PROCESS FOR THE PREPARATION OF TETRAHYDROQUINOLINYL, BENZOXAZINE AND BENZOTHIAZINE DERIVATIVES

CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U. S. Provisional Application 60/917,135, filed on May 10, 2007, which is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The present invention is directed to a novel process for the preparation of tetrahydroquinolinyl, benzoxazine and benzothiazine derivatives useful as in the treatment of disorders and conditions modulated by the cholesteryl ester transfer protein (CETP).

BACKGROUND OF THE INVENTION

Cholesterol homeostasis is maintained by dietary intake, biosynthesis, metabolism to bile acids, absorption and a process known as reverse cholesterol transport (RCT). Cholesterol is transported in the blood by lipoproteins, which contain different apolipoproteins that are recognized by different receptors on the liver and cells such as macrophages. RCT is involved in the movement of cholesterol from peripheral tissues to the liver for excretion. This pathway may represent up to 70% of the flux of cholesterol to the liver. Inherent in this process is the remodeling of the lipoprotein particles. A key player in RCT is the cholesteryl ester transfer protein (CETP), a glycoprotein that mediates the transfer of cholesteryl ester from the cardioprotective High Density Lipoprotein (HDL) particles to the pro- atherogenic LDL (Low Density Lipoprotein), VLDL (Very Low Density Lipoprotein) and IDL (Intermediate Density Lipoprotein).

CETP is a glycoprotein with a molecular weight of about 74 kDa and a primary sequence containing 476 amino acids. Although the amino acid sequence would suggest the protein to be highly hydrophobic, most of the hydrophobic residues reside mainly on the interior, as the protein is soluble in water (Hesler et al., J. Biol. Chem., 262:2275-2282, 1987). This hydrophobic

pocket allows for the binding of neutral lipids (Au-Young and Fielding, Proc. Natl. Acad. Sci., 89:4094-4098, 1992). Using the crystallographic structure of a related protein, BPI (bactericidal/permeability increasing protein) with about 20% homology to CETP, a model of CETP was published by Bruce et al., Curr. Opin. Struct. Biol., 8:426-434, 1998. The C-terminal residues were predicted to form an amphipathic helix that covers the opening of an N-terminal pocket. Lipid transfer is thought to occur through a disordering of the lipids in the lipoprotein surface followed by flipping open of the hydrophobic pocket with entry of the neutral lipid.

CETP facilitates exchange and net transfer of neutral lipids, mainly cholesteryl esters and triglycerides between plasma lipoproteins. Phospholipids can also be transferred to a lesser degree. CETP inhibitors have emerged with the potential to increase HDL cholesterol (HDL-C) to levels exceeding those of the currently available therapies.

In normal human plasma, the CETP concentration is around 1 -3 μg/ml; however, in patients with hypercholesterolemia, or mixed hyperlipidemias with hypertriglyceridemia, the CETP concentrations have been reported to be 2-3 fold higher (Marcel et al., Journal of Clinical Investigation, 85:10-17, 1990, and McPherson et al., Arteriosclerosis and Thrombosis: A Jounral of Vascular Biology, 11 (4):797-804, 1991 ). Plasma CETP activity is modulated by a variety of factors including: plasma CETP concentration, plasma levels of lipoprotein acceptors and donors, plasma triglyceride levels, physical exercise, alcohol and smoking. Circulating CETP is associated with HDL, VLDL and LDL particles (Nishida et al., Journal of Biological Chemistry, 268(22):16352-60, 1993). Most seems to be associated with HDL and only about 1 % is reported to be present in free form.

In patients with Type Ma hypercholesterolemia (familial hypercholesterolemia, LDL-C>160mg/dL), elevated levels of CETP have been reported as well as increased transfer of cholesteryl ester from HDL to VLDL and LDL (Guerin et al., Arteriosclerosis and Thrombosis: A Journal of Vascular Biology, 14(5):679-85, 1994, and Guerin et al., Arteriosclerosis and Thrombosis: A Journal of Vascular Biology, 14(2):199-206, 1994) thereby generating the smaller more dense LDL particles, which are considered to be

atherogenic. Type IV hypertriglyceridemia is characterized by elevated levels of VLDL and VLDL remnants with plasma triglycerides measuring >150mg/dL. Associated with these elevations are reduced levels of HDL and apoA-l. This may be due to an increase in the CETP-mediated transfer of cholesterol esters to VLDL. This results in the formation of large VLDL1 subfractions, which are the preferential precursors of small dense proatherogenic LDL particles (Packard and Shepard, Arterscler. Thromb. Vase. Biol., 17:3542-3556, 1997). Type MB is a mixed hyperlipidemia characterized by simultaneous elevations in both plasma cholesterol and triglycerides with increases in VLDL and LDL and decreases in HDL. The LDL particles are shifted to the small dense LDL 4 and 5 subfractions. Plasma CETP concentrations are elevated and a higher rate of transfer activity has also been reported (Guerin et al., European Journal of Clinical Investigation, 26(6):485-94, 1996). In the case of secondary dyslipidemias such as those found in diabetes, there are also reports of elevated CETP activity particularly in the presence of hypertriglyceridemia (Guerin et al, Artehoscloerosis, Thrombosis and Vascular Biology, 20(1 ):189- 97, 2001 ).

The first studies with CETP inhibitors were done in rabbits, which express high levels of CETP and are highly susceptible to atherosclerosis when fed a high cholesterol diet. Anti-sense oligonucleotides, antibodies, vaccines and small molecule inhibitors have been tested (Sugano et al., Journal of Biological Chemistry, 273(9):5033-6, 1996; Rittershaus et al., Arteriosclerosis, Thrombosis and Vascular Biology, 20(9):2106-2112, 2000; Whitlock et al., Journal of Clinical Investigation, 84(1 ):129-37, 1989; and Okamoto et al., Nature, 406:203-207, 2000). These studies showed that inhibition of CETP increased plasma HDL-C levels and particle size as well as decreasing aortic cholesterol content and lesion development. Administration of the small molecule inhibitor JTT-705, which irreversibly inactivated CETP by binding to a crucial cysteine residue (Cys13), to rabbits at a dose of 30mg/kg inhibited CETP activity, increased HDL-C (+90%), reduced non-HDL-C cholesterol and lesion size (-50% and -70%, respectively, Okamoto et al., Nature, 406:203- 207, 2000). However, in another study where rabbits had severe hypercholesterolemia, JTT-705 was not efficacious in preventing lesion

development (Huang et al., Clin. Sci., 103(6):587-594, 2002). Interestingly there were significant elevations of plasma triglycerides in this study with JTT- 705 treatment. In later clinical studies, JTT-705 was found to raise HDL-C, modestly lower LDL-C and not alter triglyceride levels (DeGrooth et al., Circulation, 105(18):2159-2165, 2002). A more potent CETP inhibitor, Torcetrapib, has shown positive results in Phase Il trials, particularly in combination with Atorvastatin (Brousseau et al., New England Journal of Medicine, 350(15):1505-1515, 2004).

SUMMARY OF THE INVENTION

The present invention is directed to a process for the preparation of a compound of formula (I)

wherein:

Li is a covalent bond or O;

Qi is C-6-10 aryl or 5- or 6-membered heteroaryl; n is 0 to 3; m is 0 to 3;

Ri is Ci-io alkyl, C _2- io alkenyl, C _2- io alkynyl, C _3- iocycloalkyl, 5- or 6- membered heteroaryl, wherein each of C _MO alkyl, C _2- io alkenyl, C _2- io alkynyl, C _3- iocycloalkyl, 5- or 6-membered heteroaryl may be optionally substituted; alternatively, Ri is phenyl optionally substituted with 1 or 2 members selected wherein R ₃ and Rb are independently selected from the group consisting

of optionally substituted Ci _-4 alkyl, halogenated Ci _-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, optionally substituted Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, optionally substituted Ci _-4 alkylthio, halo, cyano, and hydroxy, or R ₃ and Rb together with the carbon atoms of the phenyl ring to which they are attached form an optionally substituted 5- or 6-membered heterocyclyl fused to the phenyl ring; each R ₂ is independently selected from halo, hydroxy, cyano, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci _-4 alkyl, halogenated Ci _-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and -C(O)H; each R ₃ is independently selected from Ci _-4 alkyl, halogenated Ci _-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, Ci _-4 alkoxy, halo, cyano, and hydroxy;

R ₄ is Ci-8 alkyl optionally substituted with 1 -3 members independently selected from halo, oxo, hydroxy, halogenated Ci _-4 alkyl, Ci _-4 alkoxy, C _3- S cycloalkyl, CN, tert-butyldimethylsilyloxy, heterocyclyl and — NR _c Rd, wherein R _c and R _d are independently selected from H, optionally substituted Ci _-3 alkyl, -C(O)Ci _-3 alkyl, -C(O)O-Ci _-3 alkyl, and -SO ₂ Ci _-3 alkyl; alternatively R ₄ is Ci- ₄ alkyl substituted with heteroaryl or phenyl substituted with 1 to 3 members independently selected from halo, hydroxy, Ci _-3 alkyl, halogenated Ci _-3 alkyl, Ci- ₄ alkoxy, or halogenated Ci _-4 alkoxy; and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof; comprising

reacting a compound of formula (V), wherein LG ¹ is a leaving group with a compound of formula (Vl); in the presence of an organic or inorganic base; in an organic solvent; to yield the corresponding compound of formula (VII); or

reacting a compound of formula (V), wherein LG ¹ is a leaving group with a compound of formula (Vl); in the presence of an acid; in an organic solvent; to yield the corresponding compound of formula (VII);

reacting the compound of formula (VII) with a reducing agent; in the presence of an acid; in an organic solvent; to yield the corresponding compound of formula (VIII);

(X)

reacting the compound of formula (VIII) with a compound of formula (IX); in the presence of a catalyst; in the presence of an organic or inorganic base; in an organic solvent; to yield the corresponding compound of formula (X);

(XII)

(X)

reacting the compound of formula (X) with a source of hydride; in the presence of a chiral acid catalyst of the formula (C-R)

wherein Z ¹ is selected from the group consisting of hydrogen and bromo; or a chiral catalyst of the formula (C-S)

wherein Z ² is selected from the group consisting of 9-phenanthryl, 3,5- di(thfluoromethyl)phenyl, phenyl, 1-naphthyl and triphenylsilyl; in an organic solvent; to yield the corresponding compound of formula (XII), wherein the compound of formula (XII) is present in an enantiomeric excess of greater than about 50%ee; or reacting the compound of formula (X) with a suitably selected source of hydride; in the presence of a chiral acid; in an organic solvent; to yield the corresponding compound of formula (XII), wherein the compound of formula (XII) is present in an enantiomeric excess of greater than about 0%ee;

reacting the compound of formula (XII) with a compound of formula (XIII); in an organic solvent which will act as both a solvent and a catalyst; to yield the corresponding compound of formula (I).

The present invention is further directed to a process for the preparation of a compound of formula (I)

wherein:

Li is a covalent bond or O;

Qi is C-6-10 aryl or 5- or 6-membered heteroaryl; n is O to 3; m is O to 3;

Ri is C-1-10 alkyl, C _2- io alkenyl, C _2- io alkynyl, C _3- iocycloalkyl, 5- or 6- membered heteroaryl, wherein each of C _MO alkyl, C _2- io alkenyl, C _2- io alkynyl, C _3- iocycloalkyl, 5- or 6-membered heteroaryl may be optionally substituted;

alternatively, Ri is phenyl optionally substituted with 1 or 2 members selected from Ra and R _b ; wherein R ₃ and R _b are independently selected from the group consisting of optionally substituted Ci _-4 alkyl, halogenated Ci _-4 alkyl, optionally substituted C2 _-4 alkenyl, optionally substituted C2 _-4 alkynyl, optionally substituted Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, optionally substituted Ci _-4 alkylthio, halo, cyano, and hydroxy, or R ₃ and R _b together with the carbon atoms of the phenyl ring to which they are attached form an optionally substituted 5- or 6-membered heterocyclyl fused to the phenyl ring; each R ₂ is independently selected from halo, hydroxy, cyano, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci _-4 alkyl, halogenated Ci _-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and -C(O)H; each R ₃ is independently selected from Ci _-4 alkyl, halogenated Ci _-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, Ci _-4 alkoxy, halo, cyano, and hydroxy;

R ₄ is Ci _-8 alkyl optionally substituted with 1 -3 members independently selected from halo, oxo, hydroxy, halogenated Ci _-4 alkyl, Ci _-4 alkoxy, C _3- S cycloalkyl, CN, tert-butyldimethylsilyloxy, heterocyclyl and — NR _c Rd, wherein R _c and Rd are independently selected from H, optionally substituted Ci _-3 alkyl, -C(O)Ci _-3 alkyl, -C(O)O-Ci _-3 alkyl, and -SO ₂ Ci _-3 alkyl; alternatively R ₄ is Ci- ₄ alkyl substituted with heteroaryl or phenyl substituted with 1 to 3 members independently selected from halo, hydroxy, Ci _-3 alkyl, halogenated Ci _-3 alkyl, Ci- ₄ alkoxy, or halogenated Ci _-4 alkoxy; and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof; comprising

reacting a compound of formula (V), wherein LG ¹ is a leaving group with a compound of formula (Vl); in the presence of an organic or inorganic base; in an organic solvent; to yield the corresponding compound of formula (VII);

or reacting a compound of formula (V), wherein LG ¹ is a leaving group with a compound of formula (Vl); in the presence of an acid; in an organic solvent; to yield the corresponding compound of formula (VII);

reacting the compound of formula (VII) with a reducing agent; in the presence of an acid; in an organic solvent; to yield the corresponding compound of formula (VIII);

(X)

reacting the compound of formula (VIII) with a compound of formula (IX); in the presence of a catalyst; in the presence of an organic or inorganic base; in an organic solvent; to yield the corresponding compound of formula (X);

(Xl)

reacting the compound of formula (X) with a source of hydride; in the presence of an acid; in an organic solvent; to yield the corresponding compound of formula (Xl) or reacting the compound of formula (X) with H ₂ (g), in the presence of a catalyst; in an organic solvent; to yield the corresponding compound of formula

(Xi);

(Xl) (XIl) separating the enantiomers of the compound of formula (Xl); to yield the corresponding compound of formula (XII);

reacting the compound of formula (XII) with a compound of formula (XIII); in an organic solvent which will act as both a solvent and a catalyst; to yield the corresponding compound of formula (I).

In an embodiment, the present invention is directed to a process for the preparation of the compound of formula (I-S)

OH (I-S) also known as (S)-1 ,1 ,1-trifluoro-3-[(R)-2-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)- phenyl]-5-(3-trifluoromethoxy-phenyl)-3,4-dihydro-2H-quinoli n-1-yl]-propan-2-ol, or a tautomer, solvate, or pharmaceutically acceptable salts thereof; comprising

(V-S)

reacting a compound of formula (V-S), wherein LG ¹ is a leaving group, with a compound of formula (Vl-S); in the presence of an organic or inorganic base; in an organic solvent; to yield the corresponding compound of formula (VII-S); or reacting a compound of formula (V-S) with a compound of formula (Vl- S); in the presence of an acid; in an organic solvent; to yield the corresponding compound of formula (VII-S);

reacting the compound of formula (VII-S) with a reducing agent; in an organic solvent; to yield the corresponding compound of formula (VIII-S);

reacting the compound of formula (VIII-S) with a compound of formula (IX-S); in the presence of a catalyst; in the presence of an organic or inorganic

base; in an organic solvent; to yield the corresponding compound of formula (X- S);

reacting the compound of formula (X-S) with a source of hydride; in the presence of a chiral acid catalyst selected from the group consisting of the compound of the formula (C-R)

wherein Z ¹ is selected from the group consisting of hydrogen and bromo; and the compound of formula (C-S)

wherein Z ² is selected from the group consisting of 9-phenanthryl, 3,5- di(thfluoromethyl)phenyl, phenyl, 1-naphthyl and triphenylsilyl; in an organic solvent; to yield the corresponding compound of formula (XII-S), wherein the compound of formula (XII-S) is present in an enantiomeric excess of greater than 0%;

reacting the compound of formula (XII-S) with a compound of formula (XIII-S), wherein the compound of formula (XIII-S) is enantiomehcally enriched with the corresponding (S)-enantiomer; in an organic solvent which will act as both a solvent and a catalyst; to yield the corresponding compound of formula (I-S).

In an embodiment, the present invention is directed to a process for the preparation of a compound of formula (I-S)

OH (I-S) also known as (S)-1 ,1 ,1-trifluoro-3-[(R)-2-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)- phenyl]-5-(3-trifluoromethoxy-phenyl)-3,4-dihydro-2H-quinoli n-1-yl]-propan-2-ol, or a tautomer, solvate, or pharmaceutically acceptable salts thereof; comprising

(V-S)

reacting a compound of formula (V-S), with a compound of formula (Vl- S); in the presence of an organic or inorganic base; in an organic solvent; to yield the corresponding compound of formula (VII-S); or reacting a compound of formula (V-S) with a compound of formula (Vl- S); in the presence of an acid; in an organic solvent; to yield the corresponding compound of formula (VII-S);

reacting the compound of formula (VII-S) with a reducing agent; in an organic solvent; to yield the corresponding compound of formula (VIII-S);

reacting the compound of formula (VIII-S) with a compound of formula (IX-S); in the presence of a catalyst; in the presence of an organic or inorganic

base; in an organic solvent; to yield the corresponding compound of formula (X- S);

reacting compound of formula (X-S) with a source of hydride; in the presence of an acid; in an organic solvent; to yield the corresponding compound of formula (Xl-S); or reacting the compound of formula (X-S) with H ₂ (g); in the presence of a catalyst; in an organic solvent; to yield the corresponding compound of formula (Xl-S);

separating the enantiomers of the compound of formula (Xl-S) to yield the corresponding compound of formula (XII-S);

reacting the compound of formula (XII-S) with a compound of formula (XIII-S), wherein the compound of formula (XIII-S) is enantiomehcally enriched with the corresponding (S)-enantiomer; in an organic solvent which will act as both a solvent and a catalyst; at a temperature of less than about 48 ⁰ C; to yield the corresponding compound of formula (I-S).

The present invention is further directed to a process for the preparation of compounds of formula (II)

wherein:

L ₂ is a covalent bond or O;

X is O or S;

Q ₂ is C _6- io aryl or 5- or 6-membered heteroaryl; p is 0 to 3; q is 0 to 3;

Rn is C-1-10 alkyl, C2-10 alkenyl, C _2- -I ₀ alkynyl, C _3- iocycloalkyl, 5- or 6- membered heteroaryl, wherein each of C _M0 alkyl, C _2- - _I0 alkenyl, C _2- - _I0 alkynyl, C3-i ₀ cycloalkyl, 5- or 6-membered heteroaryl may be optionally substituted; alternatively Rn is phenyl optionally substituted with 1 or 2 members selected from Re and Rt; wherein R _e and R _f are independently selected from the group consisting of optionally substituted Ci _-4 alkyl, halogenated Ci _-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, optionally substituted Ci _-4 alkoxy, halogenatedCi _-4 alkoxy, optionally substituted Ci _-4 alkylthio, halo, cyano,

and hydroxy, or R _e and Rf together with the carbon atoms of the phenyl ring to which they are attached form an optionally substituted 5- or 6-membered heterocyclyl fused to the phenyl ring; each Ri2 is independently selected from halo, hydroxy, cyano, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci _-4 alkyl, halogenated Ci _-4 alkyl, C2 _-4 alkenyl, C _2-4 alkynyl and -C(O)H; each Ri ₃ is independently selected from Ci _-4 alkyl, halogenated Ci- ₄ alkyl, C _2-4 alkenyl, C _2-4 alkynyl, Ci _-4 alkoxy, halo, cyano, and hydroxy;

Ri ₄ is Ci-salkyl optionally substituted with 1 -3 members independently selected from halo, oxo, hydroxy, halogenatedCi _-4 alkyl, Ci _-4 alkoxy, C _3- S cycloalkyl, CN, tert-butyldimethylsilyloxy, optionally substituted heterocyclyl and -NRgR _h , wherein R ₉ and R _h are independently selected from H, optionally substituted Ci _-3 alkyl, -C(O)Ci _-3 alkyl, -C(O)O-Ci _-3 alkyl, and -SO ₂ Ci _-3 alkyl; alternatively, Ri ₄ is Ci _-4 alkyl substituted with heteroaryl or phenyl substituted with 1 to 3 members independently selected from halo, hydroxy, Ci _-3 alkyl, halogenatedCi _-3 alkyl, Ci _-4 alkoxy, or halogenatedCi _-4 alkoxy; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof; comprising

(XX) (XXIi) reacting a compound of formula (XX), wherein LG ² is a leaving group with a compound of formula (XXI), wherein LG ³ is a second leaving; in the presence of an inorganic base; in an organic solvent; to yield the corresponding compound of formula (XXII);

(XXIi) (XXIIi) reacting the compound of formula (XXII) with a source of hydride; in the presence of a chiral acid catalyst of the formula (C-R)

wherein Z ¹ is selected from the group consisting of hydrogen and bromo; or with a chiral catalyst of the formula (C-S)

wherein Z ² is selected from the group consisting of 9-phenanthryl, 3,5- di(trifluoromethyl)phenyl, phenyl, 1-naphthyl and triphenylsilyl; in an organic solvent; to yield the corresponding compound of formula (XXIII), wherein the desired enantiomer is present in an enantiomeric excess of greater than about 0%;

(XXV)

reacting the compound of formula (XXIII) with a compound of formula (XXIV); in the presence of a catalyst; in the presence of an organic or inorganic base; in an organic solvent; to yield the corresponding compound of formula (XXV);

reacting the compound of formula (XXV) with a compound of formula (XXVI); in an organic solvent which will act as both a solvent and a catalyst; to yield the corresponding enantiomerically enriched compound of formula (II).

