihydrobenzofuranyl, or benzoftaranyl, each optionally ind-ependently substituted with orme to three substituent groups, wherein each subwstituent group of R' is independently C;-C; alkyl, C;-C; alke=nyl, C2-C3 alkynyl, C,-C; al koxy, C>-C; alkenyloxy, C,1-C3 aJkanoyl, C,-C; alkoxycarbonyl, Ci-Cs : TL alkanoyloxy, halogen, hydroxy, carboxy, cyammo, trifluoromethyl, nitro, or C;-Cs alkylthio whereirm the sulfur atom is optionally oxi=dized to a sulfoxide or sulfone; and R? and R? are each independently C,-Cs alkyl, or a tautomer, prodrug, solvate, or salt thereof,

17. The compound of Fostmula (IB) according to claim 13 , wherein: R! is thienyl, phenyl, nap- hthyl, pyridyl, chromanyl, dihyydr—obenzofuranyl, or benzofur—anyl, each optionally indepenciently substituted with one or two substituent groups, wherein each subwstituent group of R! is indepenide=ntly methyl, ethyl, methoxxy, ethoxy, fluoro, chloro, bromo, hydroxy, trifluoromethyl, c=yano, or C;-C;s alkylthio w~herein the sulfur atom is optionally oxidized to a sulfoxide or sulfone; R? and R? are each methy-1; R* is CHy; R® is a pyridyl, imdolyl, azaindolyl, diazaindol=yl, benzofuranyl, furancopyridinyl, thienopyridinyl, bemzoxazolyl, benzimidazolyl, guiraolinyl, or isoquinolinyl group, each optionally indepencIently substituted with one to thire=e substituent groups,

wherein each substituent group of R’ is independeently methyl, phenyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminoaminocarbonyl, morpholinylcarbonyl, pyridinyl.. hydroxy, fluoro, chloro, bromo, cyano, or trifluoromethyl; and RS is C,-Cs alkyl, C3-Cs cycloalkyl, C3-Cs cycloalkylmethyl-, or benzyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of RS is independently methyl, methoxy, fluoro, chloro, bromo, cyano, trifluoromethyl, or hydroxy, or a tautomer, prodrug, solvate, or salt thereof. : : 18. A pharmaceutical composition comprising an effective amount of = compound according to to one of claims 13 to 17, or a tautomer, prodrug, solvate, or salt thereof=, and a pharmaceutically acceptable excipient or carrier.

19. A compound of Formula (JC) 3 R H 1 6 R R ac wherein: R! is an aryl or heteroaryl group, each optionally independently subsstituted with one to three substituent groups, wherein each substituent group of R' is independently C;-Cs allyl, C,-Cs alkenyl, C5-Cs alkynyl, C;-Cg cycloalkyl, heterocyclyl, aryl, heteroaryl, C;-Cs alkoxy, C,-Cs alkenyloxy, C,-Cs alkynyloxy, aryloxy, acyl, C,-Cs alkoxycarbonyl, C,-Cs alkanoyloxy, C,-Cs alkanoyl, aroyl, aminocarbonyl, C,-Cs alkylsaminocarbonyl, C;-Cs dialkylaminocarbonyl, aminocaxbonyloxy, C;-Cs alkylaminccarbonyloxy, Ci-Cs dialkylaminocarbonyloxy, C;-Cs alkanoylamino, C;-Cs alkoxyc=arbonylamino, Ci-Cs alkylsulfonylamino, aminosualfonyl, C,-Cs alkylamisnosulfonyl, C1-Cs dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyarmo, trifluoromethyl, triflucromethoxy, nitro, or amino wherein the nitrogen atom is op#tionally independently mono- or di-substituted by C,-Cs alkyl or aryl; or ureido wherein e=ither nitrogen atom is optionally independently substitated with Cy-Cs alkyl; or C,-Cs alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent grouap of R! is optionally independeently substituted with one to three substituent groupos selected from methyl, methomxy, halogen, hydroxy, oxo, cyano, heteroaryl, heterocyclyl, or amino wherein tThe nitrogen atom is optionally independently mon o- or di-substituted by C;-Cs alkyl or aryl; or ureido wherein either nitrogen atorm is optionally independently svabstituted with Ci-Cs alkyl, R® and R® are each independently C,-Cs alkyl; R* is C;-C;s alkyl, C,-Cs alkenyl, or C= -Cs alkynyl, each optionally inde=pendently substituted with one to three substituent groups, wherein each substituent group off R* is independently C;-Cs alkyl _, hydroxy, halogen, or 0X0; R? is a heteroaryl group fused with. a saturated or partially saturated carbocyclic ring optionally independently substitute«d with one to three substituent gr oups, wherein each substituent group of Ris independently C,~Cs alkyl_, C,-Cs alkenyl, C;-Cs alkynyl, C;-Cg cycloalkyl, heterocyclyl, aryl, heteroaryl, ,-Cs alkoxy, C»-Cs alkenyloxy, C,-Cs alkynyloxy, ary/loxy, acyl, Ci-Cs alkoxycarbony~], C,-Cs alkanoyloxy, aminocarbonyl, alkylaminocarbomyl, dialkylamminocarbonyl, amirocarbonyloxy, C;-Cs R alkylaminocarbonyloxy, C;-Cs di alkylaminocarbonyloxy, C,-Cs aalkanoylamino, C;-Cs alkoxycarbonylamino, C;-Cs alkylsulfonylamino, C;—Cs alkylaminosulfonyl, C 1-Cs dialkylaminosulfonyl, halogen, hydroxy, carbo=xy, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, or amino wherein the nitrogen atorm is

- optionally independently mono- or di-substituted by &C,-C;s alkyl; or ureido whe=rein either nitrogen atom is optionally independently substituted with C;-Cs alkyl; or C—1-Cs . alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of R® is optionally independently substituted wwith one to three substituent groups selected from C;-C-3 alkyl, C,-C; alkoxy, halogeen, hydroxy, oxo, cyano, heteroaryl, heterocyclyl, or amano wherein the nitrogen atomm is optionally independently mono- or di-substituted byw C;-Cs alkyl or aryl; or uresido wherein either nitrogen atom is optionally independently substituted with C4-Cs alkyl, or trifluoromethyl; and RS is hydrogen, C;-C; alkyl, C,-Cy alkenyl, C,-Cg alkynyl, carbocycle, heterocyclyl, amryl, heteroaryl, carbo cycle-C;-Cy alkyl, carboxy, trifluoromethyl, alkoxycarbonyl, aryl-Cm-Cs alkyl, aryl-C;-Cg haloalkyl, heterocyclyl-C;-Cs alkyl, hete=roaryl-C,-Cs alkyl, carbocy—=<le- Cy-Cg alkenyl, aryl-C,-Cy alkenyl, heterocyclyl-C,-Caz alkenyl, or heteroaryl-C=-Cg alkenyl, each optionally independently substituted with ore to three substituent groupss, wherein each substituent group of R® is independently C=,-Cs alkyl, C,-C; alkenyl, C=-Cs alkynyl, C;-Cg cycloalkyl, phenyl, C;-Cs alkoxy, pheno=cy, C,-Cs alkanoyl, aroyl, Cm -Cs alkoxycarbonyl, C,-Cs alkanoyloxy, aminocarbonyloxy.. C:-Cs alkylaminocarbonylcoxy, Ci-Cs dialkylamminocarbonyloxy, aminocarbonyl, C;-&C; alkylaminocarbonyl, C; -Cs dialkylaminocarbonyl, C;-Cs alkanoylamino, C;-Cs alkoxycarbonylamino, Cp -Cs alkylsulfonylamiino, C,-Cs alkylaminosulfonyl, C,-Cs dialkylaminosulfonyl, halogzen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, nitro, armino wherein the nitrogen astom is optionally independently mono- or di-substituted by C;-C; alkyl; or ureido whemrein either nitrogen atom is optionally independently substitmated with C;-Cs alkyl; or C; Cs alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, or a tautomer, prodrug, solvate, or salt thereof.

20. The compound of Formula (IC) according to claim 1S, wherein:

R' is thienyl, phenyl, naphthyl, dihydrobenzo—furanyl, benzofuranyl, chrcomanyl, dihydroindolyl, indolyl, dihydrobenzothienyl, benzothienyl, benzodio>olanyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, toenzimidazolyl, thienyl, quimolinyl, pyridiny1, pyrimidinyl, or pyrazinyl, each optional ly independently substituted with one to three substituent groups,

wherein each substituent group of R! is independently C,-C; alkyl, C,-C; alkenyl, C>-Cs alkyny’1, C;-C; alkoxy, C,-C; alkenyloxy, C,-C; aalkanoyl, C,-C; alkoxycarbonyR, C,-Cs alkanoyloxy, halogen, hydroxy, carboxy, cyamo, trifluoromethyl, nitro, or C;-C;

alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of R' is optiomnally independently substituted with a sub stituent group selected from methyl, metThoxy, halogen, hydroxy, oxo, cyano, heteroaryl, heterocyclyl, or amino whereimn the nitrogen atom is optionally independently mono- or di-substituted by C;-C=s alkyl or aryl;

R? and R? are each independently C,-C; alkyl;

R'is CHy;

R® is a N-linked heteroaryl with a fused 5-7 membered saturated carbocyclic ring opwtionally and indespendently substituted with one to three sub_stituent groups wherein each substituent group of R® is indepeendently C;-C; alkyl, C,-C; malkenyl, phenyl, C,-C; alkoxy, methoxycarbonyl, amino-carbonyl, C;-C; alkylaminocamrbonyl, CC; dialkylaminocarbonyl, heterocyclylcarbomayl, fluoro, chloro, bromo, cyano, trifluoromethyl, or C,-C; alkylthio wherein the sTulfur atom is optionally oxidizzed to a sulfoxi de or sulfone,

wherein each substituent group of R’ is optionally independe=ntly substituted with a substituent group selected from methyl, methoxys, flumoro, chloro, bromo, trifluoromethyl, heteroaryl, heterocyclyl, or amino wherein the nitrogen atom is optionally independently mnono- or di-substituted by C,-€C5 alkyl or aryl; and R¢ is C1-Cs alkyl, C,-Cs alkenyl, Cs-Cs cycloalkyl, trifliaorommethyl, phenyl, Ci-Cs cycloalkyl-C:-C; alkyl, phenyl—C;-C; alkyl, phenyl-C1-C; hal oalkyl, C3-C¢ cycloalkyl-C»- Cs alkenyl, phenyl-C,-Cs alkerayl, each optionally independently substituted with one to three substituent groups, wherein each substituent growp of R® is independently C;-C5 alkyl, C,-C; alkenyl, C2-C3 alkynyl, C;-C; alkoxy, aminocarbonyl, C;-C; alkylarminocarbonyl, C;-C; dialkylaminocarbonyl, halogen, hydroxy, carboxy, cyano, trifluomromethyl, nitro, or C;- C; alkylthio wherein the sulfur stom is optionally oxidized to a su_lfoxide or sulfone, or a tautomer, prodrug, solvate, or salt thereof.

21. The compound of Formula (IC) a<cording to claim 19, wherein: R'is thienyl, phenyl, naphthyl, pyridyl, chromanyl, dihydrobenzofuranyl, or benzofuranyl, each optionally independently substituted with one or two substituent groups, wherein each substituent group of R' is independently meth.yl, et=hyl, methoxy, ethoxy, fluoro, chloro, bromo, hydroxy, trifluoromethyl, cyano, or C;-Cs alkylthio wherein the sulfur atom is optionally oxidi zed to a sulfoxide or sulfone; R? and R® are each methyl; R*is CHy;

- R’ is a N-linked pyrrole, pyrazole, or imidazole fused to a 5-7 membered saturated oo carbocyclic ring optionally and independently substituted with one to three substituent : groups, wherein each substituent group of R® is independently methyl, phenyl, methoxycarbcanyl, aminocarbonyl, methylaminocarbonyl, dimethylamin oaminocarbonyl, morpholinylcarbonyl, fluoro, chloro, bromo, cyano, hydroxy, oxo, or trifluoromethyl; and RS is C,-Cs alkyl, C3-Cs cycloalkyl, trifluoromethyl, Ci-Cg cycloalkylmethyl-, or benzyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R® is independently naethyl, methoxy, fluoro, chloro, bromo, cyano ., trifluoromethyl, or hydroxy, or a tautomer, prodrugs, solvate, or salt thereof.