The present invention is further directed to a process for the preparation of compounds of formula (II)

wherein

L ₂ is a covalent bond or O;

X is O or S;

Q ₂ is C _6- IO aryl or 5- or 6-membered heteroaryl; p is 0 to 3; q is 0 to 3;

Rn is C-1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-iocycloalkyl, 5- or 6- membered heteroaryl, wherein each of CMO alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-iocycloalkyl, 5- or 6-membered heteroaryl may be optionally substituted; alternatively Rn is phenyl optionally substituted with 1 or 2 members selected from R _e and R _f ; wherein R _e and Rf are independently selected from the group consisting of optionally substituted Ci _-4 alkyl, halogenated Ci _-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, optionally substituted Ci _-4 alkoxy, halogenatedCi _-4 alkoxy, optionally substituted Ci _-4 alkylthio, halo, cyano, and hydroxy, or R _e and Rf together with the carbon atoms of the phenyl ring to which they are attached form an optionally substituted 5- or 6-membered heterocyclyl fused to the phenyl ring; each Ri ₂ is independently selected from halo, hydroxy, cyano, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci _-4 alkyl, halogenated Ci _-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and -C(O)H; each Ri3 is independently selected from Ci _-4 alkyl, halogenated Ci- ₄ alkyl, C _2-4 alkenyl, C _2-4 alkynyl, Ci _-4 alkoxy, halo, cyano, and hydroxy;

Ri ₄ is Ci-salkyl optionally substituted with 1 -3 members independently selected from halo, oxo, hydroxy, halogenatedCi _-4 alkyl, Ci _-4 alkoxy, C _3- S cycloalkyl, CN, tert-butyldimethylsilyloxy, optionally substituted heterocyclyl and -NRgR _h , wherein R ₉ and R _h are independently selected from H, optionally substituted Ci _-3 alkyl, -C(O)Ci _-3 alkyl, -C(O)O-Ci _-3 alkyl, and -SO ₂ Ci -3a Iky I; alternatively, Ri ₄ is Ci _-4 alkyl substituted with heteroaryl or phenyl substituted with 1 to 3 members independently selected from halo, hydroxy, Ci _-3 alkyl, halogenatedCi _-3 alkyl, Ci _-4 alkoxy, or halogenatedCi _-4 alkoxy; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof; comprising

(Ri

(XX) (XXII) reacting a compound of formula (XX), wherein LG ² is a leaving group with a compound of formula (XXI), wherein LG ³ is a second leaving; in the presence of an inorganic base; in an organic solvent; to yield the corresponding compound of formula (XXII);

J ₁ (XXIII)

(XXII) reacting the compound of formula (XXII) is reacted with a compound of formula (L); in the presence of an acid; in an organic solvent; to yield the

corresponding compound of formula (XXIII), wherein the desired enantiomer is present in an enantiomeric excess of greater than about 0%;

(XXV)

reacting the compound of formula (XXIII) with a compound of formula (XXIV); in the presence of a catalyst; in the presence of an organic or inorganic base; in an organic solvent; to yield the corresponding compound of formula (XXV);

reacting the compound of formula (XXV) with a compound of formula (XXVI); in an organic solvent which will act as both a solvent and a catalyst; to yield the corresponding enantiomerically enriched compound of formula (II).

In an embodiment, the present invention is further directed to a process for the preparation of a compound of formula (M-S)

(M-S)

(also known as (S)-1 ,1 ,1 -Trifluoro-3-[3-(S)-[3-(1 ,1 ,2,2-tetrafluoro- ethoxy)-phenyl]-8-(3-thfluoromethoxy-phenyl)-2,3-dihydro-ben zo[1 ,4]oxazin-4- yl]-propan-2-ol); or a tautomer, solvate, or pharmaceutically acceptable salt thereof; comprising

reacting a compound of formula (XX-S), wherein LG ² is a leaving group with a compound of formula (XXI-S), wherein LG ³ is a second leaving; in the presence of an inorganic base; in an organic solvent; to yield the corresponding compound of formula (XXII-S);

reacting the compound of formula (XXII-S) with a source of hydride; in the presence of a chiral acid catalyst of the formula (C-R)

wherein Z ¹ is selected from the group consisting of hydrogen and bromo; or with a chiral catalyst of the formula (C-S)

wherein Z ² is selected from the group consisting of 9-phenanthryl, 3,5- di(thfluoromethyl)phenyl, phenyl, 1-naphthyl and triphenylsilyl; in an organic solvent; to yield the corresponding compound of formula (XXIII-S), wherein the (S)-enantiomer is present in an enantiomeric excess of greater than about 0%;

(XXIII-S)

reacting the compound of formula (XXIII-S) with a compound of formula (XXIV-S); in the presence of a catalyst; in the presence of an organic or inorganic base; in an organic solvent; to yield the corresponding compound of formula (XXV-S);

reacting the compound of formula (XXV-S) with a compound of formula (XXVI-S); in an organic solvent which will act as both a solvent and a catalyst; to yield the corresponding enantiomerically enriched compound of formula (II- S).

In another embodiment, the present invention is further directed to a process for the preparation of a compound of formula (M-S)

OH (M-S)

(also known as (S)-1 ,1 ,1 -Trifluoro-3-[3-(S)-[3-(1 ,1 ,2,2-tetrafluoro- ethoxy)-phenyl]-8-(3-thfluoromethoxy-phenyl)-2,3-dihydro-ben zo[1 ,4]oxazin-4- yl]-propan-2-ol); or a tautomer, solvate, or pharmaceutically acceptable salts thereof; comprising

reacting a compound of formula (XX-S), wherein LG ² is a leaving group with a compound of formula (XXI-S), wherein LG ³ is a second leaving; in the presence of an inorganic base; in an organic solvent; to yield the corresponding compound of formula (XXII-S);

(L)

(XXIII-S) reacting the compound of formula (XXII-S) is reacted with a compound of formula (L); in the presence of an acid; in an organic solvent; to yield the corresponding compound of formula (XXIII-S), wherein the (S)-enantiomer is present in an enantiomeric excess of greater than about 0%;

(XXIII-S)

reacting the compound of formula (XXIII-S) with a compound of formula (XXIV-S); in the presence of a catalyst; in the presence of an organic or inorganic base; in an organic solvent; to yield the corresponding compound of formula (XXV-S);

reacting the compound of formula (XXV-S) with a compound of formula (XXVI-S); in an organic solvent which will act as both a solvent and a catalyst; to yield the corresponding enantiomerically enriched compound of formula (II- S).

The present invention is further directed to processes for the preparation of the compounds of formula (XII)

wherein Ri, n, R ₂ , m, R ₃ and the Qi ring are as herein defined; and wherein the compound of formula (XII) is prepared in an enantiomeric excess of one of its corresponding enantiomers of greater than about 0%ee, preferably greater than about 50%ee, more preferably, greater than about 75%ee, more preferably, greater than about 85%ee, more preferably, greater than about 90%ee, more preferably, greater than about 95%ee, more preferably, greater than about 98%ee, more preferably, greater than about 99%ee; as described in more detail herein. In an embodiment, the present invention is directed to processes for the preparation of the compound of formula (XII-S)

also known as 2-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-5-(3- trifluoromethoxy-phenyl)-1 ,2,3,4-tetrahydro-quinoline, and wherein the compound of formula (XII-S) is prepared in an enantiomeric excess of its corresponding (R)-enantiomer of greater than about 0%ee, preferably greater than about 50%ee, more preferably, greater than about 75%ee, more preferably, greater than about 85%ee, more preferably, greater than about 90%ee, more preferably, greater than about 95%ee, more preferably, greater

than about 98%ee, more preferably, greater than about 99%ee; as described in more detail herein. The compounds of formula (XII) are useful as intermediate in the synthesis of the compounds of formula (I).

The present invention is further directed to processes for the preparation of the compounds of formula (XXIII)

(XXIII) wherein LG ² , X, Rn, q and R13 are as herein defined; and wherein the compound of formula (XII) is prepared in an enantiomeric excess of one of its corresponding enantiomers of greater than about 0%ee, preferably greater than about 50%ee, more preferably, greater than about 75%ee, more preferably, greater than about 85%ee, more preferably, greater than about 90%ee, more preferably, greater than about 95%ee, more preferably, greater than about 98%ee, more preferably, greater than about 99%ee; as described in more detail herein. In an embodiment, the present invention is directed to processes for the preparation of the compound of formula (XXIII-S)

(XXIII-S) wherein LG ² is as herein defined, and wherein the compound of formula (XXIII-S) is prepared in an enantiomeric excess of its corresponding (S)- enantiomer of greater than about 0%ee, preferably greater than about 50%ee, more preferably, greater than about 75%ee, more preferably, greater than about 85%ee, more preferably, greater than about 90%ee, more preferably, greater than about 95%ee, more preferably, greater than about 98%ee, more preferably, greater than about 99%ee; as described in more detail herein. The

compounds of formula (XXIII) are useful as intermediate in the synthesis of the compounds of formula (II).

The present invention is further directed to processes for the preparation of the compounds of formula (XXXII)

(XXXII) wherein Rn, q, R13 and LG ⁵ are as herein defined; as described in more detail herein. In an embodiment, the present invention is directed to processes for the preparation of the compound of formula (XXXII-S)

(XXXII-S) wherein LG ⁵ is a leaving group, preferably LG ⁵ is bromo; as described in more detail herein. The compounds of formula (XXIII) are useful as intermediates in the synthesis of compounds of formula (II).

The present invention is further directed to a product prepared according to the process described herein. The present invention is further directed to a crystalline form of the compound of formula (N-S). In an embodiment, the crystalline form of the compound of formula (M-S) is a non-hydrate. In another embodiment, the crystalline form of the compound of formula (M-S) may be characterized by its corresponding XRD peaks, as described in more detail herein. The present invention is further directed to a process for the preparation of the crystalline form of the compound of formula (M-S), as described in more detail herein.

Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product prepared according to the

process described herein. An illustration of the invention is a pharmaceutical composition made by mixing the product prepared according to the process described herein and a pharmaceutically acceptable carrier. Illustrating the invention is a process for making a pharmaceutical composition comprising mixing the product prepared according to the process described herein and a pharmaceutically acceptable carrier.

Exemplifying the invention are methods of treating a disorder mediated by CETP (preferably selected from the group consisting atherosclerosis, peripheral vascular disease, dyslipidemia (including hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, and hypo-HDL-cholesterolemia), hyper-LDL-cholesterolemia hyperbetaliproteinemia, hypoalphalipoproteinemia, familial-hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity and Metabolic Syndrome) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: (a) atherosclerosis, (b) peripheral vascular disease, (c) dyslipidemia, (d) hypertriglyceridemia, (e) hypercholesterolemia, (f) mixed hyperlipidemia, (g) hypo-HDL-cholesterolemia, (h) hyper-LDL-cholesterolemia (i) hyperbetaliproteinemia, (j) hypoalphalipoproteinemia, (k) familial- hypercholesterolemia, (I) cardiovascular disorders, (m) angina, (n) ischemia, (o) cardiac ischemia, (p) stroke, (q) myocardial infarction, (r) reperfusion injury, (s) angioplastic restenosis, (t) hypertension, (u) vascular complications of diabetes, (v) obesity and/or (w) Metabolic Syndrome, in a subject in need thereof.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 illustrates a representative powder XRD spectra for the crystalline form of the compound of formula (N-S).

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to processes for the preparation of compound of formula (I)

wherein Q ₁ , L ₁ , n, m, R ₁ , R ₂ , R ₃ and R ₄ as are herein defined, and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof; wherein the compounds of formula (I). The compounds of formula (I) are useful in the treatment and / or prevention of diseases conditions affected by the modulation of CETP.

The present invention is directed to processes for the preparation of compound of formula (II)

wherein X, Q ₂ , L ₂ , p, q, R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ as are herein defined, and enantiomers, diastereomer, tautomers, solvates, and pharmaceutically acceptable salts thereof; wherein the compounds of formula (II). The

compounds of formula (II) are useful in the treatment and / or prevention of diseases conditions affected by the modulation of CETP.

In an embodiment, the present invention is directed to processes for the preparation of the compound of formula (I-S)

OH (I-S) also known as (S)-1 ,1 ,1-trifluoro-3-[(R)-2-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)- phenyl]-5-(3-trifluoromethoxy-phenyl)-3,4-dihydro-2H-quinoli n-1-yl]-propan-2-ol, and tautomers, solvates, and pharmaceutically acceptable salts thereof. The compound of formula (I-S) is useful in the treatment and / or prevention of diseases conditions affected by the modulation of CETP, including, but not limited to atherosclerosis, peripheral vascular disease, dyslipidemia (including hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, and hypo- HDL-cholesterolemia), hyper-LDL-cholesterolemia hyperbetaliproteinemia, hypoalphalipoproteinemia, familial-hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity and Metabolic Syndrome.

In another embodiment, the present invention is further directed to a process for the preparation of a compound of formula (M-S)

(M-S) also known as (S)-1 ,1 ,1 -trifluoro-3-[3-(S)-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)- phenyl]-8-(3-trifluoromethoxy-phenyl)-2,3-dihydro-benzo[1 ,4]oxazin-4-yl]- propan-2-ol; and tautomers, solvates and pharmaceutically acceptable salts thereof. The compound of formula (M-S) is useful in the treatment and / or prevention of diseases conditions affected by the modulation of CETP, including, but not limited to atherosclerosis, peripheral vascular disease, dyslipidemia (including hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, and hypo-HDL-cholesterolemia), hyper-LDL-cholesterolemia hyperbetaliproteinemia, hypoalphalipoproteinemia, familial- hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity and Metabolic Syndrome.

In an embodiment, the compound of formula (I-S) is prepared in an enantiomeric excess of greater than or equal to about 50%ee. In another embodiment of the present invention, the compound of formula (I-S) is prepared in an enantiomeric excess of greater than or equal to about 75%ee. In another embodiment of the present invention, the compound of formula (I-S) is prepared in an enantiomeric excess of greater than or equal to about 85%ee. In another embodiment of the present invention, the compound of formula (I-S) is prepared in an enantiomeric excess of greater than or equal to about 90%ee. In another embodiment of the present invention, the compound of formula (I-S) is prepared in an enantiomeric excess of greater than or equal to about 95%ee.

In another embodiment of the present invention, the compound of formula (I-S) is prepared in an enantiomeric excess of greater than or equal to about 98%ee. In another embodiment of the present invention, the compound of formula (I-S) is prepared in an enantiomeric excess of greater than or equal to about 99%ee.

In an embodiment, the compound of formula (M-S) is prepared in an enantiomeric excess of greater than or equal to about 50%ee. In another embodiment of the present invention, the compound of formula (N-S) is prepared in an enantiomeric excess of greater than or equal to about 75%ee. In another embodiment of the present invention, the compound of formula (M-S) is prepared in an enantiomeric excess of greater than or equal to about 85%ee. In another embodiment of the present invention, the compound of formula (M-S) is prepared in an enantiomeric excess of greater than or equal to about 90%ee. In another embodiment of the present invention, the compound of formula (M-S) is prepared in an enantiomeric excess of greater than or equal to about 95%ee. In another embodiment of the present invention, the compound of formula (M-S) is prepared in an enantiomeric excess of greater than or equal to about 98%ee. In another embodiment of the present invention, the compound of formula (M-S) is prepared in an enantiomeric excess of greater than or equal to about 99%ee.

The present invention is further directed to processes for the preparation of the compounds of formula (XII)

wherein R ₁ , n, R ₂ , m, R ₃ and the Qi ring are as herein defined; and wherein the compound of formula (XII) is prepared in an enantiomeric excess of one of its corresponding enantiomers of greater than about 0%ee, preferably greater than about 50%ee, more preferably, greater than about 75%ee, more preferably, greater than about 85%ee, more preferably, greater than about

90%ee, more preferably, greater than about 95%ee, more preferably, greater than about 98%ee, more preferably, greater than about 99%ee; as described in more detail herein. In an embodiment, the present invention is directed to processes for the preparation of the compound of formula (XII-S)

also known as 2-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-5-(3- trifluoromethoxy-phenyl)-1 ,2,3,4-tetrahydro-quinoline, and wherein the compound of formula (XII-S) is prepared in an enantiomeric excess of its corresponding (R)-enantiomer of greater than about 0%ee, preferably greater than about 50%ee, more preferably, greater than about 75%ee, more preferably, greater than about 85%ee, more preferably, greater than about 90%ee, more preferably, greater than about 95%ee, more preferably, greater than about 98%ee, more preferably, greater than about 99%ee; as described in more detail herein. The compounds of formula (XII) are useful as intermediate in the synthesis of the compounds of formula (I).

The present invention is further directed to processes for the preparation of the compounds of formula (XXIII)

(XXIII) wherein LG ² , X, Rn, q and R13 are as herein defined; and wherein the compound of formula (XXIII) is prepared in an enantiomeric excess of one of its corresponding enantiomers of greater than about 0%ee, preferably greater than about 50%ee, more preferably, greater than about 75%ee, more preferably,

greater than about 85%ee, more preferably, greater than about 90%ee, more preferably, greater than about 95%ee, more preferably, greater than about 98%ee, more preferably, greater than about 99%ee; as described in more detail herein. In an embodiment, the present invention is directed to processes for the preparation of the compound of formula (XXIII-S)

(XXIII-S) wherein LG ² is as herein defined, and wherein the compound of formula (XXIII-S) is prepared in an enantiomeric excess of its corresponding (S)- enantiomer of greater than about 0%ee, preferably greater than about 50%ee, more preferably, greater than about 75%ee, more preferably, greater than about 85%ee, more preferably, greater than about 90%ee, more preferably, greater than about 95%ee, more preferably, greater than about 98%ee, more preferably, greater than about 99%ee; as described in more detail herein. The compounds of formula (XXIII) are useful as intermediate in the synthesis of the compounds of formula (II).

The present invention is further directed to processes for the preparation of the compounds of formula (XXXII)

(XXXII) wherein Rn, q, R13 and LG ⁵ are as herein defined; as described in more detail herein. In an embodiment, the present invention is directed to processes for the preparation of the compound of formula (XXXII-S)

(XXXII-S) wherein LG ⁵ is a leaving group, preferably LG ⁵ is bromo; as described in more detail herein. The compounds of formula (XXIII) are useful as intermediates in the synthesis of compounds of formula (II).

Particularly, the present invention features a compound of Formula (I) wherein m is O. Particularly, the present invention features a compound of Formula (I) wherein n is 1 or 2. Particularly, the present invention features a compound of Formula (I) wherein Li is a covalent bond.

Particularly, the present invention features a compound of Formula (I) wherein Q ₁ is phenyl. Particularly, the present invention features a compound of Formula (I) wherein Qi is thienyl or pyridinyl.

Particularly, the present invention features a compound of Formula (I) wherein Ri is phenyl substituted with Ci _-4 alkyl, halogenated Ci _-4 alkyl, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, halo, cyano, or hydroxy. Particularly, the present invention features a compound of Formula (I) wherein Ri is phenyl substituted with halogenated Ci _-4 alkyl or halogenated Ci _-4 alkoxy, preferably phenyl substituted with -OCF ₂ CF ₂ H, -CF ₃ , or -OCF ₃ Particularly, the present invention features a compound of Formula (I) wherein n is 1 and R ₂ is selected from halo, halogenated Ci _-4 alkyl, and halogenated Ci _-4 alkoxy, preferably R ₂ is- OCF ₂ CF ₂ H or -OCF ₃

Particularly, the present invention features a compound of Formula (I) wherein R ₄ is Ci _-3 alkyl optionally substituted with 1 or 2 members each independently selected from halo, oxo, hydroxy, halogenated Ci _-4 alkyl, and heterocyclyl; preferably R ₄ is Cialkyl optionally substituted with 2 members each independently selected from halo, hydroxy, and halogenated Ci _-3 alkyl; more preferably R ₄ is Cialkyl optionally substituted with 2 members each independently selected from fluoro, hydroxy, and fluohnated Ci _-3 alkyl.

In particular, the present invention is directed to a compound of Formula (I) wherein Qi is phenyl; m is 0; n is 1 or 2; Li is a covalent bond; Ri is phenyl optionally substituted with Ci _-4 alkyl, halogenated Ci _-4 alkyl, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, halo, or cyano; each R ₂ is independently selected from halo, hydroxy, cyano, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci- ₄ alkyl, halogenated Ci _-4 alkyl, and -C(O)H; and R ₄ is Ci _-4 alkyl substituted with 1 -3 members independently selected from halo, hydroxy, halogenated Ci _-4 alkyl, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, and heterocyclyl.

In particular, the present invention is directed to a compound of Formula (I) wherein Qi is 5-or 6-membered heteroaryl selected from thienyl and pyridinyl; n is 0; m is 0; and Li is a covalent bond.

In particular, the present invention is directed to a compound of Formula (I) as shown above, wherein n is 1 ; m is 0; and the Qi — R ₂ group is

. In particular, the present invention is directed to a compound of

Formula (I) as shown above, wherein m is 0; and Ri is

In particular, the present invention is directed to a compound of Formula (I) as shown above wherein m is 0, and R ₄ is -CF ₃ .

In particular, the present invention is directed to a compound of Formula (I) wherein Qi is phenyl; m is 0; n is 1 or 2; Li is a covalent bond; Ri is - CH ₂ CH ₃ , cyclohexyl, thienyl, or phenyl optionally substituted with -OCF ₂ CF ₂ H, -CF ₃ , -F, -OCH ₃ , -CN, -Cl, Or -OCF ₃ ; each R ₂ is independently selected from -OCF ₃ , -CF ₃ , -Cl, -F, -CH ₃ , -CN, -OH, -OCH ₃ , -C(O)H, -CH(CH ₃ ) ₂ , - OCH(CH ₃ ) ₂ , and -CH ₂ CH ₃ ; and R ₄ is Ci _-3 alkyl optionally substituted with 1-3 members independently selected from -OH, halogenated Ci _-3 alkyl, and Ci- ₄ alkoxy.

In particular, the present invention is directed to a compound of Formula (I) wherein Qi is thienyl or pyridinyl; m is O; n is O; Li is a covalent bond; Ri is - CH ₂ CH ₃ , cyclohexyl, thienyl, or phenyl optionally substituted with -OCF ₂ CF ₂ H, -CF ₃ , -F, -OCH ₃ , -CN, -CL, or -OCF ₃ ; each R ₂ is independently selected

from -OCF ₃ , -CF ₃ , -Cl, -F, -CH ₃ , -CN, -OH, -OCH ₃ , -C(O)H, -CH(CH ₃ ) ₂ , - OCH(CHs) ₂ , and -CH ₂ CH ₃ ; and R ₄ is Ci _-3 alkyl optionally substituted with 1-3 members independently selected from -OH, halogenated Ci _-3 alkyl, and Ci- ₄ alkoxy.

In particular, the present invention is directed to a compound of Formula (I) as shown above wherein:

(a) Ri is Ci-βalkyl or C _3- iocycloalkyl, preferably -CH ₂ CH ₃ or

(b) Ri is phenyl optionally substituted with 1 or 2 members selected from Ra and Rb, wherein R ₃ and Rb are independently selected from the group consisting of Ci _-4 alkyl, halogenated Ci _-4 alkyl, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, cyano, and hydroxy, or R ₃ and Rb together with the carbon atoms they are attached to form 5- or 6-membered heterocyclyl fused to the phenyl ring;

S

(c) Ri is 5- or 6-membered heteroaryl, preferably ^- J ;

(d) Li is a covalent bond;

(e) Li is O;

(f) Qi is C _6- IO aryl, and preferably Q1 is phenyl;

(g) Qi is 5- or 6-membered heteroaryl; preferably thienyl, oxazolyl, thiazolyl, isoxazolyl, pyridinyl, and pyridazinyl; and more preferably thienyl and pyridinyl;

(h) each R ₂ is independently selected from halo, hydroxy, cyano, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci _-4 alkyl, halogenated Ci _-4 alkyl, and -C(O)H; preferably -CH ₃ , -CH ₂ CH ₃ , -C(O)H ₁ -O-CH ₃ , -0-CF ₃ , -O-CH(CH ₃ ) ₂ , -CH(CHs) ₂ , CN, OH, F, Cl, and -CF ₃ ;

(i) n is O, 1 , or 2;

C) m is O;

(k) R ₄ is Ci _-3 alkyl optionally substituted with 1 -3 members independently selected from halo, oxo, hydroxy, halogenated Ci _-3 alkyl, Ci _-4 alkoxy, C _3- s

cycloalkyl, CN, heterocyclyl, heteroaryl, and — NR _c Rd, wherein

Rc and R _d are independently selected from H, Ci _-3 alkyl, and -C(O)O-Ci _-3 alkyl;

(I) R ₄ is Ci _-4 alkyl optionally substituted with 1-3 members independently selected from oxo, halo, hydroxy, halogenated Ci _-5 alkyl Ci _-4 alkoxy, and 5- or 6-membered heterocyclyl; preferably selected from oxo, F, Cl, hydroxy,

— O— CH ₃ , and O ,; and more particularly R ₄ is halogenated Ci _-3 alkyl substituted with OH, preferably, R ₄ is -CF ₃ . and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof; or any possible combinations of examples (a) - (I) above.

More particularly, the present invention is directed to a compound of Formula (I) as shown above wherein m is O; n is O, 1 , or 2; Ri is -CH ₂ CH ₃ ,

. _P henyl , ,

; each R ₂ is independently selected from -CH ₃ , -CH ₂ CH ₃ , -C(O)H -O-CH ₃ , -0-CF ₃ , -O-CH(CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , CN, OH, F, Cl, and -CF ₃ ; R ₄ is Ci _-3 alkyl optionally substituted with 1 -3 members independently

selected from halogen, -CF ₃ , oxo, hydroxy, -Q-CH ₃ , and ; or R ₄ is

and Qi is phenyl., , or ; and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.

In one aspect of the present invention, the compounds of formula (I) are compounds of Formula (Ia):

wherein:

L ₁ is a covalent bond or O;

Qi is phenyl, naphthalenyl, or a heteroaryl selected from the group consisting of thienyl, oxazolyl, thiazolyl, isoxazolyl, pyridinyl, and pyridazinyl; n is O to 3; m is O to 3;

Ri is C-1-10 alkyl, C _2- ioalkenyl, C _2- ioalkynyl, C _3- iocycloalkyl, or a 5- or 6- membered heteroaryl; wherein said C _MO alkyl, C _2- ioalkenyl, C _2- ioalkynyl, C _3- locycloalkyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, cyano, hydroxy, oxo, Ci _-3 alkyl, and Ci-3alkoxy; alternately, Ri is phenyl optionally substituted with 1 to 2 members selected from R ₃ and Rb; wherein R ₃ and Rb are independently selected from the group consisting Of Ci _-4 alkyl, halogenated Ci _-4 alkyl, phenylCi _-4 alkyl, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, phenylCi _-4 alkoxy, Ci _-4 alkylthio, halogenated Ci _-4 alkylthio, halo, cyano, and hydroxy, or R ₃ and Rb together with the carbon atoms of the phenyl ring to which they are attached form a 5- or 6-membered heterocyclyl fused to the phenyl ring; said heterocyclyl optionally substituted with 1 or 2 members independently selected from halo, Ci-3alkyl, cyano, and hydroxy; each R ₂ is independently selected from the group consisting of halo, hydroxy, cyano, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci _-4 alkyl, halogenated Ci-

₄ alkyl, and -C(O)H; each R ₃ is independently selected from the group consisting of Ci _-4 alkyl, Ci _-4 alkoxy, halo, cyano, and hydroxy;

R ₄ is Ci-salkyl, halogenated Ci-salkyl, or benzyl, wherein said Ci-salkyl, halogenated Ci-salkyl, or benzyl is optionally substituted with 1 -3 members independently selected from the group consisting of oxo, hydroxy, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, C _3-8 cycloalkyl, cyano, heterocyclyl, and — NR _c R _c i; wherein R _c and Rd are independently selected from H, optionally substituted Ci- ₃ alkyl, -C(O)Ci _-3 alkyl, -C(O)O-Ci _-3 alkyl, and -SO ₂ Ci _-3 alkyl; and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.

Particularly, the present invention features a compound of Formula (Ia) wherein m is O. Particularly, the present invention features a compound of Formula (Ia) wherein n is 1 or 2. Particularly, the present invention features a compound of Formula (Ia) wherein Li is a covalent bond.

Particularly, the present invention features a compound of Formula (Ia) wherein Qi is phenyl. Particularly, the present invention features a compound of Formula (Ia) wherein Qi is thienyl or pyridinyl.

Particularly, the present invention features a compound of Formula (Ia) wherein Ri is phenyl substituted with Ci _-4 alkyl, halogenated Ci _-4 alkyl, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, halo, cyano, or hydroxy. Particularly, the present invention features a compound of Formula (Ia) wherein Ri is phenyl substituted with halogenated Ci _-4 alkyl or halogenated Ci _-4 alkoxy; preferably Ri is phenyl substituted with -OCF ₂ CF ₂ H, -CF ₃ , or -OCF ₃ Particularly, the present invention features a compound of Formula (Ia) wherein n is 1 and R ₂ is selected from halo, halogenated Ci _-4 alkyl, and halogenated Ci _-4 alkoxy, preferably R ₂ is -OCF ₂ CF ₂ H or -OCF ₃

Particularly, the present invention features a compound of Formula (Ia) wherein R ₄ is Ci _-3 alkyl substituted with 1 or 2 members each independently selected from oxo, hydroxy, Ci _-4 alkoxy, cyano, and heterocyclyl; preferably R ₄ is Cialkyl optionally substituted with hydroxy, Ci _-4 alkoxy, or cyano. Particularly, the present invention features a compound of Formula (Ia) wherein R ₄ is halogenated Ci _-2 alkyl substituted with oxo, hydroxy, Ci _-4 alkoxy, or cyano;

preferably R ₄ is fluorinatedCialkyl substituted oxo, hydroxy, Ci _-4 alkoxy, or cyano; more preferably R ₄ is fluorinatedCialkyl. Particularly, the present invention features a compound of Formula (Ia) wherein R ₄ is benzyl wherein the phenyl portion of the R ₄ group is substituted with hydroxy, Ci _-4 alkoxy, cyano, or halogenated Ci _-4 alkoxy; preferably R ₄ is benzyl wherein the phenyl portion of the R ₄ group is substituted with halogenated Ci _-4 alkoxy.

In particular, the present invention is directed to a compound of Formula (Ia) wherein Qi is phenyl; m is 0; n is 1 or 2; Li is a covalent bond; Ri is phenyl optionally substituted with Ci _-4 alkyl, halogenated Ci _-4 alkyl, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, halo, or cyano; each R ₂ is independently selected from halo, hydroxy, cyano, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci- ₄ alkyl, halogenated Ci _-4 alkyl, and -C(O)H; and R ₄ is C _h alky! substituted with 1 to 2 members independently selected from hydroxy, Ci _-4 alkoxy, oxo, halogenated Ci _-4 alkoxy, heterocyclyl, Cs-scycloalkyl, and cyano; or R ₄ is halogenated Ci _-2 alkyl optionally substituted with hydroxy, Ci _-4 alkoxy, oxo, or cyano.

In particular, the present invention is directed to a compound of Formula (Ia) wherein Qi is a heteroaryl selected from thienyl and pyridinyl; n is 0; m is 0; and Li is a covalent bond.

In particular, the present invention is directed to a compound of Formula (Ia) as shown above, wherein n is 1 ; m is 0; and the Qi — R ₂ group is

. In particular, the present invention is directed to a compound of

Formula (Ia) as shown above, wherein m is 0; and Ri is

In particular, the present invention is directed to a compound of Formula (Ia) as shown above wherein m is 0, and R ₄ is -CF ₃ .

In particular, the present invention is directed to a compound of Formula (Ia) wherein Qi is phenyl; m is 0; n is 1 or 2; Li is a covalent bond; Ri is - CH ₂ CH ₃ , cyclohexyl, thienyl, or phenyl optionally substituted with -OCF ₂ CF ₂ H, -CF ₃ , -F, -OCH ₃ , -CN, -Cl, Or -OCF ₃ ; each R ₂ is independently selected from

-OCF ₃ , -CF ₃ , -Cl, -F, -CH ₃ , -CN, -OH, -OCH ₃ , -C(O)H, -CH(CH ₃ ) ₂ , - OCH(CHs) ₂ , and -CH ₂ CH ₃ ; and R ₄ is Ci _-4 alkyl optionally substituted with 1 to 2 members independently selected from -OH, -OCH ₃ , and Ci _-4 alkoxy; or R ₄ is halogenated Ci _-2 alkyl optionally substituted with hydroxy, Ci _-4 alkoxy, oxo, or cyano.

In particular, the present invention is directed to a compound of Formula (Ia) wherein Q ₁ is phenyl; m is O; n is 1 or 2; L ₁ is a covalent bond; R ₁ is - CH ₂ CH ₃ , cyclohexyl, thienyl, or phenyl substituted at the 3-position with - OCF ₂ CF ₂ H, -CF ₃ , -F, -OCH ₃ , -CN, -Cl, Or -OCF ₃ ; each R ₂ is independently selected from -OCF ₃ , -CF ₃ , -Cl, -F, -CH ₃ , -CN, -OH, -OCH ₃ , -C(O)H, - CH(CH ₃ ) ₂ , -OCH(CH ₃ ) ₂ , and -CH ₂ CH ₃ ; and R ₄ is flourinated C _1-2 alkyl optionally substituted with hydroxy, C _1-4 alkoxy, oxo, or cyano.

In particular, the present invention is directed to a compound of Formula (Ia) wherein Q ₁ is thienyl or pyridinyl; m is O; n is O; L ₁ is a covalent bond; R ₁ is -CH ₂ CH ₃ , cyclohexyl, thienyl, or phenyl optionally substituted with -OCF ₂ CF ₂ H, -CF ₃ , -F, -OCH ₃ , -CN, -CL, or -OCF ₃ ; each R ₂ is independently selected from -OCF ₃ , -CF ₃ , -Cl, -F, -CH ₃ , -CN, -OH, -OCH ₃ , -C(O)H, -CH(CH ₃ ) ₂ , - OCH(CH ₃ ) ₂ , and -CH ₂ CH ₃ ; and R ₄ is C _1-4 alkyl optionally substituted with 1-2 members independently selected from -OH, -OCH ₃ , and C _1-4 alkoxy; or R ₄ is halogenated C _1-2 alkyl optionally substituted with hydroxy, C _1-4 alkoxy, oxo, or cyano.

In particular, the present invention is directed to a compound of Formula (Ia) as shown above wherein:

(a) R ₁ is d-βalkyl or C _3-1 ocycloalkyl, preferably -CH ₂ CH ₃ or

(b) R ₁ is phenyl optionally substituted with 1 or 2 members selected from Ra and Rb, wherein R ₃ and Rb are independently selected from the group consisting Of C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkoxy, cyano, and hydroxy, or R ₃ and Rb together with the carbon atoms they are attached to form 5- or 6-membered heterocyclyl fused to the phenyl ring;

preferably R ₁ is phenyl,

S

(c) Ri is 5- or 6-membered heteroaryl, preferably ^- J ;

(d) Li is a covalent bond;

(e) Li is O;

(f) Qi is phenyl;

(g) Qi is a heteroaryl selected from the group consisting of thienyl, oxazolyl, thiazolyl, isoxazolyl, pyridinyl, and pyridazinyl; and more preferably thienyl and pyridinyl;

(h) each R ₂ is independently selected from halo, hydroxy, cyano, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci _-4 alkyl, halogenated Ci _-4 alkyl, and -C(O)H; preferably -CH ₃ , -CH ₂ CH ₃ , -C(O)H ₁ -O-CH ₃ , -0-CF ₃ , -O-CH(CH ₃ ) ₂ , -CH(CHs) ₂ , CN, OH, F, Cl, and -CF ₃ ;

(i) n is O, 1 , or 2;

G) m is O;

(k) R ₄ is Ci _-3 alkyl optionally substituted with 1 or 2 members independently selected from oxo, hydroxy, cyano, Ci _-4 alkoxy, heterocyclyl, and — NRcRd, wherein R _c and Rd are independently selected from H, Ci _-3 alkyl, and -C(O)O-Ci _-3 alkyl;

(I) R ₄ is halogenated Ci _-2 alkyl optionally substituted with oxo, hydroxy, Ci _-4 alkoxy, or cyano; preferably R ₄ is fluorinatedCialkyl optionally substituted with hydroxy; more preferably R ₄ is -CF ₃ ; and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof; or any possible combinations of examples (a) - (I) above.

More particularly, the present invention is directed to a compound of Formula (Ia) as shown above wherein m is O; n is O, 1 , or 2; Ri is -CH ₂ CH ₃ ,

or ; each R ₂ is independently selected from -CH ₃ , -CH ₂ CH ₃ , -C(O)H -O-CH ₃ , -0-CF ₃ , -O-CH(CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , CN, OH, F, Cl, and -CF ₃ ; R ₄ is halogenated Ci _-2 alkyl optionally substituted with oxo, hydroxy, or

-0-CH ₃ ; and Q1 is phenyl., , or .

In particular, the present invention is further directed to a compound of Formula (Ia) wherein

(a) m is O;

(b) n is 1 , 2, or 3;

(c) m and n are both O;

(d) m is O and n is 1 ;

(e) m is O and n is 2;

(f) L ₁ is a bond;

(g) Li is O;

(m) R ₁ is -CH ₂ CH ₃ , , or phenyl; (n) Q ₁ is phenyl or naphthalenyl;

(o) Qi is phenyl;

(p) Qi is a selected from the group consisting of thienyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, and pyridizinyl;

(v) R ₂ is -0-CF ₃ ;

(w) R ₂ is F;

(x) R ₂ is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ ;

(Y) R ₂ Is -C(O)H ₁ CN ₁ OH,

(Z) R ₂ is -O-CH(CH ₃ ) ₂ , F, Cl, Or -CF ₃ ;

(aa) R ₂ is -0-CH ₃ , -0-CF ₃ , or -O-CH(CH ₃ ) ₂ ;

(bb) R ₄ is Ci _-3 alkyl optionally substituted with 1 or 2 members independently selected from oxo, hydroxy, and — O- CH ₃ ;

(cc) R ₄ is halogenated Ci _-2 alkyl optionally substituted with oxo, hydroxy, or -0-CH ₃ ;

(dd) R ₄ is -CF ₃ ;

(ee) R ₄ is -CH ₂ CF ₃ ;

(ff) R ₄ is -CH(CH ₃ ) ₂ ;

O

-CCH ₂ -N O

(gg) R4 is \

(hh) m is 0, n is 1 , and Li is a bond; (ii) m is O, n is 2, and Li is a bond;

(jj) m is O, n is 1 , Li is a bond, and Ri is or

(kk) m is O, n is 1 , L ₁ is a bond, Qi is phenyl, and Ri is

(II) m is O, n is 1 , Li is a bond, Ri is or

(mm) m is 0, n is 1 , Li is a bond, Ri is or

(nn) m is 0, n is 1 , L ₁ is a bond, Q ₁ is phenyl, and R ₁ is

(00) m is 0, n is 1 , L ₁ is a bond, Q ₁ is phenyl, and R ₁ is

(pp) m is 0, n is 1 , L ₁ is a bond, Q ₁ is phenyl, and R ₁ is

or , and R ₂ is -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ ,

-C(O)H, CN, OH, -O-CH(CH ₃ ) _2j F, Cl, -CF ₃ , -0-CH ₃ , -0-CF ₃ , or -O-CH(CH ₃ ) ₂ ;

(qq) m is O, n is 1 , L ₁ is a bond, Qi is R ₂ is — O-CF? or F;

(rr) m is O, n is 1 , Li is a bond, Qi is and R ₂ is -CH ₃ , -CH ₂ CH _3, -CH(CHs) ₂ , -C(O)H, CN, OH, -O-CH(CH ₃ ) ₂ , F, Cl, -CF ₃ , -0-CH ₃ , -0-CF ₃ , or -O-CH(CH ₃ ) ₂ ; or enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof; or any possible combinations of (a)-(rr) as listed above.