22. The compound o=f Formula (IC) according to claim 19, wherein: R! is thienyl, pohenyl, naphthyl, dihydrobenzofuranyl, benzofuranyl, chromanyl, dihydroindolyl, indolyl, dihydrobenzothienyl, bemzothienyl, benzodioxolanyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzimidazolyl, thienyl, quinolinyl, pyridinyl, pyrirmidinyl, or pyrazinyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R! is independently C ;-C; alkyl, C2-C; alkenyl, C,-C; alkynyl, C;~-C 5 alkoxy, C,-C; alkenyloxy, C;-C; alkanoy/l, C;-C; alkoxycarbonyl, Ci-C, alkanoyloxy, halogen, hydroxy, carboxy, cyano, trifluoromethyl, nitro, aryl, heteroaryl, heterocyclyl, or C;-C; alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone,

wherein each substituent group of R! is optionally independently substituted with 2 substituent group s elected from methyl, methoxy, Imalogen, hydroxy, oxo, cyan=o, heteroaryl, heterocyclyl, or amino wherein the nitrogen atom is optionally

. independently mono- or di-substituted by C,-Cs alkyl wor aryl; R? and R? are each independemtly C;-C; alkyl; R'is CH; . R’ isa N-linked heteroaryl with a fused 5-7 membered satura. ted carbocyclic ring optionally and independently subst® tuted with one to three substituent groups wherein each substitue=nt group of R’ is independentiwy C;-Cs alkyl, C,-C3 alkenyl, - phenyl, C-C; alkoxy, methoxycarbonyl, aminocarbonywl, C;-C; alkylaminocarbony=1, Ci-C; dialkylaminocambonyl, heterocyclylcarbonyl, flimoro, chloro, bromo, cyano, trifluoromethyl, hydroxyl, oxo, or Ci-C; alkylthio where-n the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of R’ is optionally inclependently substituted with a substituent group selected from methyl, metho=xy, fluoro, chloro, bromo, trifluoromethyl, het-eroaryl, heterocyclyl, or amino wherein the nitrogen atom is - optionally independe=ntly mono- or di-substituted by Cxa-Cs alkyl or aryl; and

. RS is C-Cs alkyl, C-Cs alkenyl, C3-Cs cycloalkyl, trisfluoromethyl, phenyl, Ci-Cg cycloalkyl-Ci-C; alkyl, p henyl-C;-C; alkyl, phenyl-C,-C; haloalkyl, C;-C¢ cycloalkyl-C=- C; alkenyl, phenyl-C;-C=s alkenyl, each optionally indepen dently substituted with one t-o . three substituent groups, wherein each substituerst group of RS is independently C,- C; alkyl, C;-C; alkenyl, C,-C=4 alkynyl, C;-C; alkoxy, aminocarbonyl, Ci-Cs allcylaminocarbonyl, C;-C=, dialkylaminocarbonyl, aalogen, hydroxy, carboxy, cyano, trifluoromethyl, nitro, or C,; - C; alkylthio wherein thes sulfur atom is optionally oxidizecH to a sulfoxide or sulfone,

or— a tautomer, prodrug, solvate, or salt thereof.

23. The compound of Formula (IC) according to claim 19, wherein: R 1 is thienyl, phenyl, naphthyl, pyridyl, ckaromanyl, dihydrobenzofuranyl, or toenzofuranyl, each optionally independently substitutecd with one or two substituent groups , wherein each substituent group off R! is independently methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, hydroxy, trifluoromethyl, pyridinyl, pyrinrmidinyl, pyrazinyl, cyano, or C,-C;s alkylthio whereira the sulfur atom is optionally oxidized to a sulfoxide or sulfone; wherein each substituent group «of R! is optionally independently substituted with a substituent group selected from cy~ano or halogen R= snd R® are each methyl; R= is CH; R= is a N-linked pyrrole, pyrazole, or imidazole fused to a 5-7 membered saturated } carbocyclic ring optionally and inclependently substituted with one to three substituent groups, wherein each substituent group of R® is independently methyl, phenyl, methoxycarbonyl, =aminocarbonyl, methylaminocarbonyl, dimethylaminoaminocarbonyl, m_ormpholinylcarbonyl, fluoro, chloro, bromo, cyano, hydroxy, oxo, or trifluoromethyl; =and RS is C-Cs alkyl, C3-Cs cycloalkyl, trifluoromethyl, C3-C¢ cycloalkylm ethyl-, or benzyl, each optionally independently subst-ituted with one to three substituent groups,

wherein each substituent group of R® is inedependently methyl, methoxy, fluoro, chloro, bromo, cyano, trifluoromethyl, or hydroxy. or a tamatomer, prodrug, solvate, or salt thereof.

24. The compound of Formula (IC) according to c=laim 19, wherein: R! is thienyl, phenyl, naphthyl, pyridyl, chromany®, dihydrobenzofuranyl, or benz=ofuranyl, each optionally independently substituted with one or two substituent groups, wherein each substituent group of R' is immdependently methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, hydroxy, trifluoromethyl, furanyl, thienyl, pyrrolyM, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazoNyl, pyrazolidinyl, isoxazolyl, isothiazolyl, : oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, piperidinyl, morpholinyl, : thiomorpholinyl, pyridazinyl, pyrimiedinyl, pyrazinyl, piperazirayl, indolyl, benzofuranyl, benzothienyl, indazolyl, Yoenzimidazolyl, cyano, or Cxg-Cs alkylthio wherein the sulfur atom is optionally oxidi=zed to a sulfoxide or sulfone; wherein each substituent group o_f R! is optionally independently substituted with a substituent group selecte-d from C,-Cs alkyl, C:-Cs alkoxy, C;-Cs alkoxycarbonyl, acyl, aminocar bonyl, C;-Cs alkylaminocardbonyl, C;-Cs dialkylaminocarbonyl, C,-Cs alk=anoylamino, hydroxyl, cyano=, halogen or amino wherein the nitrogen atom is optionally independently mono- or di- substituted by C,-Cs alkyl, R% and R® are each methyl; Ris CH; R® is a N-linked pyrrole, pyrazole, or imideazole fused to a 5-7 membesred saturated carbocyclic ring optionally and independently substituted with one to three substituent groups,

V0 2005/030213 PCT/ US2004/031009 wherein each substituent group of R53 is independently =methyl, phenyl, methoxycarbonyl, aminocarbonyl, meth ylaminocarbonyl, dimethylaminoaminocarbony?], morpholinylcarbonyl, fluoro, chloro, bromo, cyano, : hydroxy, oxo, or trifluoromethyl; and R® is C-Cs alkyl, C3-Cs cycloalkyl, trifluoromethyl, C3-Cs cycloalkylmesthyl-, or benzyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of RS is independently methyl, methoxy, flucro, chloro, bromo, cyano, trifluoromethyl, or hydroxy, or a tautomer, prodrug, solvate, or sa lt thereof.

25. A pharmaceutical composition comprising an effective amount of a compeound according to one of claims 19 to 24, or a tautomer, prodrug, solvate, or salt thereof, and a pharmaceutically acceptable excipient or carrier.

26. A compound of Formula (IID) } 3 BP ’ 2 4- R R R (ID) wherein: R! is an aryl or heteroaryl group, each optionally independently substituted. with one to three substituent groups, wherein each substituent growap of R! is independently C;-Cs alkyl, C;—C;s alkeny1, C;-Cs alkynyl, C;-Cg cycloalkyl, heterocyclyl, aryl, heteroaryl, C;-Cs alkoxy, C:-Cs alkenyloxy, C;-Cs alkynylox wy, aryloxy, acyl, C;-Cs alkoxycarbonyl, C 4-Cs alkaroyloxy, C)-Cs alkanoyl, aroyl, aminocarbonyl, C,-Cs alkylaminoccarbonyl, C,-Cs dialkylaminocarbonyl, armninocarbonyloxy, C;-Cs alkylaminocarbonyloxy, Ci-Cs dialkylaminocarbonyloxy, C;-Cs alkanoylamino, C,-Cs a_lkoxycarbonylamino, Ci-Cs alkylsulfonylamino, ammninosulfonyl, CC; alk—ylaminosulfonyl, Ci-Cs dialkylaminosulfonyl, h-alogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, or amino wherein the nitrogen ator is optionally independently _- mono- or di-substituted by C,-C; alkyl or aryl; or ureido wherein either nitrogen atom is ’ optionally independently substituted with C,-Cs alkyl; or &C;-Cs alkylthio wherein the sulfur atom is optionally ox<idized to a sulfoxide or sulfone,

. wherein each substituemt group of R' is optionally ind_ependently substituted with one to three substituent groups selected from methyl, rmethoxy, halogen, hydroxy, 0x0, cyano, heteroaryM, heterocyclyl, or amino whe=rein the nitrogen atom is optionally independently mono- or di-substituted by C, -Cs alkyl or aryl; or ureido wherein either nitrogerx atom is optionally independeratly substituted with C;-Cs alkyl; R? and R® are each independently C,-Cs alkyl, wherein one or both are independently substituted with hydroxy, C1-Cs alkoxy, C;-Cs alkylthio wherein tlhe sulfur atom is optionally oxidized to a sulfoxide or sulfone, amino wherein the nitrogen atom. is optionally independently mono- or di-substituted by C,-Cs allkyl or aryl; R* is C,-Cs alkyl, C>-C; alkenyl , or C,-Cs alkynyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R? is independently C;-C; alkyl, hydroxy, halogen, or 0X0; R® is a heteroaryl group optionally independently substituted w-ith one to three substituent groups, ’ wherein each substituent greoup of R° is independently C;-Cs alkyl, C;-Cs alkenyl, Cp-Cs : alkynyl, C;-Cs cycloalkyl, heterocyclyl, aryl, heteroar yl, C;-Cs alkoxy, Cs-C;

alkenyloxy, C.-C; alkynyloxy, aryloxy, acyl, Ci-Cs alkoxyc arbonyl, C;-Cs alkanoyloxy, aminocarbon'yl, alkylaminocarbonyl, dialkylaminocarbonyM, aminocarbonyloxy, Ci-Cs alkylaminocarbonyloxy, C;-Cs dialkylaminocarbonyloxy, CZi-Cs alkanoylamino, C;-Cs alkoxycarborrylamino, Ci-Cs alkylsulfonylamino, C;-Cs alkylaminosulfonyl, Ci-Cs dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, triflucromethylthio, nitro, or amino wkerein the nitrogen atom is optionally independently mono- or di-substituted by Cy-C;s alkyl, or ureido wherein either nitrogen atom is optionally independently substitutecd with C;-Cs alkyl; or C1-Cs alkylthio wherein the sulfur atom is optionally oxidized to a— sulfoxide or sulfone, wherein each substituent group of R® is optionally independently substituted with one to three substituent groups selected from C,-C; al kyl, C-C; alkoxy, halogen, hydroxy, ©xo, cyano, heteroaryl, heterocyclyl, or amino ~wherein the nitrogen atom is ’ optionally independently mono- or di-substituted by Cm-Cs alkyl or aryl; or ureido wherein either nitrogen atom is optionally independe mtly substituted with C,-Cs alkyl or trifluoromethyl; and RS is hydrogen, C;-Cs alkyl, C;-C; alkenyl, C,-Cs alkynyl, cazrbocycle, heterocyclyl, aryl, heteroaryl, trifluoromethyl, carbocycle-Cy-Cs alkyl, carboxy, alkoxycarbonyl, aryl-C;-Cg alkyl, aryl-C;-C; haloalkyl, heterocyclyl-C;-Cs alkyl, heteroaaryl-C,-Cq alkyl, carbocycle- C,-Cs alkenyl, aryl-C»-Cs alkenyl, heterocyclyl-C;-Cs alkenyl, or heteroaryl-C;-Cs alkenyl, each optionally independently substituted with one te three substituent groups, wherein each substituent group of RS is independently C,-C=5 alkyl, C,-C; alkenyl, C5-Cs alkynyl, C3-C; cycloalkyl, phenyl, C;-Cs alkoxy, phenoxy, C,-Cs alkanoyl, aroyl, C1-Cs alkoxycarbonyl, C;-Cs alkanoyloxy, aminocarbonyloxy, Cu -Cs alkylaminocarbonyloxy, C,-Cs dialk:ylaminocarbonyloxy, aminocarbonyl, C;-Cs alkylaminocarbonyl, C;-C;s dialkylaminocarbonyl, C;-Cs alkanoylamino, C;-C; alkoxycarbonylammino, C;-C; alkylsulfonylamino, C;-Cs alkylaminosulfonyl, C;-Cs dia lkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, nitro, amin © wherein the nitrogen atom is optionally independently mono- or di-substituted by C;—Cs alkyl; or ureido wherein