In another aspect of the present invention, the compounds of formula (I) are compounds of Formula (Ib):

wherein:

Ri is C-1-10 alkyl, C _2- i ₀ alkenyl, C _2- i ₀ alkynyl, C _3- i ₀ cycloalkyl, or a 5- or 6- membered heteroaryl; wherein said C _M0 alkyl, C _2- i ₀ alkenyl, C _2- i ₀ alkynyl, C _3- locycloalkyl, or 5- or 6-membered heteroaryl is optionally substituted with halo,

cyano, or hydroxy, oxo, Ci _-3 alkyl, or Ci _-3 alkoxy; alternatively, Ri is phenyl optionally substituted with 1 to 2 members selected from R ₃ and Rb; wherein R ₃ and R _b are independently selected from the group consisting Of Ci _-4 alkyl, halogenated Ci _-4 alkyl, phenylCi _-4 alkyl, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, phenylCi _-4 alkoxy, Ci _-4 alkylthio, halogenated Ci _-4 alkylthio, halo, cyano, and hydroxy, or R ₃ and Rb together with the carbon atoms of the phenyl ring to which they are attached form a 5- or 6-membered heterocyclyl fused to the phenyl ring; said heterocyclyl optionally substituted with 1 or 2 members independently selected from halo, Ci _-3 alkyl, cyano, and hydroxy; each of R _2a , R2b, and R _2c is independently absent or selected from the group consisting of halo, hydroxy, cyano, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci _-4 alkyl, halogenated Ci _-4 alkyl, and -C(O)H;

R ₃ is absent or selected from the group consisting of Ci _-4 alkyl, Ci _-4 alkoxy, halo, cyano, and hydroxy;

R ₄ is Ci _-8 alkyl, halogenated Ci _-8 alkyl, or benzyl; wherein said Ci _-8 alkyl, halogenated Ci-salkyl, or benzyl is optionally substituted with 1 -3 members independently selected from the group consisting of oxo, hydroxy, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, C _3-8 cycloalkyl, cyano, heterocyclyl, and — NR _c Rci; wherein R _c and Rd are independently selected from H, optionally substituted Ci _-3 alkyl, -C(O)Ci _-3 alkyl, -C(O)O-Ci _-3 alkyl, and -SO ₂ Ci _-3 a Iky I; and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.

Particularly, the present invention features a compound of Formula (Ib) wherein Ri is phenyl substituted with Ci _-4 alkyl, halogenated Ci _-4 alkyl, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, halo, cyano, or hydroxy. Particularly, the present invention features a compound of Formula (Ib) wherein Ri is phenyl substituted with halogenated Ci _-4 alkyl or halogenated Ci _-4 alkoxy; preferably Ri is phenyl substituted with -OCF ₂ CF ₂ H, -CF ₃ , or -OCF ₃ Particularly, the present invention features a compound of Formula (Ib) wherein R _2a and R ₂ b are both absent and R _2c is selected from halo, halogenated Ci _-4 alkyl, and halogenated Ci _-4 alkoxy, preferably R _2c is -OCF ₂ CF ₂ H Or -OCF ₃

Particularly, the present invention features a compound of Formula (Ib) wherein R ₄ is Ci _-3 alkyl substituted with 1 or 2 members each independently

selected from oxo, hydroxy, Ci _-4 alkoxy, cyano, and heterocyclyl; preferably R ₄ is Ci-alkyl optionally substituted with hydroxy, Ci _-4 alkoxy, or cyano. Particularly, the present invention features a compound of Formula (Ib) wherein R ₄ is halogenated Ci _-2 alkyl optionally substituted with oxo, hydroxy, Ci _-4 alkoxy, or cyano; preferably R ₄ is fluorinated Ci _-2 alkyl optionally substituted with oxo, hydroxy, Ci _-4 alkoxy, or cyano; more preferably R ₄ is fluorinatedCi-3 alkyl substituted with hydroxy. Particularly, the present invention features a compound of Formula (Ib) wherein R ₄ is benzyl wherein the phenyl portion of the R ₄ group is substituted with hydroxy, Ci _-4 alkoxy, cyano, or halogenated Ci _-4 alkoxy, preferably R ₄ is benzyl wherein the phenyl portion of the R ₄ group is substituted with halogenated Ci _-4 alkoxy.

In particular, the present invention is directed to a compound of Formula (Ib) wherein Ri is phenyl optionally substituted with Ci _-4 alkyl, halogenated Ci- ₄ alkyl, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, halo, or cyano; each R _2a , R2b, and R _2c is independently absent or selected from halo, hydroxy, cyano, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci _-4 alkyl, halogenated Ci _-4 alkyl, and -C(O)H; R ₃ is absent; and R ₄ is C _h alky! substituted with 1 to 2 members independently selected from hydroxy, Ci _-4 alkoxy, oxo, halogenated Ci _-4 alkoxy, heterocyclyl, C _3- 8cycloalkyl, cyano; or R ₄ is halogenated Ci _-2 alkyl optionally substituted with hydroxy, Ci _-4 alkoxy, oxo, or cyano.

In particular, the present invention is directed to a compound of Formula (Ib) wherein Ri is phenyl optionally substituted at the 3-position with Ci _-4 alkyl, halogenated Ci _-4 alkyl, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, halo, or cyano; each R _2a, R _2b, and R _2c is independently absent or selected from halo, hydroxy, cyano, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci _-4 alkyl, halogenated Ci _-4 alkyl, and -C(O)H; R ₃ is absent; and R ₄ is fluorinated Ci _-2 alkyl optionally substituted with hydroxy, Ci _-4 alkoxy, oxo, or cyano.

In particular, the present invention is directed to a compound of Formula (Ib) as shown above wherein:

(a) Ri is Ci _-6 alkyl or C _3- i ₀ cycloalkyl, preferably -CH ₂ CH ₃ or

(b) Ri is phenyl optionally substituted with 1 or 2 members selected from Ra and Rb, wherein R ₃ and Rb are independently selected from the group

consisting of Ci _-4 alkyl, halogenated Ci _-4 alkyl, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, cyano, and hydroxy, or R ₃ and Rb together with the carbon atoms they are attached to form 5- or 6-membered heterocyclyl fused to the phenyl ring;

pre ,fera _u b.ly _D Ri ■ is p _u heny ,l,

S

(c) Ri is 5- or 6-membered heteroaryl, preferably ^—-^ ;

(d) each of R _2a , R2b, and R _2c is independently absent or selected from halo, hydroxy, cyano, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci _-4 alkyl, halogenated Ci _-4 alkyl, and -C(O)H; preferably -CH ₃ , -CH ₂ CH ₃ , -C(O)H, -O-CH ₃ , -0-CF ₃ , -O-CH(CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , CN, OH, F, Cl, and -CF ₃ ;

(e) R ₃ is absent;

(f) R ₄ is Ci _-3 alkyl optionally substituted with 1 or 2 members independently selected from oxo, hydroxy, cyano, Ci _-4 alkoxy, heterocyclyl, and — NRcRd, wherein R _c and Rd are independently selected from H, Ci _-3 alkyl, and -C(O)O-Ci _-3 alkyl;

(g) R ₄ is halogenated Ci _-2 alkyl optionally substituted with oxo, hydroxy, Ci _-4 alkoxy, or cyano; preferably R ₄ is fluohnated Cialkyl optionally substituted with hydroxy; more preferably R ₄ is -CF ₃ . and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof; or any possible combinations of examples (a) - (g) above.

In another aspect of the present invention, the compounds of formula (I) are compounds of Formula (Ic):

wherein: each R _2a , R2b, R2c is independently absent or selected from the group consisting of halo, hydroxy, cyano, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci _-4 alkyl, halogenated Ci _-4 alkyl, and -C(O)H;

R ₄ is Ci-salkyl, halogenated Ci-salkyl, or benzyl, wherein said Ci-salkyl, halogenated Ci _-8 alkyl, or benzyl is optionally substituted with 1 -3 members independently selected from the group consisting of halo, oxo, hydroxy, Ci _-4 alkoxy, C _3- S cycloalkyl, cyano, heterocyclyl, heteroaryl, tert- butyldimethylsilyloxy, and — NR _c Rci; wherein R _c and R _d are independently selected from H, optionally substituted Ci _-3 alkyl, -C(O)Ci _-3 alkyl, -C(O)O-Ci _-3 alkyl, and SO ₂ Ci _-3 alkyl;

R ₅ is selected from the group consisting of Ci _-4 alkyl, halogenated Ci- ₄ alkyl, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci _-4 alkylthio, halo, cyano, and hydroxy; and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.

In particular, the present invention is directed to a compound of Formula (Ic) wherein R _2a is absent or halo, preferably R _2a is absent. In particular, the present invention is directed to a compound of Formula (Ic) wherein R _2b is absent, halo, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci _-4 alkyl, or halogenated Ci- 4 alkyl; preferably R ₂ b is absent, halo, -OCF ₃ , -CF ₃ ; more preferably R ₂ b is absent. In particular, the present invention is directed to a compound of Formula (Ic) wherein R _2c is halo, hydroxy, cyano, Ci _-4 alkoxy, halogenated Ci-

₄ alkoxy, Ci _-4 alkyl, or halogenated Ci _-4 alkyl; preferably R _2c is halo or halogenated Ci _-4 alkoxy; more preferably R _2c is -OCF ₃ or F.

In particular, the present invention is directed to a compound of Formula (Ic) wherein R ₄ is C _h alky! substituted with 1 or 2 members each independently selected from oxo, hydroxy, Ci _-4 alkoxy, cyano, and heterocyclyl; preferably R ₄ is Cialkyl optionally substituted with hydroxy, Ci _-4 alkoxy, or cyano. In particular, the present invention is directed to a compound of Formula (Ic) wherein R ₄ is halogenated Ci _-2 alkyl optionally substituted with oxo, hydroxy, Ci- ₄ alkoxy, or cyano. In particular, the present invention is directed to a compound of Formula (Ic) wherein R ₄ is fluorinated Ci _-2 alkyl optionally substituted with oxo, hydroxy, Ci _-4 alkoxy, or cyano; preferably R ₄ is fluorinatedCi-alkyl optionally substituted with hydroxy; more preferably R ₄ is - CF ₃ .. In particular, the present invention is directed to a compound of Formula (Ic) wherein R ₄ is benzyl wherein the phenyl portion of the R ₄ group is substituted with hydroxy, Ci _-4 alkoxy, cyano, or halogenated Ci _-4 alkoxy, preferably R ₄ is benzyl wherein the phenyl portion of the R ₄ group is substituted with halogenated Ci _-4 alkoxy.

In particular, the present invention is directed to a compound of Formula (Ic) wherein R ₅ is Ci _-4 alkyl, halogenated Ci _-4 alkyl, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci _-4 alkylthio, halo, cyano, or hydroxy; preferably R ₅ is halogenated Ci- ₄ alkyl, halogenated Ci _-4 alkoxy, or halo; more preferably R ₅ is -OCF ₃ Or- OCF ₂ CF ₂ H.

In particular, the present invention is directed to a compound of Formula (I) selected from the group consisting of:

1 ,1 ,1 -Trifluoro-3-[2-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-5-(3- trifluoromethoxy-phenyl)-3,4-dihydro-2H-quinolin-1 -yl]-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[2-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-5-(4- trifluoromethyl-phenyl)-3,4-dihydro-2H-quinolin-1 -yl]-propan-2-ol;

3-{5-(4-Chloro-3-methyl-phenyl)-2-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]- 3,4-dihydro-2H-quinolin-1 -yl}-1 ,1 ,1 -trifluoro-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[2-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-5-(4- trifluoromethoxy-phenyl)-3,4-dihydro-2H-quinolin-1 -yl]-propan-2-ol;

3-[2-[3-(1 ,1 ,2,2-Tetrafluoro-ethoxy)-phenyl]-1 -(3,3,3-trifluoro-2-hydroxy-

propyl)-1 ,2,3,4-tetrahydro-quinolin-5-yl]-benzonitrile;

1 ,1 ,1 -Trifluoro-3-{5-(3-fluoro-phenyl)-2-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)- phenyl]-3,4-dihydro-2H-quinolin-1 -yl}-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[2-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-5-(3- trifluoronnethyl-phenyl)-3,4-dihydro-2H-quinolin-1 -yl]-propan-2-ol;

S-iδ-CS-Chloro-phenyl^-^i .i ^^-tetrafluoro-ethoxyJ-phenyll-S^- dihydro-2H-quinolin-1 -yl}-1 ,1 ,1 -trifluoro-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[5-(3-trifluoronnethoxy-phenyl)-2-(3-trifluoron nethyl- phenyl)-3,4-dihydro-2H-quinolin-1 -yl]-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[2-phenyl-5-(3-trifluoromethoxy-phenyl)-3,4-dih ydro-2H- quinolin-1 -yl]-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[2-[4-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-5-(3- trifluoronnethoxy-phenyl)-3,4-dihydro-2H-quinolin-1 -yl]-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[2-(3-fluoro-phenyl)-5-(3-trifluoronnethoxy-phe nyl)-3,4- dihydro-2H-quinolin-1 -yl]-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[2-(3-methoxy-phenyl)-5-(3-trifluoronnethoxy-ph enyl)- 3,4-dihydro-2H-quinolin-1 -yl]-propan-2-ol;

3-[1 -(3,3,3-Trifluoro-2-hydroxy-propyl)-5-(3-trifluoronnethoxy-p henyl)- 1 ,2,3,4-tetrahydro-quinolin-2-yl]-benzonitrile;

3-[2-(3-Chloro-phenyl)-5-(3-trifluoromethoxy-phenyl)-3,4- dihydro-2H- quinolin-1 -yl]-1 ,1 ,1-trifluoro-propan-2-ol;

3-[2,5-Bis-(3-trifluoronnethoxy-phenyl)-3,4-dihydro-2H-qu inolin-1 -yl]- 1 ,1 ,1 -trifluoro-propan-2-ol ;

1 ,1 ,1 -Trifluoro-3-[2-thiophen-2-yl-5-(3-trifluoromethoxy-phenyl)- 3,4- dihydro-2H-quinolin-1 -yl]-propan-2-ol;

3-[2-Ethyl-5-(3-trifluoromethoxy-phenyl)-3,4-dihydro-2H-q uinolin-1 -yl]- 1 ,1 ,1 -trifluoro-propan-2-ol ;

3-[2-Cyclohexyl-5-(3-trifluoromethoxy-phenyl)-3,4-dihydro -2H-quinolin-1 - yl]-1 , 1 ,1 -trifluoro-propan-2-ol;

3-[2-[3-(1 ,1 ,2,2-Tetrafluoro-ethoxy)-phenyl]-1 -(3,3,3-trifluoro-2-hydroxy- propyl)-1 ,2,3,4-tetrahydro-quinolin-5-yl]-phenol;

1 -[2,5-Bis-(3-thfluoromethoxy-phenyl)-3,4-dihydro-2H-quinolin -1-yl]-3- methyl-butan-2-ol;

1 -[2,5-Bis-(3-trifluoromethoxy-phenyl)-3,4-dihydro-2H-quinoli n-1-yl]-3- chloro-propan-2-ol;

1 -[2,5-Bis-(3-tπfluoronnethoxy-phenyl)-3,4-dihydro-2H-quinol in-1-yl]-3- fluoro-propan-2-ol;

(αS,2R)-3,4-Dihydro-α-(methoxymethyl)-2,5-bis-[3- (trifluoronnethoxy)phenyl]-1 (2/-/)-quinolineethanol;

(αS,2S)-3,4-Dihydro-α-(methoxymethyl)-2,5-bis-[3- (trifluoronnethoxy)phenyl]-1 (2/-/)-quinolineethanol;

(αf?,2R)- 3,4-Dihydro-α-(methoxymethyl)-2,5-bis-[3- (trifluoronnethoxy)phenyl]-1 (2/-/)-quinolineethanol;

(αR,2S)-3,4-Dihydro-α-methyl-2,5-bis-[3-(trifluorometho xy)phenyl]- 1 (2/-/)-quinolineethanol;

(αf?,2R)-5-(3-Fluorophenyl)-3,4-dihydro-α-methyl-2-[3- (trifluoronnethoxy)phenyl]-1 (2/-/)-quinolineethanol;

(αf?,2S)-5-(3-Fluorophenyl)-3,4-dihydro-α-methyl-2-[3- (trifluoronnethoxy)phenyl]-1 (2/-/)-quinolineethanol;

1 ,1 ,1 -Trifluoro-3-[5-(3-fluoro-phenyl)-2-(3-trifluoronnethoxy-phe nyl)-3,4- dihydro-2H-quinolin-1 -yl]-propan-2-ol;

(αR2R)-3,4-Dihydro-5-(3-methoxyphenyl)-α-methyl-2-[3- (trifluoronnethoxy)phenyl]-1 (2/-/)-quinolineethanol;

(αf?,2S)-3,4-Dihydro-5-(3-methoxyphenyl)-α-methyl-2-[3- (trifluoronnethoxy)phenyl]-1 (2/-/)-quinolineethanol;

(αf?,2S)-3,4-Dihydro-5-(3-methoxyphenyl)-α-methyl-2-[3- (trifluoronnethoxy)phenyl]-1 (2/-/)-quinolineethanol;

(αS,2R)-3,4-Dihydro-α-methyl-2-[3-(1 ,1 ,2,2-tetrafluoroethoxy)phenyl]-5- [3-(trifluoronnethoxy)phenyl]-1 (2/-/)-quinolineethanol;

(αS,2S)-3,4-Dihydro-α-methyl-2-[3-(1 ,1 ,2,2-tetrafluoroethoxy)phenyl]-5- [3-(trifluoronnethoxy)phenyl]-1 (2/-/)-quinolineethanol;

3-[2-[3-(1 ,1 ,2,2-Tetrafluoro-ethoxy)-phenyl]-1 -(3,3,3-trifluoro-2-hydroxy- propyl)-1 ,2,3,4-tetrahydro-quinolin-5-yl]-benzaldehyde;

1 ,1 ,1 -Trifluoro-3-{2-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-5-thiophen-3- yl-3,4-dihydro-2H-quinolin-1 -yl}-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-{5-(3-isopropyl-phenyl)-2-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)- phenyl]-3,4-dihydro-2H-quinolin-1 -yl}-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-{5-(3-isopropoxy-phenyl)-2-[3-(1 ,1 ,2,2-tetrafluoro- ethoxy)-phenyl]-3,4-dihydro-2H-quinolin-1-yl}-propan-2-ol;

(αf?,2R)-3,4-Dihydro-α-methyl-2-[3-(1 ,1 ,2,2-tetrafluoroethoxy)phenyl]-5- [3-(trifluoronnethoxy)phenyl]-1 (2/-/)-quinolineethanol;

1 ,1 ,1 -Trifluoro-3-{5-(3-methoxy-phenyl)-2-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)- phenyl]-3,4-dihydro-2H-quinolin-1 -yl}-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-{2-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-5-thiophen-2- yl-3,4-dihydro-2H-quinolin-1 -yl}-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-{5-pyridin-3-yl-2-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]- 3,4-dihydro-2H-quinolin-1 -yl}-propan-2-ol;

(αR2R)-5-(3-Fluorophenyl)-3,4-dihydro-α-methyl-2-[3-(1 ,1 ,2,2- tetrafluoroethoxy)phenyl]-1 (2H)-quinolineethanol;

(2R,αS)-3,4-Dihydro-2-[3-(1 ,1 ,2,2-tetrafluoroethoxy)phenyl]-5-[3- (trifluoronnethoxy)phenyl]-α-(tπfluoronnethyl)-1 (2/-/)-quinolineethanol;

(2R,αR)-3,4-Dihydro-2-[3-(1 ,1 ,2,2-tetrafluoroethoxy)phenyl]-5-[3- (trifluoronnethoxy)phenyl]-α-(tπfluoronnethyl)-1 (2H)-quinolineethanol;

(2S,αS)-3,4-Dihydro-2-[3-(1 ,1 ,2,2-tetrafluoroethoxy)phenyl]-5-[3- (trifluoronnethoxy)phenyl]-α-(tπfluoronnethyl)-1 (2H)-quinolineethanol;

(2S,αS)-3,4-Dihydro-2-[3-(1 ,1 ,2,2-tetrafluoroethoxy)phenyl]-5-[3- (trifluoronnethoxy)phenyl]-α-(tπfluoronnethyl)-1 (2H)-quinolineethanol;

(2S,αR)-3,4-Dihydro-2-[3-(1 ,1 ,2,2-tetrafluoroethoxy)phenyl]-5-[3- (trifluoronnethoxy)phenyl]-α-(tπfluoronnethyl)-1 (2H)-quinolineethanol;

3-{5-(4-Chloro-3-ethyl-phenoxy)-2-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]- 3,4-dihydro-2H-quinolin-1 -yl}-1 ,1 ,1 -trifluoro-propan-2-ol;

3-{5-(2,3-Dichloro-phenoxy)-2-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-3,4- dihydro-2H-quinolin-1 -yl}-1 , 1 ,1 -trifluoro-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[2-[2-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-5-(3- trifluoromethoxy-phenyl)-3,4-dihydro-2H-quinolin-1 -yl]-propan-2-ol; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.