. cither nitrogen atom is optionally independently sumbstituted with C,-Cs alkyls. or C, -Cs Co alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfore, or a tautomer, prodrug, =solvate, or salt thereof.

27. The compound of Formula (ID) according to claim 26, wherein: R! is thienyl, pheenyl, naphthyl, dihydrobenzofimranyl, benzofuranyl, cEaromanyl, dihydroindolyl, indolyl, dihydrobenzothienyl, benzothienyl, benzodmoxolanyl, benzoxazolyl, be=nzisoxazolyl, benzpyrazolyl, be=nzimidazolyl, thienyl, q uinolinyl, pyridinyl, pyrimicdinyl, or pyrazinyl, each optionally= independently substituted with one to three substituert groups, wherein each su_bstituent group of R! is independer tly C;-C; alkyl, C,-Cs alkernyl, C,-Cs alkynyl, C;-C; aalkoxy, C,-C; alkenyloxy, C;-Cs alk<anoyl, C,-C; alkoxycarbonyl, Ci-C; alkanoyloxy, halogen, hydroxy, carboxy, cyano, trifluoromethyl, nitro, or C-C; alkylthio wherein the sulfur atom is optionally oxid ized to a sulfoxide or sulfomne, wherein eaclm substituent group of R! is optionally independently substituted with a substituent group selected from methyl, methoxy, halogen, hydroxy, ox—o, cyano, heteroaryl, Paeterocyclyl, or amino wherein the nitrogen stom is eoptionally independently mono- or di-substituted by C,-Cs alkyl or aryl; R? and R® are each =independently C;-C; alkyl where=in one or both are inde—pendently substituted with h. ydroxy, C;-Cs alkoxy, R* is CHy; R® is an imidazoolyl, pyridyl, indolyl, azaindoolyl, diazaindolyl, ben=ofuranyl, furanopyridinyl, furanopyrimidinyl, benzothienyl, thienopyridinyl, thienopymrimidiny]l, benzoxazolyl, o=xazolopyridinyl, benzothiazolyl, thiazolopyridinyl, benzirmidazolyl,

We 2005/030213 PCT/US2004/031009 imidazolopyridinyl, quinoliny], Or isoquinolinyl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R’® is independently C;-C; alkyl, €,-Cs alkenyl, phenyl, C;-C; alkoxy, methoxycarbonyl, aminocarbonyl, C,-C; alkyla minocarbonyl, C;-C; dialkylaminocarbonyl, heterocyclylcarbonyl, fluoro, chloro, tmromo, cyano, trifluoromethyl, or C,-C; alkylthio wherein the sulfur atom is optionally= oxidized to a sulfoxide or sulfone, wherein each substituent group of R’is optionally independently sub stituted with a substituent group selected from imethyl, methoxy, fluoro, claloro, bromo, trifluoromethyl, heteroaryl, Ieterocyclyl, or amino wherein the nitarogen atom is optionally independently morxzo- or di-substituted by Cy-Cs alkyl or aryl and RS is C}-Cs alkyl, C,-C; alkenyl, C;-C¢ cycloalkyl, trifluoromethyl, phenyl, C3;-Cs ; cycloalkyl-Cy-C; alkyl, phenyl-C;-Cs alkyl, phenyl-C,;-C; haloalkyl, C;-Cs -cycloalkyl-Ca- C; alkenyl, phenyl-C,-C; alkenyl, each optionally independently substitute=d with one to three substituent groups, wherein each substituent group of R® is independently C;-C; alkyl, C;-C; alkenyl, C,-Cs alkynyl, C;-C3 alkoxy, amminocarbonyl, C,-C; alkylaminocarbwonyl, C;-Cs dialkylaminocarbonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, nitro, or C;- C; alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide cor sulfone, or a tautomer, prodrug, solvate, or salt thereof.

28. The compound of Formula (ID) according to claim 26, wherein: R! is thienyl, phenyl, naphthyl, pyridyl, chromanyl, dihydrobenzofuranyl, or benzeofuranyl, each optionally independently substituted with one or two substituent groups,

wherein each substituent group of R.! is independently methyl, ethya], methoxy, ethoxy, fluoro, chloro, bromo, hydroxy, trifl 1x cromethyl, cyano, or C,-Cs alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone; R? and R® are each methyl wherein one or Booth are independently substistuted with hydroxy, methoxy; R*is CH,; R> is a pyridyl, indolyl, azaindolyl, Woenzofuranyl, furanopyridiny=1, thienopyridinyl, benzoxazolyl, benzimidazolyl, quinoldnyl, or isoquinolinyl grouro, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R’ is independently methyl, phenyl, methoxycarbonyl, amirmocarbonyl, me—thylaminocarbonyl, dimethylaminoaminocarbony], morpholinylearbonyl, fluoro, chloro, bromo, cyano, or trifluoromethyl; and . RS is C,-Cs alkyl, Cs-Cs cycloalkyl, C3-C cycloalkylmethyl-, trifluoro_methyl, or benzyl, each optionally independently substituted with one to three substituent groups, - wherein each substituent group of R® iss independently methyl, methoxy, fluoro, chloro, : bromo, cyano, trifluoromethyl, or hydroxy, or a tautomer, prodrug, solvate, or salt thereof’.

29. The compound of Formula (ID) according to claim 26, wherein: R! is phenyl, dihydrobenzofuranyl, or Wbenzofuranyl, each optionally independently substituted with one to three substituent g=roups,

wherein each suabstituent group of R' is independently C;—C; alkyl, C,-C; alkenyl, C»-C3 alkynyl, C,-C; alkoxy, C;-C; alkenyloxy, C;-C; alkanoyl_, C;-C; alkoxycarbonyl, C1-Cs alkanoyloxy, halogen, hydroxy, carboxy, cyano, trifl uoromethyl, nitro, or C1-Cs alkylthio wherein the sulfur atom is optionally oxidized to» a sulfoxide or sulfone; and R? and R® are each independently C;-C; alkyl each optionally imdependently substituted with hydroxy, C-C; alkoxy, or a tautomer, prodrug, solvate, or salt thereof.

30. A pharmaceutical composition comprising an effective amoumat of a compound according to one of claims 26 to 29, or a tautomer, prodrug, solvate, or salt thmereof, and a pharmaceutically acceptable excipient or carrier.

31. A method of modulating the glucocorticoid receptor function in a patient, the method comprising administering to the patient an effective amount of & pharmaceutically acceptable compound according to one of claims 1 to 11, 13 to 17, 19 to 24, or 26 to 29, or a tautomer, prodrug, solvate, or salt thereof.

32. A method of treating a disease-state or condition mediated boy the glucocorticoid receptor function in a patient in need of such treatment, the method cormprising administering to the patient an effective amount of a pharmaceutically acceptable compound according to one of claims 1 to 11, 13 to 17, 19 to 24, or 26 to 29, or a tautomer, prodrug, solvate, or salt thereof.

33. A method of treating a disease-state or condition selected fi-om: type II diabetes, obesity, cardiovascular diseases, hypertension, arteriosclerosis, neurological diseases, adrenal and pituitary tumors, and glazucoma, in a patient in need of such treatment, the method comprising administering to the patient an effective amount of a pharmaceutically acceptable compound according to one of claims 1 to 11, 13 to 17, 19 to 24, or 26 to 29, or a tautomer, prodrug, solvate, or salt thereof.

\ CJ WO 2005/030213 PCT/US2004/031009

34. A method of treating & disease characterized by inflammactory, allergic, or prolifer amtive processes, in a patient in ne-ed of such treatment, the method comprising administering to= the patient an effective amount of a pharmaceutically acceptable compound according to om=e of claims 1 to 11, 13 to 17, 19 to 24, or 26 to 29, or a tautomer, prodmrug, solvate, or salt thereo £=.

35. The method according to claim 34, wherein the disease is se=lected from: (i) lung disezmses; (ii) rheumatic diseases/autoirmnmune diseases/joint diseases; (iii) adlergic diseases; (iv) vasculitis diseases; (v) demmatologicaml diseases; (vi) renal diseases; (vii) hepatic diseases; (viii) gastrointestinal diseases; (ix_) proctological diseases; (x) eye dise=ases; (xi) diseases of the car, pose, and throat (ENT) are=a; (xii) neurological diseases; (xiii) blood diseases; (xiv) tu—amor diseases; (xv) endocrine dise=ases; (xvi) organ and tissue transpla-ntations and graft-versus-Mhost diseases; (xvii) severe stames of shock; (xviii) substitution therapy; and (xix) pain of : inflammatory genesis.

36. The method according ®o claim 35, wherein the disease is s elected from: type I diabe=tes, : osteoarthritis, Guillain-Barre syndrome, restenosis followings percutaneous translum—inal coronary angioplasty, Alzheimer disease, acute and chronic pair, atherosclerosis, reperfussion injury, bone resorption disea=ses, congestive heart failure, myocarclial infarction, thermal inj wiry, multiple organ injury second. ary to trauma, acute purulent meningmitis, necrotizing enterocol—itis, and syndromes associated with hemodialysis, leukopheresis, and g=ranulocyte transfusion.

37. A method of treating a «disease-state or condition mediated oy the glucocorticoid recey—tor function in a patient in nesed of such treatment, the method. comprising sequentially or simultaneously adminpisterings to the patient: (2) an effective armount of a pharmaceuticexally acceptable compound accord ing to one of claims 1 to 11, 13 to 1 7, 19 to 24, or 26 t0 29, cor a tautomer, prodrug, solvate, or salt thereof; and (b) a pgpharmaceutically acceptable glucocorticoid.

38. Alt for the in vitro diagnostic determination of the glucocomrticoid receptor function iz a sample, comprising: (a) a diagnostically effecative amount of a compound accordim g to one of claims 1, 13, ~19, or 26, or a tautomer, rwrodrug, solvate, or salt thereof: and

- N (b) instructions for use of the diagnosstic kit.