More particularly, the present invention is directed to a compound of Formula (I) selected from the group consisting of

OH ; and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.

In particular, the present invention is directed to a compound of Formula (I) selected from the group consisting of

acceptable

Particularly, the present invention features a compound of Formula (II) wherein q is O. Particularly, the present invention features a compound of Formula (II) wherein p is 1 or 2. Particularly, the present invention features a compound of Formula (II) wherein L ₂ is a covalent bond.

Particularly, the present invention features a compound of Formula (II) wherein Q ₂ is phenyl. Particularly, the present invention features a compound of Formula (II) wherein Q ₂ is thienyl or pyridinyl. Particularly, the present invention features a compound of Formula (II) wherein X is O.

Particularly, the present invention features a compound of Formula (II) wherein Rn is phenyl substituted with Ci _-4 alkyl, halogenated Ci _-4 alkyl, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, halo, cyano, hydroxy, halogenated Ci- ₄ alkylthio, or an optionally substituted five membered heterocyclyl ring fused to the phenyl ring forming a bicyclic ring system. Particularly, the present invention features a compound of Formula (II) wherein Rn is phenyl substituted with Ci _-4 alkyl, halogenated Ci _-4 alkyl, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, halo, cyano, or hydroxy. Particularly, the present invention features a compound of Formula (II) wherein Rn is phenyl substituted with halogenated Ci _-4 alkyl or halogenated Ci _-4 alkoxy, preferably Rn is phenyl substituted with -OCF ₂ CF ₂ H, -CF ₃ , or -OCF ₃ Particularly, the present invention features a compound of Formula (II) wherein Rn is d-β alkyl substituted with hydroxy, Ci _-4 alkoxy, oxo, halo, or cyano. Particularly, the present invention features a compound of Formula (II) wherein Rn is furanyl or thienyl optionally substituted with Ci _-3 alkyl, Ci _-3 alkoxy, hydroxy, or cyano.

Particularly, the present invention features a compound of Formula (II) wherein p is 1 , 2, or 3 and each Ri ₂ is independently selected from halo, halogenated Ci _-4 alkyl, and halogenated Ci _-4 alkoxy, preferably Ri ₂ is - OCF ₂ CF ₂ H, -OCF ₃ Or F. Particularly, the present invention features a compound of Formula (II) wherein p is 1 and Ri ₂ is halogenated Ci _-4 alkoxy, preferably Ri ₂ is -OCF ₂ CF ₂ H.

Particularly, the present invention features a compound of Formula (II) wherein Ri ₄ is Ci _-3 alkyl optionally substituted with 1 or 2 members each independently selected from halo, oxo, hydroxy, halogenatedCi _-4 alkyl, and optionally substituted heterocyclyl; preferably Ri ₄ is Cialkyl optionally substituted with 3 members each independently selected from halo, hydroxy, and halogenatedCi _-3 alkyl.

In particular, the present invention is directed to a compound of Formula (II) wherein X is O; Q ₂ is phenyl; q is O; p is 1 , 2, or 3; L ₂ is a covalent bond; Rn is phenyl optionally substituted with Ci _-4 alkyl, halogenatedCi _-4 alkyl, Ci _-4 alkoxy, halogenatedCi _-4 alkoxy, or cyano; each Ri ₂ is independently selected from halo, hydroxy, cyano, Ci _-4 alkoxy, halogenatedCi _-4 alkoxy, Ci _-4 alkyl, halogenatedCi _-4 alkyl, and -C(O)H; and Ri ₄ is Ci _-4 alkyl substituted with 1 -3

members independently selected from halo, hydroxy, oxo, halogenatedCi- ₄ alkyl, Ci _-4 alkoxy, and halogenatedCi _-4 alkoxy.

In particular, the present invention is directed to a compound of Formula (II) wherein Q ₂ is phenyl; p is 1 ; q is 0; and L ₂ is a covalent bond.

In particular, the present invention is directed to a compound of Formula (II) as shown above, wherein p is 1 ; q is 0; and the Q ₂ — Re group is

. In particular, the present invention is directed to a compound of

Formula (II) as shown above, wherein q is 0; and Rn is

In particular, the present invention is directed to a compound of Formula (II) as shown above wherein q is 0, and Ri ₄ is -CF ₃ .

In particular, the present invention is directed to a compound of Formula (II) wherein X is O; Q ₂ is phenyl; q is 0; p is 1 or 2; L ₂ is a covalent bond; Rn is Ci- ₅ alkyl substituted with oxo, hydroxy, or Ci _-3 alkoxy, thienyl optionally substituted with Ci _-3 alkyl or Ci _-3 alkoxy, furanyl, or phenyl optionally substituted with halogenatedCi- ₄ alkyl, halogenatedCr ₄ alkoxy, Ci _-4 alkoxy, or halo; each Ri ₂ is independently selected from halo, C _r4 alkyl, halogenatedCi- ₄ alkyl, halogenatedCi- ₄ alkoxy, and Ci _-4 alkoxy; and Ri ₄ is Ci _-3 alkyl optionally substituted with 1 -3 members independently selected from halo, -OH, halogenatedCi _-3 alkyl, and Ci _-4 alkoxy.

In particular, the present invention is directed to a compound of Formula (II) wherein X is O; Q ₂ is phenyl; q is 0; p is 1 or 2; L ₂ is a covalent bond; Rn is Ci- ₅ alkyl substituted with oxo, hydroxy, or Ci _-3 alkoxy, thienyl optionally substituted with Ci _-3 alkyl or Ci _-3 alkoxy, furanyl, or phenyl optionally substituted with -OCF ₂ CF ₂ H, -CF ₃ , -F, -OCH ₃ , -Cl, Or -OCF ₃ ; each R _i2 is independently selected from -OCF ₃ , -CF ₃ , and -F; and Ri ₄ is Ci _-3 alkyl optionally substituted with 1 -3 members independently selected from halo, -OH, halogenatedCi- ₃ alkyl, and Ci _-4 alkoxy.

In particular, the present invention is directed to a compound of Formula (II) wherein Q ₂ is thienyl or pyridinyl; X is O; q is O; p is O; L ₂ is a covalent bond;

Rn is Ci- ₅ alkyl substituted with oxo, hydroxy, or Ci _-3 alkoxy, thienyl optionally substituted with Ci _-3 alkyl or Ci _-3 alkoxy, furanyl, or phenyl optionally substituted with halogenatedCi- ₄ alkyl, halogenatedCr ₄ alkoxy, Ci _-4 alkoxy, or halo; and Ri ₄ is Ci-3alkyl optionally substituted with 1 -3 members independently selected from halo, -OH, halogenatedCi- ₃ alkyl, and Ci _-4 alkoxy.

In particular, the present invention is directed to a compound of Formula (II) as shown above wherein:

(a) X is O;

(b) X is S;

(c) Rn is Ci _-6 alkyl substituted with hydroxy, oxo, or Ci _-3 alkoxy;

(d) Rn is thienyl optionally substituted with Ci _-3 alkyl or Ci _-3 alkoxy;

(e) Rn is phenyl optionally substituted with 1 or 2 members selected from Re and Rf, wherein R _e and Rf are independently selected from the group consisting of Ci _-4 alkyl, halogenatedCi _-4 alkyl, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, phenylCi _-3 alkoxy, -S-CF ₃ , halo, cyano, and hydroxy, or R _e and R _f together with the carbon atoms they are attached to form 5- or 6-membered heterocyclyl fused to the phenyl ring; preferably Rn is phenyl,

(f) Rn is optionally substituted 5- or 6-membered heteroaryl, preferably,

(g) L ₂ is a covalent bond;

(h) Q ₂ is Cθ-io aryl, and preferably Q ₂ is phenyl;

(i) Q ₂ is 5- or 6-membered heteroaryl; preferably thienyl, oxazolyl, thiazolyl, isoxazolyl, pyridinyl, and pyridazinyl; and more preferably thienyl and pyridinyl;

(j) each Ri2 is independently selected from halo, hydroxy, cyano, Ci _-4 alkoxy, halogenatedCi _-4 alkoxy, Ci _-4 alkyl, halogenatedCi _-4 alkyl, and -C(O)H; preferably -CH ₃ , -CH ₂ CH ₃ , -C(O)H ₁ -O-CH ₃ , -0-CF ₃ , -O-CH(CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , CN, OH, F, Cl, and -CF ₃ ; more preferably-O-CF _3, F, and -CF ₃ ;

(k) p is 1 , 2, or 3;

(I) q is O;

(m) R ₁₄ is -C(O)O-Ci _-4 alkyl, preferably -C(O)O-CH ₃ or -C(O)O-CH ₂ CH ₃ ;

(n) Ri ₄ is Ci _-3 alkyl optionally substituted with 1 -3 members independently selected from halo, oxo, hydroxy, halogenatedCi _-3 alkyl, Ci _-4 alkoxy, tert-butyldimethylsilyloxy, C _3- s cycloalkyl, CN, heterocyclyl, and -NR _g R _h , wherein R ₉ and R _h are independently selected from H, -S(O) ₂ -Ci- ₄ alkyl, Ci _-3 alkyl, -C(O)-Ci _-3 alkyl, and -C(O)O-Ci _-3 alkyl; more preferably R _M is Ci-5 alkyl optionally substituted with 1 -2 members independently selected from oxo, F, -CF ₃ , hydroxy, tert-butyldimethylsilyloxy, -NH ₂ , — N(CH ₃ ) ₂ ,

-0-CH ₃₁ -O-CH ₂ CH _{3 5} ,

°2 ^CH 3; more preferably Ri ₄ is Ci-alkyl substituted with one to three halo, OH and -CF ₃ , more preferably Ri ₄ is -CF ₃ ; and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof; or any possible combinations of examples (a) - (n) above.

More particularly, the present invention is directed to a compound of Formula (II) as shown above wherein q is O; p is 1 , 2, or 3; Rn is -CH ₂ -CH=CH ₂ , -CH ₂ CH ₂ CH ₂ OH, -CH ₂ CH ₂ CH ₂ -O-CH ₃ , or

Ri ₂ is independently selected from — O— CF ₃ , F, or — CF ₃ ; and Ri ₄ is -C(O)O-CH ₃ , -C(O)O-CH ₂ CH ₃ , or Ci _-3 alkyl optionally substituted with 1-3 members independently selected from halo, oxo, F, -CF ₃ , hydroxy, NH ₂ ,

H ₃ COOS _{j anc} | SO ₂ CH ₃ . _anc | enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.

In one aspect of the present invention, the compounds of formula (II) are compounds of Formula (Ma):

wherein:

X is O or S;

L ₂ is a covalent bond or O;

Q.2 is phenyl, naphthalenyl, or a heteroaryl selected from the group consisting of thienyl, oxazolyl, thiazolyl, isoxazolyl, pyridinyl, and pyridazinyl; p is O to 3; q is O to 3;

Rn is C-1-10 alkyl, C2-ioalkenyl, C2-ioalkynyl, C3-iocycloalkyl, or a 5- or 6- membered heteroaryl; wherein said C _MO alkyl, C ₂ -ioalkenyl, C ₂ -ioalkynyl, C ₃ - iocycloalkyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, cyano, hydroxy, oxo, Ci _-3 alkyl, and Ci-3alkoxy; alternatively, Rn is phenyl optionally substituted with 1 to 2 members selected from R _e and Rt; wherein R _e and Rf are independently selected from the group consisting Of Ci _-4 alkyl, halogenatedCi _-4 alkyl, phenylCi _-4 alkyl, Ci _-4 alkoxy, halogenated Ci- 4 alkoxy, phenylCi _-4 alkoxy, Ci _-4 alkylthio, halogenatedCi _-4 alkylthio, halo, cyano, and hydroxy, or R _e and Rf together with the carbon atoms of the phenyl ring to which they are attached form a 5- or 6-membered heterocyclyl fused to the phenyl ring; said heterocyclyl optionally substituted with 1 or 2 members independently selected from halo, Ci _-3 alkyl, cyano, and hydroxy; each Ri2 is independently selected from the group consisting of halo, hydroxy, cyano, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci _-4 alkyl, halogenatedCi _-4 alkyl, and -C(O)H;

each Ri ₃ is independently selected from the group consisting of Ci _-4 alkyl, Ci _-4 alkoxy, halo, cyano, and hydroxy;

Ri ₄ is Ci _-8 alkyl, halogenated Ci _-8 alkyl, or benzyl, wherein said Ci _-8 alkyl, halogenated Ci-salkyl, or benzyl is optionally substituted with 1 -3 members independently selected from the group consisting of oxo, hydroxy, Ci _-4 alkoxy, halogenatedCi _-4 alkoxy, C3-8 cycloalkyl, cyano, tert-butyldimethylsilyloxy, heterocyclyl optionally substituted with 1 or 2 Ci _-3 alkyl groups, and — NR _g R _h ; wherein R ₉ and Rh are independently selected from H, optionally substituted Ci- 3 alkyl, -C(O)Ci _-3 alkyl, -C(O)O-Ci _-3 alkyl, and -SO ₂ Ci _-3 alkyl; and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.

Particularly, the present invention features a compound of Formula (Ma) wherein X is O. Particularly, the present invention features a compound of Formula (Ma) wherein q is O. Particularly, the present invention features a compound of Formula (Ma) wherein p is 1 or 2. Particularly, the present invention features a compound of Formula (Ma) wherein L ₂ is a covalent bond. Particularly, the present invention features a compound of Formula (Ma) wherein Q ₂ is phenyl. Particularly, the present invention features a compound of Formula (Ma) wherein Q ₂ is thienyl or pyridinyl.

Particularly, the present invention features a compound of Formula (Ma) wherein Rn is phenyl substituted with Ci _-4 alkyl, halogenated Ci _-4 alkyl, Ci _-4 alkoxy, halogenatedCi _-4 alkoxy, halo, cyano, or hydroxy. Particularly, the present invention features a compound of Formula (Ma) wherein Rn is phenyl substituted with halogenated Ci _-4 alkyl or halogenatedCi _-4 alkoxy, preferably Rn is phenyl substituted with -OCF ₂ CF ₂ H, -CF ₃ , or -OCF ₃ Particularly, the present invention features a compound of Formula (Ma) wherein Rn is phenyl substituted with Ci _-4 alkyl, halogenated Ci _-4 alkyl, Ci _-4 alkoxy, halogenated Ci- ₄ alkoxy, halo, cyano, hydroxy, halogenated Ci _-4 alkylthio, or an optionally substituted five membered heterocyclyl ring fused to the phenyl ring forming a bicyclic ring system. Particularly, the present invention features a compound of Formula (Ma) wherein Rn is Ci-6 alkyl substituted with hydroxy, Ci _-4 alkoxy, oxo, halo, or cyano. Particularly, the present invention features a compound of

Formula (Ma) wherein Rn is furanyl or thienyl optionally substituted with Ci- ₃ alkyl, Ci _-3 alkoxy, hydroxy, or cyano.

Particularly, the present invention features a compound of Formula (Ma) wherein p is 1 and R12 is halo, halogenated Ci _-4 alkyl, or halogenated Ci- ₄ alkoxy, preferably R12 is -OCF ₂ CF ₂ H or -OCF ₃ . Particularly, the present invention features a compound of Formula (Ma) wherein p is 1 , 2, or 3 and each Ri ₂ is independently selected from halo, halogenated Ci _-4 alkyl, and halogenated Ci _-4 alkoxy; preferably Ri ₂ is -OCF ₂ CF ₂ H, -OCF ₃ Or F. Particularly, the present invention features a compound of Formula (Ma) wherein p is 1 and Ri ₂ is halogenated Ci _-4 alkoxy, preferably R12 is - OCF ₂ CF ₂ H.

Particularly, the present invention features a compound of Formula (Ma) wherein Ri ₄ is Ci _-3 alkyl substituted with 1 to 3 members each independently selected from halo, oxo, hydroxy, Ci _-4 alkoxy, cyano, and heterocyclyl; preferably Ri ₄ is Cialkyl substituted with hydroxy, Ci _-4 alkoxy, or cyano. Particularly, the present invention features a compound of Formula (Ma) wherein Ri ₄ is Ci _-3 alkyl substituted with — NR _g R _h , wherein R ₉ and R _h are independently selected from H, optionally substituted Ci _-3 alkyl, — C(O)Ci _-3 alkyl, -C(O)O-Ci _-3 alkyl, and — SO ₂ Ci _-3 alkyl. Particularly, the present invention features a compound of Formula (Ma) wherein Ri ₄ is halogenatedCi _-2 alkyl optionally substituted with oxo, hydroxy, Ci _-4 alkoxy, or cyano; preferably Ri ₄ is fluohnatedCialkyl optionally substituted with hydroxy. Particularly, the present invention features a compound of Formula (Ma) wherein Ri ₄ is benzyl wherein the phenyl portion of the Ri ₄ group is optionally substituted with hydroxy, Ci- ₄ alkoxy, cyano, or halogenatedCi _-4 alkoxy, preferably Ri ₄ is benzyl wherein the phenyl portion of the Ri ₄ group is optionally substituted with halogenatedCi _-4 alkoxy.

In particular, the present invention is directed to a compound of Formula (Na) wherein X is O; Q ₂ is phenyl; q is O; p is 1 or 2; L ₂ is a covalent bond; Rn is phenyl optionally substituted with Ci _-4 alkyl, halogenatedCi _-4 alkyl, Ci _-4 alkoxy, halogenatedCi _-4 alkoxy, or cyano; each Ri ₂ is independently selected from halo, hydroxy, cyano, Ci _-4 alkoxy, halogenatedCi _-4 alkoxy, Ci _-4 alkyl, halogenatedCi _-4 alkyl, and -C(O)H; and Ri ₄ is Ci _-3 alkyl substituted with 1 to 3

members independently selected from halo, hydroxy, Ci _-4 alkoxy, oxo, halogenatedCi _-4 alkoxy, C _3-8 cycloalkyl, cyano; or R ₁₄ is halogenatedCi-alkyl optionally substituted with hydroxy, Ci _-4 alkoxy, oxo, or cyano.