Co

39. A method of making a compound of Formula (IA) 3 : R H

2 +R R¥* | R RR CF; Ia) where R!, R%, R®, R?, and R® are as defin ed in claim 1, the method comprising: (3) reacting an ester of Formula (I) with a suitable reducing agent in a suitable solvent to form a diol of Formula (IIT) 3 3 R\ HO CFs reduction R\ HO_ CF, R2 OR — » OH R' rR! Oo II iH] ; (b) reacting the diol of Formula (IIT) wander suitable oxidative cleavage conditions to form a : ketone of Formula (IV) 3 3 oO R Ho CFs oxidative NL 2 —_— 2 R R' cleavage R R! CF, n v ; and (¢) reacting the ketone of Formula (TV) with a suitable organometallic reagent R'R*M where M is Li or MgX and X is Cl, Br or |, in a suitable solvent to formmn the compound of Formula (1A) 3 3 SN me De 2 2 5 Rd CF, RR RR Iv IA ;or (a”) reacting the trifluoroacetamide of Feormula (X) with a vinyl magnesium bromide compound bearing R? and R® in a suitable solvent to provide the trifluorometh ylenone of Formula XD

A RS Pr Q Rf RR ©O F AO ——— A 3 ) 3 R CF, CH, X Xi : (v") reacting the trifluoromethylenone of Formula (XI) with a suitable organo copper reagent generatecd from an organometallic reagent RNA where M is Li or MgX an d a copper salt CuX, wh_ere X is Cl, Br, or I, in a suitable solveent to form the ketone of Forrmula (TV) 3 2 3 SEWER NI 2 R! CF R CF, CuX 3 Xi \" : and performing step (c) as set forth above.

40. A methocd of making a compound of Formula (JA) 3 : R H R* RN R' CF, (IA) . where R!, RZ_ R®, RY, and R? are as defined claim 1, the method comprising: © (a") reacting an ester of Formula (I) with a suit=able reducing agent in a suistable solvent to form a diol of Formula (I) 3 3 R\ HO__CFs__ reduction R\ HO_ CF, R? OR R? OH R! rR! 0 i it : (b") reacting the diol of Formula (III) under suitamble oxidative cleavage conditions to form a ketone of Formula (IV)

3 3 R\ Ho_ CF, on oxidative NL 2 — 2 R Rr! cleavage R Rr! CF, 1 Vv : (c”) reacting the ketone of Formula (IV) with a suitable epoxi_dizing reagent, such as a sumitable sulfur ylide, in a suitable solvent to form the epoxide of F='ormula (V) 2 R® © RZ =? SL Epoxide : R CF, ——— R CF, Formation \ Vv ;

(d1”) reacting the epoxide of Formula (V) with a suitable meta 1 acetylide reagent, where EM isa suitable metal amd PG is an appropriate protecting groups, in a suitable solvent to af=ford a protected alkynes intermediate, followed by removing the protecting group to fomm an alkyne of Fornala (XXXI)

= M Rr H RA 4 R? = } R' CF, ——_"R Z 3 Deprotection CF, v XX or

(d2”) reacting the ketene of Formula (IV) with a suitable pro pargylating reagent in a suitable solvent to form aatkyne of Formula ({XXT) R”® © R® H Ge Rnalit IZ R! CF, R' CF, v XXX! :

(e”) reacting the alkyne of Formula (XXXI) with a suit.able coupling partner, su ch as optionally substituted and protected anilines or amino pyridines, wherein R’ is a R® substituent as defined in claim 1, Aisa C or N, X is I or Br, and PG is H or a sumitable protecting group, in the presence of suitable catalysts, bamse and solvent to form alksme of Formula XXXIV)

3 3 R' , R H , RB OH A R #4 Coupling R FZ R' Trew FR HNL CF, = Nr CF, PG

H. N = XXVI ba XXXIV . amd (f1”) cyclizing the alkyne of Formula (X3CXIV) in the presence of a suitable base &aud in a suitable solvent to form the compound of Formula (1A) = -_ A R' 3 3 H A 0 a, ri PA Cydlization R2_\ H 1 = ——— 1 N R HN. R H CF4 PG CF, XXXIV (IA) = or (£2) N-deprotecting of the compound of Formula (XXXIV) by reaction with a suitables acid in : a suitable solvent to form an amine salt, followed by cyclizing of the amine salt in the presence of a swaitable base and in a suitable solvent tc form the compound of Formwmula (JA) = -_ R R' 3 3 /) Rr? R H Zi NA N-Deprotection R2 R* OH N R' HN Cyclization ! N CF, “pg R cr, H XXXIV (IA)

41. A method of making a compound of Formula (IB) 3 R H 2 a R (1B) where R', R2, R%, R™, R®, and RE are as defined in claim 13 , the method comprising: (a) reacting an optionally substituted phenol of Formula (XV) with an acryloyl chleoride of nT Formula (XVI) in the presence of a suitable bemse, followed by cyclization of the intermediate ester by treatment with a suitable Lewis acid to form a lactone of Formula XVI) 0] H Q 0 2 R R' + Cf _— a ' R 2 3 R R R Xv Xvi xvi (b) reacting the lactone of Formula (XVII) with a suitable amine HNR’R’®, followed by treatment of the intermediate phenol with methyl iodide in the presence of a suitable base to form an amide of Formula (XVIII) 0 , Me RZ? © R HNR"R™ ==" R® 3 Ng 34 Rr R Mel R™ XVI XVI : (¢) reacting the amide of Formula (XVII) with a suitable organometallic reagexa t RM, where ’ M is Li or MgX and X is Cl, Br, or I, ira a suitable solvent to form a ketorme of Formula Xx) OMe R* © Me RZ OQ R" RM 3 NT —_— 3 rR? R R I R R R™ Xviil XIX . (d) reacting the ketone of Formula (XIX) with a suitable organometallic re=agent R°R'M . where M is Li or MgX and X is Cl, Br. or [, in a suitable solvent to form whe compound of Formula (IB)

2 2 RS R5R4M ARS R R® e— R R3 R . Me XIX IB, R! = R'

42. A me=thod of making a compound of Formula (IB) 3 R H 2 +R R R (IB) where R? , R% R% R% R®, and R® are as defined Hin claim 13, the method compris=ing: (a®) rea_cting an amide of Formula (XXXVI) with a vinyl magnesium brommide compound bearing R? and R? in a suitable solvent to provide an enone of Formula (XXXVI)

R3 .

3

1. ase MgBr JL Rr N ~ CH, ee rR? rR® CH, XXXVI XXXVI = (b’) reacting the enone of Formula (XXXVI) with a suitable organocopper reagent generated fromm an organometallic reagent R'M, w~here M is Li or MgX, and a c opper salt CuX, where X is Cl, Br, or], in a suitable solve=nt to form a ketone of Formula (XX) 3 2 30 RN RR ~_ _ R R° CuxX . XXXVI XX and

(¢’) reacting the ketone of Formula (XX) with a suitable or-ganometallic reagent RRM, where M is Li ox MgX, and X is Cl, Br, or 1, in a suitable solvent to form the compounci of Formula (IB) 3 3 NM, Few NIE 2 6 ——— 2 5 rs R RR RR . XX 1B .