In particular, the present invention is directed to a compound of Formula (Ma) wherein X is O; q is 0; and L ₂ is a covalent bond. In particular, the present invention is directed to a compound of Formula (Ma) as shown above, wherein

p is 1 ; q is 0; and the Q ₂ — Ri ₂ group is . In particular, the present invention is directed to a compound of Formula (Ma) as shown above, wherein

q is 0; and Rn is . In particular, the present invention is directed to a compound of Formula (Ma) as shown above wherein q is 0, and Ri ₄ is -CF ₃ .

In particular, the present invention is directed to a compound of Formula (Na) wherein X is O; Q ₂ is phenyl; q is 0; p is 1 or 2; L ₂ is a covalent bond; Rn is Ci _-5 alkyl substituted with oxo, hydroxy or Ci-3alkoxy; thienyl optionally substituted with Ci _-3 alkyl or Ci _-3 alkoxy; furanyl; or phenyl optionally substituted with -OCF ₂ CF ₂ H, -CF ₃ , -F, -OCH ₃ , -Cl, Or -OCF ₃ ; each R ₁₂ is independently selected from -OCF ₃ , -CF ₃ , -F; and Ri ₄ is Ci _-4 alkyl optionally substituted with 1 to 2 members independently selected from -OH and -OCH ₃ ; or Ri ₄ is halogenatedCi _-2 alkyl optionally substituted with hydroxy, Ci _-4 alkoxy, oxo, or cyano.

In particular, the present invention is directed to a compound of Formula (Na) wherein X is O; Q ₂ is thienyl or pyridinyl; q is O; p is O; L ₂ is a covalent bond; Rn is phenyl optionally substituted with Ci _-4 alkyl, halogenatedCi _-4 alkyl, Ci _-4 alkoxy, halogenatedCi _-4 alkoxy, halo, or cyano; and R ₁₄ is C _1-3 alkyl substituted with 1 to 3 members independently selected from halo, hydroxy, C _{1- 4} alkoxy, oxo, halogenatedC _1-4 alkoxy, heterocyclyl, C _3- 8cycloalkyl, and cyano; or R ₁₄ is halogenatedC _1-2 alkyl optionally substituted with hydroxy, C _1-4 alkoxy, oxo, or cyano.

In particular, the present invention is directed to a compound of Formula (Na) as shown above wherein:

(a) X is O;

(b) X is S;

(c) Rn is Ci-βalkyl substituted with hydroxy, oxo, or Ci-3alkoxy;

(d) Rn is thienyl optionally substituted with Chalky! or Ci-3alkoxy;

(e) Rn is phenyl optionally substituted with 1 or 2 members selected from Re and Rf, wherein R _e and Rf are independently selected from the group consisting of Ci _-4 alkyl, halogenatedCi _-4 alkyl, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, phenylCi _-3 alkoxy, -S-CF ₃ , halo, cyano, and hydroxy, or R _e and R _f together with the carbon atoms they are attached to form 5- or 6-membered heterocyclyl fused to the phenyl ring; preferably Rn is phenyl,

(f) Rn is optionally substituted 5- or 6-membered heteroaryl, preferably,

(g) L ₂ is a covalent bond;

(h) Q ₂ is phenyl;

(i) Q ₂ is thienyl, oxazolyl, thiazolyl, isoxazolyl, pyridinyl, and pyridazinyl; and more preferably thienyl and pyridinyl;

(j) each Ri ₂ is independently selected from halo, hydroxy, cyano, Ci _-4 alkoxy, halogenatedCi _-4 alkoxy, Ci _-4 alkyl, halogenatedCi _-4 alkyl, and -C(O)H; preferably -CH ₃ , -CH ₂ CH ₃ , -C(O)H ₁ -O-CH ₃ , -0-CF ₃ , -O-CH(CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , CN, OH, F, Cl, and -CF ₃ ; more preferably-O-CF _3, F, and -CF ₃ ;

(k) p is 1 , 2, or 3;

(I) q is 0;

(m) R ₁₄ is -C(O)O-Ci _-4 alkyl, preferably -C(O)O-CH ₃ or -C(O)O-CH ₂ CH ₃ ;

(n) Ri ₄ is Ci _-3 alkyl optionally substituted with 1 or 2 members independently selected from oxo, hydroxy, Ci _-4 alkoxy, C _3- s cycloalkyl, CN, heterocyclyl, and — NR _g R _h , wherein R ₉ and R _h are independently selected from H, -S(O) ₂ -Ci _-4 alkyl, Ci _-3 alkyl, -C(O)-Ci _-3 alkyl, and -C(O)O-Ci _-3 alkyl,

(o) Ri ₄ is Ci _-3 alkyl optionally substituted with 1 or 2 members independently selected from oxo, hydroxy, -NH ₂ , — N(CH ₃ ) ₂ , -Q-CH ₃ ,

H

|\|

^ 0 _t M H ₃ rCnOnOςS^ ^H _{> and} , / ^ ^ Sc _n O ₂ rCμH ₃ .

(p) Ri ₄ is halogenated Ci _-2 alkyl optionally substituted with oxo, hydroxy, Ci _-4 alkoxy, or cyano; preferably Ri ₄ is fluorinatedCialkyl oprionally substituted with hydroxy; more preferably Ri ₄ is -CF ₃ ; and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof; or any possible combinations of examples (a) - (p) above.

More particularly, the present invention is directed to a compound of Formula (Ma) as shown above wherein q is O; p is 1 , 2, or 3; Rn is -CH ₂ -CH=CH ₂ , -CH ₂ CH ₂ CH ₂ OH, -CH ₂ CH ₂ CH ₂ -O-CH ₃ , or

-CH ₂ -C(O)-C(CHs) ₃ , Ph,

Ri2 is independently selected from — O— CF ₃ , F, or — CF ₃ ; and Ri ₄ is -C(O)O-CH ₃ , -C(O)O-CH ₂ CH ₃ , or Ci_ ₃ alkyl optionally substituted with 1-2 members independently selected from oxo, hydroxy, NH ₂ , — N(CH ₃ ) ₂ , -Q-CH ₃ ,

NH .N.

H ₃ COOS^ _and SO ₂ CH ₃ J _0n R ₁₄ j _s _CF ₃ .

In particular, the present invention is further directed to a compound of Formula (Ma) wherein

(a) X is O;

(b) q is O;

(C) p is 1 , 2, or 3;

(d) q and p are both O;

(e) q is O and p is 1 ;

(f) q is O and p is 2;

(g) L ₂ is a bond; (h) L ₂ is O;

(n) R ₁₁ is -CH ₂ CH ₃ , ^u ~^ , or phenyl; (o) R ₁₁ Js -CH ₂ CH ₂ CH ₂ OH;

(r) Q ₂ is phenyl or naphthalenyl; (s) Q ₂ is phenyl;

(t) Q ₂ is a selected from the group consisting of thienyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, and pyridizinyl;

(aa) Ri ₂ is -0-CF ₃ ; (bb) R ₁₂ is -CF ₃ (CC) Ri ₂ is F;

(dd) Ri ₂ is -CH ₃ , -CH ₂ CH _3, or -CH(CH ₃ ) ₂ ; (ee) Ri ₂ is -C(O)H, CN, OH, (ff) Ri ₂ is -O-CH(CH ₃ ) _2j F, Cl, Or -CF ₃ ; (gg) R ₁₂ is -0-CH ₃ , -0-CF ₃ , or -O-CH(CH ₃ ) ₂ ; (hh) Ri ₄ is Ci _-3 alkyl substituted with 1 or 2 members independently selected from oxo, hydroxy, — O— CH ₃ , and — O- CH ₂ CH ₃

(ii) Ri ₄ is Ci _-3 alkyl substituted with substituted heterocyclyl selected from

(jj) Ri ₄ is Ci _-3 alkyl substituted with

(kk) Ri ₄ is halogenatedCi _-2 alkyl optionally substituted with oxo, hydroxy, or -0-CH ₃ ;

(II) R ₁₄ is -CF ₃ ;

(mm) R ₁₄ is -CH ₂ CH _{3 ,} or -CH ₂ CH ₂ CH ₃ ;

(nn) R ₁₄ is -CH ₂ CI or R ₁₄ is -CF ₃ ;

(oo) R ₁₄ is -CH(CH ₃ ) ₂ or R ₁₄ is -CH ₂ OCH ₃ ;

(pp) q is 0, n is 1 , and L ₂ is a bond; (qq) q is 0, n is 2, and L ₂ is a bond; (rr) q is 0, n is 3, and L ₂ is a bond

(ss) q is 0, n is 1 , L ₂ is a bond, and Rn is or

(tt) q is 0, n is 1 , L ₂ is a bond, Q ₂ is phenyl, and Rn is

(uu) q is 0, n is 1 , L ₂ is a bond, Rn is and Q ₂ is

(vv) q is 0, n is 1 , L ₂ is a bond, Rn is , and the

Q ₂ -Ri ₂ group is

(ww) q is 0, p is 1 , 2, or 3, L ₂ is a bond, Q ₂ is phenyl, and Rn is

or _j and each Ri ₂ is independently selected from F, -CF ₃ , and -0-CF ₃ ;

(xx) q is 0, p is 2 or 3, L ₂ is a bond, Q ₂ is each Ri ₂ is independently selected from — O— CF _3, -CF _3, or F;

(yy) q is 0, p is 1 , L ₂ is a bond, Q ₂ is and Ri ₂ is -CH ₃ , -CH ₂ CH ₃ , -CH(CHs) ₂ , -C(O)H, CN, OH, -O-CH(CH ₃ ) ₂ , F, Cl, -CF ₃ , -0-CH ₃ , -0-CF ₃ , or -O-CH(CH ₃ ) ₂ ; or enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof; or any possible combinations (a) - (yy) listed above.

In another aspect of the present invention, the compounds of formula (II) are compounds of Formula (Mb):

wherein:

Rn is Ci-io alkyl, C _2- i ₀ alkenyl, C _2- i ₀ alkynyl, C _3- i ₀ cycloalkyl, or a 5- or 6- membered heteroaryl; wherein said C _M0 alkyl, C _2- i ₀ alkenyl, C _2- i ₀ alkynyl, C _3- locycloalkyl, or 5- or 6-membered heteroaryl is optionally substituted with halo, cyano, or hydroxy, oxo, Ci _-3 alkyl, or Ci _-3 alkoxy; alternatively, Rn is phenyl optionally substituted with 1 to 2 members selected from R _e and Rf, wherein R _e and R _f are independently selected from the group consisting of Ci _-4 alkyl, halogenatedCi _-4 alkyl, phenylCi _-4 alkyl, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, phenylCi _-4 alkoxy, Ci _-4 alkylthio, halogenatedCi _-4 alkylthio, halo, cyano, and hydroxy, or R _e and Rf together with the carbon atoms of the phenyl ring to which they are attached form a 5- or 6-membered heterocyclyl fused to the phenyl ring; said heterocyclyl optionally substituted with 1 or 2 members independently selected from halo, Ci _-3 alkyl, cyano, and hydroxy;

each of Ri _2a , Ri2b, and Ri _2c is independently absent or selected from the group consisting of halo, hydroxy, cyano, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci _-4 alkyl, halogenatedCi _-4 alkyl, and -C(O)H;

Ri3 is absent or selected from the group consisting of Ci _-4 alkyl, Ci _-4 alkoxy, halo, cyano, and hydroxy;

Ri ₄ is Ci-salkyl, halogenated Ci-salkyl, or benzyl, wherein said Ci-salkyl, halogenated Ci _-8 alkyl, or benayl is optionally substituted with 1-3 members independently selected from the group consisting of oxo, hydroxy, Ci _-4 alkoxy, halogenatedCi _-4 alkoxy, C _3- S cycloalkyl, cyano, heterocyclyl, and — NR _g R _h ; wherein R ₉ and Rh are independently selected from H, optionally substituted Ci- ₃ alkyl, -C(O)Ci _-3 alkyl, -C(O)O-Ci _-3 alkyl, and -SO ₂ Ci _-3 alkyl; and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.

Particularly, the present invention features a compound of Formula (Mb) wherein Rn is phenyl substituted with Ci _-4 alkyl, halogenated Ci _-4 alkyl, Ci _-4 alkoxy, halogenatedCi _-4 alkoxy, halo, cyano, or hydroxy. Particularly, the present invention features a compound of Formula (Mb) wherein Rn is phenyl substituted with halogenated Ci _-4 alkyl or halogenatedCi _-4 alkoxy, preferably Rn is phenyl substituted with -OCF ₂ CF ₂ H, -CF ₃ , or -OCF ₃ Particularly, the present invention features a compound of Formula (Mb) wherein Rn is phenyl substituted with Ci _-4 alkyl, halogenated Ci _-4 alkyl, Ci _-4 alkoxy, halogenated Ci- ₄ alkoxy, halo, cyano, hydroxy, halogenated Ci _-4 alkylthio, or an optionally substituted five membered heterocyclyl ring fused to the phenyl ring forming a bicyclic ring system. Particularly, the present invention features a compound of Formula (Mb) wherein Rn is Ci-6 alkyl substituted with hydroxy, Ci _-3 alkoxy, oxo, halo, or cyano. Particularly, the present invention features a compound of Formula (Mb) wherein Rn is furanyl or thienyl optionally substituted with Ci- salkyl, Ci _-3 alkoxy, hydroxy, or cyano.

Particularly, the present invention features a compound of Formula (Mb) wherein Ri _2a and Ri ₂ b are both absent and Ri _2c is selected from halo, halogenated Ci _-4 alkyl, and halogenated Ci _-4 alkoxy, preferably Ri _2c is - OCF ₂ CF ₂ H or -OCF ₃ . Particularly, the present invention features a compound of Formula (Mb) wherein Ri _2a , Ri ₂ b, and Ri _2c are each independently absent or

selected from halo, halogenated Ci _-4 alkyl, and halogenated Ci _-4 alkoxy, preferably Ri _2a , Ri2b, and Ri2 _C are independently absent, -OCF ₂ CF ₂ H, -OCF ₃ Or F.

Particularly, the present invention features a compound of Formula (Mb) wherein Ri ₄ is C _h alky! substituted with 1 or 2 members each independently selected from oxo, hydroxy, Ci _-4 alkoxy, cyano, and heterocyclyl; preferably Ri ₄ is C- ₁ - ₃ alkyl substituted with hydroxy, Ci _-4 alkoxy, or cyano. Particularly, the present invention features a compound of Formula (Mb) wherein Ri ₄ is C _h alky! substituted with — NR _g R _h , wherein R ₉ and R _h are independently selected from H, optionally substituted Ci _-3 alkyl, -C(O)Ci _-3 alkyl, -C(O)O-Ci _-3 alkyl, and — SO ₂ Ci _-3 alkyl. Particularly, the present invention features a compound of Formula (Mb) wherein Ri ₄ is halogenatedCi _-2 alkyl optionally substituted with oxo, hydroxy, Ci _-4 alkoxy, or cyano; preferably Ri ₄ is fluohnatedCialkyl optionally substituted with hydroxy. Particularly, the present invention features a compound of Formula (Mb) wherein R _M is benzyl wherein the phenyl portion of the Ri ₄ group is substituted with hydroxy, Ci _-4 alkoxy, cyano, or halogenatedCi _-4 alkoxy, preferably Ri ₄ is benzyl wherein the phenyl portion of the Ri ₄ group is substituted with halogenatedCi _-4 alkoxy.

In particular, the present invention is directed to a compound of Formula (lib) wherein Rn is phenyl optionally substituted with Ci _-4 alkyl, halogenatedCi. ₄ alkyl, Ci _-4 alkoxy, halogenatedCi _-4 alkoxy, or cyano; each Ri _2a , Ri ₂ b, and Ri _2c is independently absent or selected from halo, hydroxy, cyano, Ci _-4 alkoxy, halogenatedCi _-4 alkoxy, Ci _-4 alkyl, halogenatedCi _-4 alkyl, and -C(O)H; and Ri ₄ is Ci _-3 alkyl substituted with 1 to 2 members independently selected from hydroxy, Ci _-4 alkoxy, oxo, halogenatedCi _-4 alkoxy, C _3-8 cycloalkyl, cyano; or R _M is halogenatedCi _-2 alkyl optionally substituted with hydroxy, Ci _-4 alkoxy, oxo, or cyano.

In particular, the present invention is directed to a compound of Formula (lib) as shown above wherein:

(a) Rn is Ci-βalkyl substituted with hydroxy, oxo, or Ci _-3 alkoxy;

(b) Rn is thienyl optionally substituted with Ci _-3 alkyl or Ci _-3 alkoxy;

(c) Rn is phenyl optionally substituted with 1 or 2 members selected from Re and Rf, wherein R _e and Rf are independently selected from the group

consisting of Ci _-4 alkyl, halogenatedCi _-4 alkyl, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, phenylCi _-3 alkoxy, -S-CF ₃ , halo, cyano, and hydroxy, or R _e and R _f together with the carbon atoms they are attached to form 5- or 6-membered heterocyclyl fused to the phenyl ring;

(d) Rn is phenyl,

(e) Rn is an optionally substituted 5- or 6-membered heteroaryl,

(f) Ri2a, Ri2b, and Ri2c are each independently absent or selected from halo, hydroxy, cyano, Ci _-4 alkoxy, halogenatedCi _-4 alkoxy, Ci _-4 alkyl, halogenatedCi _-4 alkyl, and -C(O)H; preferably absent or selected from -CH ₃ , -CH ₂ CH ₃ , -C(O)H, -0-CH ₃ , -0-CF ₃ , -O-CH(CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , CN, OH, F, Cl, and -CF ₃ ; more preferably absent or selected from — O— CF ₃ , F, and -CF ₃ ;

(g) Ri ₄ is -C(O)O-Ci _-4 alkyl, preferably -C(O)O-CH ₃ or -C(O)O-CH ₂ CH ₃ ;

(h) Ri ₄ is Ci _-3 alkyl optionally substituted with 1 or 2 members independently selected from oxo, hydroxy, Ci _-4 alkoxy, C _3- s cycloalkyl, CN, heterocyclyl, and — NR _g R _h , wherein R ₉ and R _h are independently selected from H, -S(O) ₂ -Ci _-4 alkyl, Ci _-3 alkyl, -C(O)-Ci _-3 alkyl, and -C(O)O-Ci _-3 alkyl,

(i) Ri ₄ is Ci _-3 alkyl optionally substituted with 1 or 2 members independently selected from oxo, hydroxy, -NH ₂ , — N(CH ₃ ) ₂ , -Q-CH ₃ ,

(j) Ri ₄ is halogenated Ci _-2 alkyl optionally substituted with oxo, hydroxy, Ci _-4 alkoxy, or cyano; preferably Ri ₄ is fluorinatedCi _-3 alkyl optionally substituted with hydroxy; more preferably R _M is -CF ₃ ; and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof; or any possible combinations of examples (a) - (j) above.

In another aspect of the present invention, the compounds of formula (II) are compounds of Formula (lie):

wherein: each Ri2a, Ri2b, and Ri2c is independently absent or selected from the group consisting of halo, hydroxy, cyano, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci _-4 alkyl, halogenatedCi _-4 alkyl, and -C(O)H;

Ri ₄ is Ci-salkyl, halogenated Ci-salkyl, or benzyl, wherein said Ci-salkyl, halogenated Ci _-8 alkyl, or benzyl is optionally substituted with 1 -3 members independently selected from the group consisting of halo, oxo, hydroxy, Ci _-4 alkoxy, C _3-8 cycloalkyl, cyano, heterocyclyl, heteroaryl, tert-

butyldimethylsilyloxy, and — NR _g R _h , wherein R ₉ and Rh are independently selected from H, optionally substituted Ci _-3 alkyl, -C(O)Ci _-3 alkyl, -C(O)O-Ci _-3 alkyl, and SO ₂ Ci _-3 alkyl;

Ri5 is selected from the group consisting of Ci _-4 alkyl, halogenatedd- ₄ alkyl, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci _-4 alkylthio, halo, cyano, and hydroxy; and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.

In particular, the present invention is directed to a compound of Formula (lie) wherein Ri _2a is absent, halo, or halogenatedCi _-3 alkyl; preferably Ri _2a is absent, F, or CF _3, more preferably Ri _2a is absent. In particular, the present invention is directed to a compound of Formula (lie) wherein Ri _2b is absent or halo; preferably Ri ₂ b is absent or F; more preferably Ri ₂ b is absent. In particular, the present invention is directed to a compound of Formula (lie) wherein Ri _2c is halo, hydroxy, cyano, Ci _-4 alkoxy, halogenated Ci _-4 alkoxy, Ci _-4 alkyl, or halogenatedCi _-4 alkyl; preferably Ri _2c is halo, halogenatedCi _-4 alkyl or halogenated Ci _-4 alkoxy; more preferably, R _12c is-CF ₃ , -OCF ₃ or F.

In particular, the present invention is directed to a compound of Formula (lie) wherein Ri ₄ is Ci _-3 alkyl substituted with 1 or 2 members each independently selected from oxo, hydroxy, Ci _-4 alkoxy, cyano, and heterocyclyl; preferably Ri ₄ is Cialkyl optionally substituted with hydroxy, Ci _-4 alkoxy, or cyano.

Particularly, the present invention features a compound of Formula (lie) wherein Ri ₄ is Ci _-3 alkyl substituted with — NR _g R _h , wherein R ₉ and R _h are independently selected from H, optionally substituted Ci _-3 alkyl, — C(O)Ci _-3 alkyl, -C(O)O-Ci _-3 alkyl, and — SO ₂ Ci _-3 alkyl. Particularly, the present invention features a compound of Formula (lie) wherein Ri ₄ is halogenatedCi _-2 alkyl optionally substituted with oxo, hydroxy, Ci _-4 alkoxy, or cyano; preferably R ₁₄ is fluohnateddalkyl optionally substituted with hydroxy, more preferably R14 is - C _F 3. Particularly, the present invention features a compound of Formula (lie) wherein R ₁₄ is benzyl wherein the phenyl portion of the R ₁₄ group is substituted with hydroxy, C _1-4 alkoxy, cyano, or halogenatedC _1-4 alkoxy, preferably benzyl wherein the phenyl portion of the R ₁₄ group is substituted with halogenatedC _1-4

alkoxy. In particular, the present invention is directed to a compound of Formula (lie) wherein Ri ₄ is halogenatedCi _-2 alkyl optionally substituted with oxo, hydroxy, Ci _-4 alkoxy, or cyano; preferably R _M is fluohnatedCialkyl optionally substituted with hydroxy; more Ri ₄ is preferably -CF ₃ .

In particular, the present invention is directed to a compound of Formula (lie) wherein Ri ₅ is halogenatedCi _-4 alkyl, halogenated Ci _-4 alkoxy, or halo; preferably Ri ₅ is -CF _3, -OCF ₃ Or-OCF ₂ CF ₂ H, more preferably Ri ₅ is -OCF ₃ Or -OCF ₂ CF ₂ H.

In particular, the present invention is directed to a compound of Formula (II) selected from the group consisting of:

1 ,1 ,1 -Trifluoro-3-[3-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-8-(3- trifluoromethoxy-phenyl)-2,3-dihydro-benzo[1 ,4]oxazin-4-yl]-propan-2-ol;

3-[3,8-Bis-(3-thfluoromethoxy-phenyl)-2,3-dihydro-benzo[1 ,4]oxazin-4- yl]-1 ,1 ,1 -trifluoro-propan-2-ol;

3-[3-(3-Benzyl-phenyl)-8-(3-thfluoromethoxy-phenyl)-2,3-d ihydro- benzo[1 ,4]oxazin-4-yl]-1 ,1 ,1 -thfluoro-propan-2-ol;

3-[3-(2,2-Difluoro-benzo[1 ,3]dioxol-5-yl)-8-(3-thfluoromethoxy-phenyl)- 2,3-dihydro-benzo[1 ,4]oxazin-4-yl]-1 ,1 ,1 -thfluoro-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[8-(3-trifluoromethoxy-phenyl)-3-(3- trifluoromethylsulfanylmethyl-phenyl)-2,3-dihydro-benzo[1 ,4]oxazin-4-yl]- propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[8-(3-trifluoromethoxy-phenyl)-3-(3- trifluoromethylsulfanyl-phenyl)-2,3-dihydro-benzo[1 ,4]oxazin-4-yl]-propan-2-ol;

3-[3-(3-Ethoxy-phenyl)-8-(3-trifluoromethoxy-phenyl)-2,3- dihydro- benzo[1 ,4]oxazin-4-yl]-1 ,1 ,1 -thfluoro-propan-2-ol;

(2S)- 3-[(3S)-2,3-dihydro-3-[3-(1 ,1 ,2,2-tetrafluoroethoxy)phenyl]-8-[3- (thfluoromethoxy)phenyl]-4H-1 ,4-benzoxazin-4-yl]- 1 ,2-Propanediol;

(2S)-3-[(3R)-2,3-dihydro-3-[3-(1 ,1 ,2,2-tetrafluoroethoxy)phenyl]-8-[3- (thfluoromethoxy)phenyl]-4H-1 ,4-benzoxazin-4-yl]-1 ,2-Propanediol;

2-Methyl-1 -[3-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-8-(3- trifluoromethoxy-phenyl)-2,3-dihydro-benzo[1 ,4]oxazin-4-yl]-propan-2-ol;

3-[3-Allyl-8-(3-trifluoromethoxy-phenyl)-2,3-dihydro-benz o[1 ,4]oxazin-4- yl]-1 ,1 ,1 -trifluoro-propan-2-ol;

3-[4-(3,3,3-Trifluoro-2-hydroxy-propyl)-8-(3-trifluoromet hoxy-phenyl)-3,4- dihydro-2H-benzo[1 ,4]oxazin-3-yl]-propan-1 -ol;

1 ,1 ,1 -Trifluoro-3-[3-(3-methoxy-propyl)-8-(3-trifluoronnethoxy-ph enyl)- 2,3-dihydro-benzo[1 ,4]oxazin-4-yl]-]propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[3-(3-methoxy-propyl)-8-(3-trifluoronnethoxy-ph enyl)- 2,3-dihydro-benzo[1 ,4]oxazin-4-yl]-propan-2-ol;

3-[3-(5-Ethyl-thiophen-2-yl)-8-(3-trifluoromethoxy-phenyl )-2,3-dihydro- benzo[1 ,4]oxazin-4-yl]-1 ,1 ,1 -trifluoro-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[3-(3-methoxy-thiophen-2-yl)-8-(3-trifluoronnet hoxy- phenyl)-2,3-dihydro-benzo[1 ,4]oxazin-4-yl]-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[3-(5-methoxy-thiophen-2-yl)-8-(3-trifluoronnet hoxy- phenyl)-2,3-dihydro-benzo[1 ,4]oxazin-4-yl]-propan-2-ol;

S-l ^β -tS.S-Difluoro-phenylVa-p-ti .i ^^-tetrafluoro-ethoxy^phenyl]^^- dihydro-benzo[1 ,4]oxazin-4-yl}-1 ,1 ,1 -trifluoro-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-{8-(3-fluoro-phenyl)-3-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)- phenyl]-2,3-dihydro-benzo[1 ,4]oxazin-4-yl}-propan-2-ol;

1 -Fluoro-3-[3-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-8-(3- trifluoromethoxy-phenyl)-2,3-dihydro-benzo[1 ,4]oxazin-4-yl]-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[8-(3-trifluoromethoxy-phenyl)-3-(3-trifluorome thyl- phenyl)-2,3-dihydro-benzo[1 ,4]oxazin-4-yl]-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[3-(3-methyl-thiophen-2-yl)-8-(3-trifluorometho xy- phenyl)-2,3-dihydro-benzo[1 ,4]oxazin-4-yl]-propan-2-ol;

3-[3-(3-Ethyl-thiophen-2-yl)-8-(3-trifluoromethoxy-phenyl )-2,3-dihydro- benzo[1 ,4]oxazin-4-yl]-1 ,1 ,1 -trifluoro-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[3-furan-2-yl-8-(3-thfluoromethoxy-phenyl)-2,3- dihydro- benzo[1 ,4]oxazin-4-yl]-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[3-[2-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-8-(3- trifluoromethoxy-phenyl)-2,3-dihydro-benzo[1 ,4]oxazin-4-yl]-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[3-phenyl-8-(3-trifluoromethoxy-phenyl)-2,3-dih ydro- benzo[1 ,4]oxazin-4-yl]-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[3-(4-thfluoromethoxy-phenyl)-8-(3-trifluoromet hoxy- phenyl)-2,3-dihydro-benzo[1 ,4]oxazin-4-yl]-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[3-(3-methoxy-phenyl)-8-(3-trifluoromethoxy-phe nyl)- 2,3-dihydro-benzo[1 ,4]oxazin-4-yl]-propan-2-ol;

3-[3-(3-Chloro-phenyl)-8-(3-trifluoromethoxy-phenyl)-2,3- dihydro- benzo[1 ,4]oxazin-4-yl]-1 ,1 ,1 -trifluoro-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[3-thiophen-2-yl-8-(3-trifluoromethoxy-phenyl)- 2,3- dihydro-benzo[1 ,4]oxazin-4-yl]-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[3-furan-3-yl-8-(3-trifluoronnethoxy-phenyl)-2, 3-dihydro- benzo[1 ,4]oxazin-4-yl]-propan-2-ol;

1 ,1 ,1 -Trifluoro-3-[3-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-8-(3- trifluoronnethoxy-phenyl)-2,3-dihydro-benzo[1 ,4]thiazin-4-yl]-propan-2-ol; and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.

More particularly, the present invention is directed to a compound of Formula (II) selected from the group consisting of

and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.

In particular, the present invention is directed to a compound of Formula (II) selected from the group consisting of

enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.

The term "substituted" refers to a radical in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).

With reference to substituents, the term "independently" means that when more than one of such substituent is possible, such substituents may be the same or different from each other.

The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine. Substituents that are substituted with multiple halogens are substituted in a manner that provides compounds, which are stable.

"C _a- b" (where a and b are integers) refers to a radical containing from a to b carbon atoms inclusive. For example, Ci-3 denotes a radical containing 1 , 2 or 3 carbon atoms.

"Alkyl" whether used alone or as part of a substituent group refers to straight and branched carbon chains having 1 to 10 carbon atoms or any number within this range. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, and butyl. In preferred embodiments, the alkyl group is C-1-8 alkyl, with Chalky! being particularly preferred. The term "alkoxy" refers to an -Oalkyl substituent group, wherein alkyl is defined supra. Similarly, the terms "alkenyl" and "alkynyl" refer to straight and branched carbon chains having 2 to 10 carbon atoms or any number within this range, wherein an alkenyl chain has at least one double bond in the chain and an alkynyl chain has at least one triple bond in the chain.

The term "cycloalkyl" refers to saturated or partially unsaturated, monocyclic or polycyclic hydrocarbon rings of from 3 to 20 carbon atom members (preferably from 3 to 14 carbon atom members). Examples of such rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or adamantyl.

In certain embodiments, wherein the alkyl, alkenyl, alkynyl, alkoxy, and/or cycloalkyl as defined herein can be optionally substituted, such alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl can be substituted with one, two or three groups independently selected from halo (F, Cl, Br, or I), oxo, cyano, amino, alkoxy, cycloalkyl, carboxy, hydroxy, heterocyclyl, and halogenatedalkyl; and/or one group selected from optionally substituted aryl and optionally substituted heteroaryl.

"Halogenated alkyl" refers to a saturated branched or straight chain alkyl radical derived by removal of at least 1 hydrogen atom from the parent alkyl and substituting it with a halogen; the parent alkyl chain contains from 1 to 10 carbon atoms with 1 or more hydrogen atoms substituted with halogen atoms up to and including substitution of all hydrogen atoms with halogen. Preferred halogenated alkyl groups are fluorinated alkyls, including thfluoromethyl substituted alkyls and perfluorinated alkyls; more preferred fluorinated alkyls include trifluoromethyl, perfluoroethyl, 1 ,1 ,2,2-tetrafluoroethyl,

2,2,2-trifluoroethyl, perfluoropropyl, 1 ,1 ,2,2,3,3-Hexafluoro-propyl, 3,3,3- trifluoroprop-1-yl, 3,3,3-trifluoroprop-2-yl; a particularly preferred fluorinated alkyls are trifluoromethyl and 1 ,1 ,2,2-tetrafluoroethyl.

IHalogenated alkoxy" refers to a radical derived from a halogenated alkyl radical attached to an oxygen atom having one open valence for attachment to a parent structure. Preferred halogenated alkoxy groups are fluorinated alkoxy groups, including trifluoromethoxy and 1 ,1 ,2,2-tetrafluoro- ethoxy.

"Alkylthio" refers to an alkyl group as defined herein attached through one or more sulfur (S) atoms. For example, an alkylthio group can include — S— Ci _-6 alkyl optionally substituted with, for example, one, two, or three groups selected from, halo (F, Cl, Br, or I), amino, alkoxy, carboxy, and hydroxy.

"Oxo" whether used alone or as part of a substituent group refers to an O= to either a carbon or a sulfur atom. For example, phthalimide and saccharin are examples of compounds with oxo substituents.

The term "aryl" refers to an unsaturated monocyclic or polycyclic ring, preferably an aromatic monocyclic ring of 6 carbon members or to an unsaturated, aromatic polycyclic ring of from 10 to 14 carbon members. Preferred aryl groups for the practice of this invention are phenyl and naphthalenyl. In certain embodiments, the aryl ring is a C _6- ioaryl. "Ph" when used herein refers to phenyl. In certain embodiments, wherein the aryl is optionally substituted, the aryl can be substituted with one, two or three groups independently selected from optionally substituted alkyl, halogenated alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, -CHO, cyano, amino, optionally substituted alkoxy, halogenated alkoxy, carboxy, hydroxy, and optionally substituted heterocyclyl.

The term "arylalkyl" means an alkyl group substituted with an aryl group (e.g., benzyl, phenylethyl, naphthylmethyl). Similarly, the term "arylalkoxy" indicates an alkoxy group substituted with an aryl group (e.g., benzyloxy). In particularly preferred embodiments, the alkyl moiety of the arylalkyl group is (Ci-3) and the aryl moiety is (Cβ-io)-

"Heterocyclyl" or "heterocycle" is a 3- to 8-member, preferably 5-7 membered saturated, or partially saturated single or fused ring system which

consists of carbon atoms and from 1 to 6 heteroatoms selected from N, O and S. The heterocyclyl group may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Example of heterocyclyl groups include, but are not limited to, 2-imidazoline, imidazolidine; morpholine, oxazoline, 1 ,3-dioxolane, 2-pyrroline, 3-pyrroline, pyrrolidine, pyridone, pyhmidone, piperazine, piperidine, indoline, tetrahydrofuran, 2-pyrroline, 3- pyrroline, 2-imidazoline, 2-pyrazoline, indolinone. A "heterocyclyl" can be a partially unsaturated ring such as 2-pyrroline, 3-pyrroline, 2-imidazoline, 2- pyrazoline, or indolinone. In certain embodiments, wherein the "heterocyclyl" or "heterocycle" is optionally substituted, the "heterocyclyl" or "heterocycle" can be substituted with, one, two or three groups independently selected from Ci-βalkyl, halogenatedd-βalkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, halo, hydroxy, -CN, and/or one group selected from aryl, heteroaryl, heterocyclyl, -SO ₃ H, - C(O)OH, -C(O)O-Ci - ₄ alkyl, C(O)NR ¹ R", -OR', -SR', -C(O)R', -N(R')(R"), - S(O) ₂ -R', and -S(O) ₂ -N(R')(R"), wherein R' and R" are independently selected from H, Ci- ₆ -alkyl, aryl, and heteroaryl.

"Heteroaryl" refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Preferably, the term "heteroaryl" refers to an aromatic ring of 5 or 6 members wherein the ring consists of carbon atoms and has at least one heteroatom member. Suitable heteroatoms include nitrogen, oxygen or sulfur. In the case of 5 membered rings, the heteroaryl ring contains one member of nitrogen, oxygen or sulfur and, in addition, may contain up to three additional nitrogens. In the case of 6 membered rings, the heteroaryl ring may contain from one to three nitrogen atoms. For the case wherein the 6 membered ring has three nitrogens, at most two nitrogen atoms are adjacent. The term heteroaryl includes a heteroaryl ring fused to a benzene ring (benzo fused heteroaryl), a 5 or 6 membered heteroaryl ring (containing one of O, S or N and, optionally, one additional nitrogen), a 5 to 7 membered cycloalkyl ring or a 5 to 7 membered heterocyclic ring. For such compounds in which the heteroaryl ring is fused to a moiety as described above, the point of attachment is through the heteroaryl ring portion of the compound.

Examples of heteroaryl groups include, and are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, tetrazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridinyl, pyridazinyl, pyhmidinyl or pyrazinyl; fused heteroaryl groups include indolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolizinyl, quinoxalinyl, quinolinyl, isoquinolinyl or quinazolinyl. Preferred are thienyl, oxazolyl, thiazolyl, isoxazolyl, pyridinyl, and pyridazinyl. In certain embodiments, wherein the heteroaryl is optionally substituted, the heteroaryl can be optionally substituted with one, two or three groups independently selected from alkyl, halogenatedalkyl, alkenyl, alkynyl, halo, -CHO, cyano, amino, optionally substituted alkoxy, halogenatedalkoxy, carboxy, hydroxy, and heterocyclyl.

Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g., arylalkyl, alkylamino) it shall be interpreted as including those limitations given above for "alkyl" and "aryl." Designated numbers of carbon atoms (e.g., CrCβ) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root. For alkyl, and alkoxy substituents the designated number of carbon atoms includes all of the independent member included in the range specified individually and all the combination of ranges within in the range specified. For example d-β alkyl would include methyl, ethyl, propyl, butyl, pentyl and hexyl individually as well as sub-combinations thereof (e.g. Ci _-2 , Ci _-3 , Ci _-4 , Ci _-5 , C _2- 6, C _3- 6, C _4-6 , C _5- 6, C _2-5 , etc.).

Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a "phenylCr C ₆ alkylaminocarbonylCi-C ₆ alkyl" substituent refers to a group of the formula

Abbreviations used in the specification, particularly the Schemes and Examples, are as follows: CETP Cholesteryl Ester Transfer Protein DCE Dichloroethane DCM Dichloromethane

DIPEA or DIEA = Diisopropylethylamine DMF N,N-Dimethylformamide EtOAc Ethyl Acetate HFIPA Hexafluoroisopropyl alcohol HPLC High Pressure Liquid Chromatography

2-Me-THF or 2-methyl-tetrahydrofuran 2-methyl-THF MTBE Methyl f-Butyl Ether Pd/C Palladium on Carbon Catalyst

Pd ₂ (OAc) ₂ Palladium(ll)acetate Pd(PPhIs) ₄ Tetrakistriphenylphosphine palladium (O) Pd(PPhIs) ₂ CI ₂ Bis(thphenylphosphine)palladium (II) chloride Pt/C Platinum on Carbon Catalyst RT or rt Room temperature TBAF Tetra-n-butyl ammonium fluoride thhydrate TEA Thethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran

As used herein, unless otherwise noted, the term "isolated form" shall mean that the compound is present in a form which is separate from any solid mixture with another compound(s), solvent system or biological environment.

Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Preferably, wherein the compound is present as an enantiomer, the enantiomer is present

at an enantiomeric excess of greater than or equal to about 75%, more the enantiomer is present at an enantiomeric excess of greater than or equal to about 85%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%. Similarly, wherein the compound is present as a diastereomer, the diastereomer is present at an diastereomeric excess of greater than or equal to about 75%, more preferably, the diastereomer is present at an diastereomeric excess of greater than or equal to about 85%, more preferably, at an diastereomeric excess of greater than or equal to about 90%, more preferably still, at an diastereomeric excess of greater than or equal to about 95%, more preferably still, at an diastereomeric excess of greater than or equal to about 98%, most preferably, at an diastereomeric excess of greater than or equal to about 99%.

Furthermore, some of the crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

The term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

The term "subject" as used herein, refers to an animal, preferably a mammal, most preferably a human, who is the object of treatment, observation or experiment.

The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician,

which includes alleviation of the symptoms of the disease or disorder being treated.

One skilled in the art will recognize that, where not otherwise specified, the reaction step(s) is performed under suitable conditions, according to known methods, to provide the desired product.