43. A method of making a compound of Formula (IB) 3 R H +R (I=) where R., R?, R%, R*, R® and RP are as defined in claim 13, the m ethod comprising: (a”) reacting a ketone of Formula (IV) with a suitable base and —in a suitable solvent mixture tao provide an acid of Formula (XXIX) R2 rR? RZ R3 0 Cleavage > J 1 —_— 1 R CF, R OH Iv XXIX ; (b”) reacting the acid. of Formula (XXXIX) with a suitable amine. HNR”R™’, such that -NR”R™ * will function as a leaving group in the subsequent reaction, under suitable couplings conditions to form the amide of Formula (XXX) 2 3 0 2 3 0 I SLLLLIES SD R' OH R! N” R™ XXIX XOX . (c”) reacting the amide of Formula (XXX) with a suitable org=anometallic reagent, such as =a Grignard reagent, where M is MgBr or MgCl, or an orgarnolithium reagent, where M i=s Li, in a suitable solvent to provide a ketone of Formula (33)

RRR 0 RSM RZ rR Oo PPS R" >< 6 R' N” R R Rr" XXX : XX ; and (d”) reacting tlhe ketone of Formula (XX) with a suitable organometallic reagent RRYEM, where M is Li or MgX, and X is Cl, Br, or I, in a suitable solvent to form the compound of Formulan (IB) 2 3 3 8 R’ R® R>7 RY R XX 1B :

44. A method o=f making a compound of Formula (IC) 3 R H [=] ) +R

Ic . where RY, R%, R®_R% R’, and RS are as defined in claim 19, th e method comprising: (a) reacting am ester of Formula (II) with a suitable reducing agent in a suitable solvent to form a diol of Formula (III) 3 3 R HO CF, , Reduction R\\ HO CF, rR? OR" R= OH =3 R' 0) il i (b) reacting time diol of Formula (IIT) with a suitable alkyl or aryl sulfonyl chloride reage nt, . such that FR'SO,0 functions as a leaving group in the mext step, followed by reacting the resulting iratermediate with a suitable base to provide an_ epoxide of Formula (V)

3 0 3 R R\ HO_ CF, 1) RSO,CI SP R R' 2) Base R' CF, il / . (c) reacting the epoxide of Formumla (V) with an appropriate nuclecophile R’H, in the presence of a suitable base, to provide the compound of Formula (IC) 3 fe) 3 2 —— 2 5 R rR CF, Base R R' R V IC .

45. A method of making a compoumd of Formula (IC) 3 R H 2 +R R 6 R R" R (IO) where RY, R%, R?, R*, RS, and RS are as defined in claim 19, the method comprising: (8’) reacting an ester of Formula (II) with a suitable reducing agent in a suitable solvent to form a diol of Formula (IIT) RR rR: HO CF, , Reduction HO CF, R? oR MM — R2 OH 1 R 1 fo R 1 1 ; (b’) reacting the diol of Formula (III) under suitable oxidative cle=avage conditions to form a ketone of Formula (IV)

3 oxidative ”3 R\ HO CF, cleavage NM 2 OH —mm» 2 R R . CF, hy Iv : (c’) reacting the ketone of Formula (IV) with a suitable epoxidiz=ing reagent, such as a suitable sulfur ylide, in a suzitable solvent to provide an epoxide of Feormula (V) RY 0] epoxide rR: Q SM formation SP R cr, — = R CF R' 3 R' *. and (d") reacting the epoxide of Formula (V) with an appropriate nu_cleophile RH, in the presence of a suitable base, to provide the compound of Formula (IC 3 oO 3 2 —_——— 2 5 R CF R R 3 3 Base R’ "2 IC .

46. A method of making a compound of Formula (ID) 3 R H i 5 2 +R R R! r® R (ID) where R', R?, R}, R*, R®, and RC are as defined in claim 26, the maethod comprising; (a) reacting a cyano compound of Formula (XXX VII) with a =suitable alkene in the presence= of a suitable base to provide an alkene of Formula (XXXIX CN CN ES Co alkene Base XXXVI IXXIX : (b) reacting the alkene of Formula (XXXIX) with a suitable reducing agent to provide am aldehyde of Formula (XXXX)

(e} CN H Shh Reducti<on RS —_— XXXIX XXXX : (¢) reactimg the aldehyde of Formula (XXXX) with a suitable reducing agent —to provide an alcoheol of Formula (XXXXT) B ° HQ

H . reductiora XXXX XXX (d) reactimng the alcohol of Formula (XXXXT) with a suitable alkylating agent inm the presence of a suitable base to provide an ether of Forrmula (XXXXII) H S— Ps alkylation A ——— XXXX1 XXXX IH : (e) reactimg the ether of Formula (XXXXII) ummder suitable oxidative cleavage conditions to provicde an aldehyde of Formula (XXXXIIT) —Q —~Q oxidative cleavage Q = > H . XXXXII XXX ; (f) reacting the aldehyde of Formula (3OCXXII) with a suitable nucleophilic trifluo romethylating reagent to provide the trifluoromethyl alcohol of Formula (XXXIV)

~~ — Q ? 6 OH XXXII XXXXIV ; (g) reacting the trifluoromethyl alcohol of Formula (XX3=CXIV) with a suitable oxidiz®ng reagent to provide the trifluoromethylketone of Formula (XXXXV) —— 0 (0) H o oxidation cr, CF, XXXIV XXXXV ; and (h) reacting the ketone of Formula (XXXXV) with a suitable organometallic reagent R°R*M, where M js Li or MgX, and X is Cl, Br, or Lin a suitable= solvent to form the compound of Formula (ID) N AN 0} 0] H

RRM +R CF - R 8 CF, XXXXV iD }