One skilled in the art will recognize that, in the specification and claims as presented herein, wherein a reagent or reagent class/type (e.g. base, solvent, etc.) is recited in more than one step of a process, the individual reagents are independently selected for each reaction step and may be the same of different from each other. For example wherein two steps of a process recite an organic or inorganic base as a reagent, the organic or inorganic base selected for the first step may be the same or different than the organic or inorganic base of the second step.

To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about". It is understood that whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value.

To provide a more concise description, some of the quantitative expressions herein are recited as a range from about amount X to about amount Y. It is understood that wherein a range is recited, the range is not limited to the recited upper and lower bounds, but rather includes the full range from about amount X through about amount Y, or any range therein.

One skilled in the art will recognize that wherein a reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.

Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography.

The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomehc pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts." Other salts may, however, be useful in the preparation of compounds according to this invention or of their

pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochlohde, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

Representative acids and bases which may be used in the preparation of pharmaceutically acceptable salts include the following: acids including acetic acid, 2,2-dichloroactic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1 S)- camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuhc acid, ethane-1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydrocy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hipuric acid,

hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1 ,5- disulfonic acid, 1 -hydroxy-2-naphthoic acid, nicotine acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmithc acid, pamoic acid, phosphoric acid, L- pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartahc acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and bases including ammonia, L- arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1 H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

The present invention is directed to processes for the preparation of compounds of formula (I), as described in more detail in Scheme 1 , below.

(VIM)

(Xl) (XII)

Scheme 1

Accordingly, a suitably substituted compound of formula (V), wherein LG ¹ is a suitably selected leaving group such as Br, Cl, I, and the like, preferably Br; a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (Vl), a known compound or compound prepared by known methods; wherein the compound

of formula (Vl) is preferably present in an amount in the range of form about 1.0 to about 5.0 molar equivalents (relative to the moles of the compound of formula (V)), more preferably, in an amount in the range of form about 1.0 to about 2.0 molar equivalents, more preferably in an amount of about 1.0 equivalent; in the presence of an organic or inorganic base such as choline hydroxide, TBAF, Cs ₂ CO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , NaOH, KOH, NaH, preferably in the presence of an inorganic base such as Cs ₂ CO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , NaOH, KOH, NaH, and the like, more preferably Cs ₂ CO ₃ ; wherein the base is preferably present in an amount in the range of from about 1 to about 5.0 molar equivalents (relative to the moles of the compound of formula (V)), preferably about 2.0 molar equivalents; in an organic solvent such as 2-methyl-THF, THF, toluene, acetonitrile, ethanol, methanol, and the like, preferably, 2-methyl-tetrahydrofuran; (one skilled in the art will recognize that wherein the base is NaH, the solvent is preferably not an aqueous solvent);at a temperature in the range of from about room temperature to about solvent reflux temperature, preferably at about room temperature; to yield the corresponding compound of formula (VII).

Alternatively, a compound of formula (V), wherein LG ¹ is a suitably selected leaving group such as Br, Cl, I, and the like, preferably Br, a known compound or compound prepared by known methods is reacted with a compound of formula (Vl) a known compound or compound prepared by known methods; wherein the compound of formula (Vl) is preferably present in an amount in the range of form about 1.0 to about 5.0 molar equivalents (relative to the moles of the compound of formula (V)), more preferably, in an amount in the range of from about 1.0 to about 2.0 molar equivalents, more preferably in an amount of about 1.0 molar equivalent; in the presence of an acid such as toluenesulfonic acid, HCI, acetic acid, and the like, wherein the acid is preferably present in an amount in the range of from about a catalytic amount to about 1 molar equivalent (relative to the moles of the compound of formula (V));

in an organic solvent such as 2-methyl-THF, THF, toluene, acetonitrile, ethanol, methanol, and the like, preferably, 2-methyl-tetrahydrofuran; (one skilled in the art will recognize that wherein the base is NaH, the solvent is preferably not an aqueous solvent); at a temperature in the range of from about room temperature to about solvent reflux temperature, preferably at about room temperature; to yield the corresponding compound of formula (VII).

Preferably, the compound of formula (VII) is not isolated. Optionally, the compound of formula (VII) is isolated and / or purified according to known methods for example by solvent evaporation, crystallization, column chromatography, re-crystallization, and the like.

The compound of formula (VII), is reacted with a suitably selected reducing agent such as SnCI ₂ , SnCI ₂ dihydrate, iron filings, and the like, preferably SnCb, wherein the reducing agent is preferably present in an amount in the range of from about 2.0 to about 8.0 molar equivalents (relative to the moles of the compound of formula (VII)), more preferably, in an amount in the range of from about 3.0 to about 5.0 molar equivalents, more preferably, in an amount of about 4.0 equivalents; in the presence of an acid such as HCI, H ₂ SO ₄ , and the like, preferably 4N HCI, wherein the acid is preferably present in an amount in the range of from about 1.0 to about 4.0 molar equivalents; in an organic solvent such as 2-methyl-THF, THF, toluene, acetonitrile, ethanol, methanol, and the like, preferably, 2-methyl-tetrahydrofuran; preferably in the same solvent as used in the previous step; at a temperature in the range of from about room temperature to about solvent reflux temperature, preferably at about 78 ⁰ C; to yield the corresponding compound of formula (VIII).

One skilled in the art will recognize that wherein a suitably substituted compound of formula (VII) is reacted to yield the corresponding compound of formula (VIII), a compound of formula (T1 )

may be prepared as a transient intermediate, which intermediate is preferably not isolated.

The compound of formula (VIII) is reacted with a suitably substituted compound of formula (IX), a known compound or compound prepared by known methods; wherein the compound of formula (IX) is preferably present in an amount in the range of from about 1 .0 to about 2.0 molar equivalents (relative to the moles of the compound of formula (VIII)), more preferably, in an amount of about 1 .0 molar equivalent; in the presence of a suitably selected catalyst such as a palladium catalyst, such as Pd(PPh ₃ ) ₄ , Pd ₂ (OAc) ₂ , and the like, preferably Pd(PPh ₃ ) ₄ , wherein the catalyst is preferably present in an amount greater than or equal to about a catalytic amount, more preferably, about 0.5 mol%; in the presence of an organic or inorganic base such as Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ , TEA, DIPEA, pyridine, and the like, preferably 2N Na ₂ CO ₃ , more preferably, an aqueous 2N Na ₂ CO ₃ solution; wherein the base is preferably present in an amount in the range of from about 1 .0 to about 5.0 molar equivalents (relative to the moles of the compound of formula (VIII)), more preferably, in an amount of about 2.0 molar equivalents; in an organic solvent such as toluene, THF, 2-methyl-THF, acetonitrile, and the like, preferably toluene; at a temperature in the range of from about room temperature to about solvent reflux temperature, preferably at about 8O ⁰ C, to yield the corresponding compound of formula (X).

The compound of formula (X) is optionally reacted with a suitably selected acid such as tosic (toluenesulfonic) acid, HCI, camphorsulfonic acid, and the like, preferably tosic (toluenesulfonic) acid; optionally in an organic solvent such as toluene, THF, 2-methyl-THF, and the like, preferably toluene; to yield the corresponding acid addition salt of the compound of formula (X).

Preferably, the acid is selected to yield a corresponding salt, which may be readily crystallized, precipitated, purified and / or isolated according to known methods.

The compound of formula (X) is converted to the corresponding compound of formula (XII), and isolated in an enantiomeric excess of one of its corresponding enantiomers, preferably its corresponding (R)-enantiomer, according to either Method A or Method B which are described in more detail below.

Method A: The compound of formula (X), as either its corresponding free base or corresponding acid addition salt, is reacted with a suitably selected source of hydride, such as diludine, a suitably substituted diludine derivative or a diludine-like hydride source(also known as 2,6-dimethyl-1 ,4-dihydro-pyhdine- 3,5-dicarboxylic acid diethyl ester) preferably diludine; wherein the diludine is preferably present in an amount in the range of from about 2.0 to about 5.0 molar equivalents (relative to the moles of the compound of formula (X)), more preferably, in an amount in the range of from about 2.5 to about 3.0 molar equivalents; more, preferably about 3.0 molar equivalents; in the presence of a suitably selected chiral acid catalyst of the formula (C-R)

wherein Z ¹ is selected from the group consisting of hydrogen, bromo, and the like, preferably hydrogen or bromo; or with a suitably selected chiral catalyst of the formula (C-S)

wherein Z ² is selected from the group consisting of 9-phenanthryl, 3,5- di(trifluoromethyl)phenyl, phenyl, 1-naphthyl, triphenylsilyl, and the like; wherein the compound of formula (C-R) or (C-S) is present in an amount in the range of from about 0.5% mol to about 100% mol, preferably, the compound of formula (C-R) or (C-S) is present in an amount in the range of from about 3 mol% to about 100 mol %, preferably, at about 3 mol % about 6 mol%; in an organic solvent such as ethyl acetate, toluene, acetonitrile, ethanol, heptane, 2-methyl-THF, DCE, chlorophenyl, and the like, preferably ethyl acetate; at a temperature in the range of from about room temperature to about 8O ⁰ C, preferably at about 56 ⁰ C, to yield the corresponding compound of formula (XII), wherein the compound of formula (XII) is the compound of formula (Xl) wherein the (R)-enantiomer is present in an enantiomeric excess of greater than 0%. Preferably, the compound of formula (XII) is prepared with an enantiomeric enrichment of greater than or equal to about 50%ee, more preferably greater than or equal to about 75%ee, more preferably greater than or equal to about 85%ee, more preferably greater than or equal to about 90%ee, more preferably greater than or equal to about 95%ee, more preferably greater than or equal to about 98%ee, more preferably greater than or equal to about 99%ee.

Alternatively, the compound of formula (X), as either its corresponding free base or corresponding acid addition salt, is reacted with a suitably selected source of hydride such as diludine, a suitably substituted diludine derivative or a diludine-like hydride source (also known as 2,6-dimethyl-1 ,4-dihydro-pyhdine- 3,5-dicarboxylic acid diethyl ester) preferably diludine; wherein the diludine is preferably present in an amount in the range of from about 2.0 to about 4.0 molar equivalents (relative to the moles of the compound of formula (X)),

preferably, in an amount in the range of from about 2.5 to about 3.0 molar equivalents, more preferably about 3.0 molar equivalents; in the presence of a chiral acid L-tartaric acid, (1 S)-(+)-10- camphorsulfonic acid, and the like; wherein the chiral acid is preferably present in an enantiomeric excess of greater than or equal to about 75%ee, more preferably in an enantiomeric excess of greater than or equal to about 80%ee, more preferably in an enantiomeric excess of greater than or equal to about 90%ee, more preferably in an enantiomeric excess of greater than or equal to about 95%ee, more preferably in an enantiomeric excess of greater than or equal to about 98%ee, more preferably in an enantiomeric excess of greater than or equal to about 99%ee; and wherein the acid is preferably present in an amount in the range of from about a catalytic amount to about 1 molar equivalent, more preferably about a catalytic amount; in an organic solvent such as ethyl acetate, benzene, DCM, acetonithle, 2-methyl-THF, and the like, preferably ethyl acetate; at a temperature in the range of from about room temperature to about solvent reflux temperature, preferably at about 58 ⁰ C, to yield the corresponding compound of formula (XII), wherein the compound of formula (XII) is present in an enantiomeric excess of greater than 0%ee. Preferably, the compound of formula (XII) is prepared with an enantiomeric enrichment of greater than or equal to about 75%ee, more preferably greater than or equal to about 85%ee, more preferably greater than or equal to about 90%ee, more preferably greater than or equal to about 95%ee, more preferably greater than or equal to about 98%ee, more preferably greater than or equal to about 99%ee.

Method B: The compound of formula (X), as either its corresponding free base or corresponding acid addition salt, is reacted with a suitably selected source of hydride such as diludine, a suitably substituted diludine derivative or a diludine-like hydride source (also known as 2,6-dimethyl-1 ,4-dihydro-pyhdine- 3,5-dicarboxylic acid diethyl ester) preferably diludine; wherein the diludine is preferably present in an amount in the range of from about 2.0 to about 5.0 molar equivalents (relative to the moles of the compound of formula (X)), more

preferably, in an amount in the range of from about 2.0 to about 3.0 molar equivalents, more preferably, in an amount of about 2.5 molar equivalents; in the presence of an acid such as HCI, tartaric acid, toluenesulfonic acid, camphorsulfonic acid (including (1 S)-(+)-10-camphorsulfonic acid and (1 R)-(+)-10-camphorsulfonic acid), and the like; wherein the acid is preferably present in an amount in the range of from about a catalytic amount to about 1 molar equivalent, more preferably about a catalytic amount; in an organic solvent such as ethyl acetate, benzene, DCM, acetonithle, 2-methyl-THF, and the like, preferably ethyl acetate; at a temperature in the range of from about room temperature to about solvent reflux temperature, preferably at about 48 ⁰ C, to yield the corresponding compound of formula (Xl).

Alternatively, the compound of formula (X), preferably as the corresponding free base, is reacted with H ₂ (g), in the presence of a catalyst such as iridium, Pd/C, Pt, and the like, preferably iridium; wherein the catalyst is present in an amount in the range of from about a catalytic amount to about 10 weight percent; in an organic solvent such as ethanol, methanol, isopropanol, and the like; at a temperature in the range of from about room temperature to about solvent reflux temperature, preferably at about 5O ⁰ C, to yield the corresponding compound of formula (Xl).

The compound of formula (Xl) is separated into its corresponding enantiomers according to known methods, for example by chiral chromatography or classical resolution, to yield the corresponding compound of formula (XII). Preferably the compound of formula (XII) is isolated as the (R)- enantiomer, in an enantiomeric excess of greater than or equal to about 85%ee, more preferably at about 90%ee, more preferably at about 95%ee, more preferably at about 98%ee, more preferably at about 99%ee.

The compound of formula (XII) is reacted with a suitably substituted compound of formula (XIII), wherein the compound of formula (XIII) is preferably enantiomerically enriched with the corresponding (S)-enantiomer or the corresponding (R)-enantiomer; wherein the enantiomerically enriched compound of formula (XIII) is preferably present in an enantiomeric excess of

greater than of equal to about 80%ee, more preferably, in an enantiomeric excess of greater than of equal to about 90%ee, more preferably, in an enantiomeric excess of greater than of equal to about 95%ee, more preferably, in an enantiomeric excess of greater than of equal to about 98%ee, more preferably, in an enantiomeric excess of greater than of equal to about 99%ee; and wherein the compound of formula (XIII) is preferably present in an amount in the range of from about 1.0 to about 10.0 molar equivalents (relative to the moles of the compound of formula (XII)), more preferably, in an amount in the range of from about 2.0 to about 4.0 molar equivalents, more preferably in an amount of about 3.0 equivalents; in an organic solvent which will act as both a solvent and a catalyst as HFIPA, 2,2,2-trifluoroethanol, 1 ,1 ,1 -trifluoroisopropanol, and the like, preferably HFIPA; preferably at a temperature in the range of from about room temperature to about reflux temperature, more preferably at a temperature in the range of from about 3O ⁰ C to about 6O ⁰ C, more preferably still, at a temperature of less than about 48 ⁰ C, more preferably at about room temperature, to yield the corresponding enantiomerically enriched compound of formula (I). Thus, wherein the compound of formula (XII) is reacted with (S) enantiomerically enriched compound of formula (XIII) then the compound of formula (I) is prepared as its corresponding (S) enantiomerically enriched compound. Similarly, wherein the compound of formula (XII) is reacted with (R) enantiomerically enriched compound of formula (XIII) then the compound of formula (I) is prepared as its corresponding (R) enantiomerically enriched compound.

Preferably, the compound of formula (I) is isolated according to known methods, for example by solvent evaporation, precipitation, and the like. The compound of formula (I) may be further optionally purified according to known methods, for example re-crystallization, column chromatography, and the like.

In an embodiment, the present invention is directed to processes for the preparation of a compound of formula (I-S), as described in more detail in Scheme 2, below.

(V-S)

OH Scheme 2

Accordingly, a compound of formula (V-S), wherein LG ¹ is a suitably selected leaving group such as Br, Cl, I, and the like, preferably Br, a known compound or compound prepared by known methods is reacted with a compound of formula (Vl-S), also known as 1-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)- phenyl]-ethanone; wherein the compound of formula (Vl-S) is preferably present in an amount in the range of form about 1.0 to about 5.0 molar equivalents (relative to the moles of the compound of formula (V-S)), more preferably, in an amount in the range of from about 1.0 to about 2.0 molar equivalents, more preferably, in an amount of about 1.0 molar equivalent; in the presence of an organic or inorganic base such as choline hydroxide, TBAF, Cs ₂ CO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , NaOH, KOH, NaH, preferably in the presence of an inorganic base such as Cs ₂ CO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , NaOH, KOH, NaH, and the like, more preferably Cs ₂ CO ₃ ; wherein the base is preferably present in an amount in the range of from about 1.0 to about 5.0 molar equivalents (relative to the moles of the compound of formula (V-S)), preferably about 2.0 equivalents; in an organic solvent such as 2-methyl-THF, THF, toluene, acetonitrile, ethanol, methanol, and the like, preferably, 2-methyl-tetrahydrofuran; (one skilled in the art will recognize that wherein the base is NaH, the solvent is preferably not an aqueous solvent);at a temperature in the range of from about room temperature to about solvent reflux temperature, preferably at about room temperature; to yield the corresponding compound of formula (VII-S).

Alternatively, a compound of formula (V-S), a wherein LG ¹ is a suitably selected leaving group such as Br, Cl, I, and the like, preferably Br, a known compound or compound prepared by known methods is reacted with a compound of formula (Vl-S), also known as 1-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)- phenyl]-ethanone; wherein the compound of formula (Vl-S) is preferably present in an amount in the range of form about 1.0 to about 5.0 molar equivalents (relative to the moles of the compound of formula (V-S)), more preferably, in an amount in the range of from about 1.0 to about 2.0 molar equivalents, more preferably, in an amount of about 1.0 equivalent; in the presence of an acid such as toluenesulfonic acid, HCI, acetic acid, and the like, wherein the acid is preferably present in an amount in the range of from about a catalytic amount to about 1.0 molar equivalent (relative to the moles of the compound of formula (V-S)); in an organic solvent such as 2-methyl-THF, THF, toluene, acetonitrile, ethanol, methanol, and the like, preferably, 2-methyl-tetrahydrofuran; (one skilled in the art will recognize that wherein the base is NaH, the solvent is preferably not an aqueous solvent); at a temperature in the range of from about room temperature to about solvent reflux temperature, preferably at about room temperature; to yield the corresponding compound of formula (VII-S).

Preferably, the compound of formula (VII-S) is not isolated. Optionally, the compound of formula (VII-S) is isolated and / or purified according to known methods for example by solvent evaporation, crystallization, column chromatography, re-crystallization, and the like.

The compound of formula (VII-S), also known as 3-(2-bromo-6-nitro- phenyl)-1-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-propenone is reacted with a suitably selected reducing agent such as SnCI ₂ , SnCI ₂ dihydrate, iron filings, and the like, preferably SnCI ₂ , wherein the reducing agent is preferably present in an amount in the range of from about 2.0 to about 8.0 molar equivalents (relative to the moles of the compound of formula (VII-S)), more preferably, in an amount in the range of from about 3.0 to about 5.0 molar equivalents, more preferably, in an amount of about 4.0 equivalents;

in the presence of an acid such as HCI, H ₂ SO ₄ , and the like, preferably 4N HCI, wherein the acid is preferably present in an amount in the range of from about 1.0 to about 4.0 molar equivalents; in an organic solvent such as 2-methyl-THF, THF, toluene, acetonitrile, ethanol, methanol, and the like, preferably, 2-methyl-tetrahydrofuran; preferably in the same solvent as used in the previous step; at a temperature in the range of from about room temperature to about solvent reflux temperature, preferably at about 78 ⁰ C; to yield the corresponding compound of formula (VIII-S).

One skilled in the art will recognize that wherein a suitably substituted compound of formula (VII-S) is reacted to yield the corresponding compound of formula (VIII-S), a compound of formula (T1 -S)

may be prepared as a transient intermediate, which intermediate is preferably not isolated.

The compound of formula (VIII-S), also known as 5-bromo-2-[3-(1 , 1 ,2,2- tetrafluoro-ethoxy)-phenyl]-quinoline, is reacted with a compound of formula (IX-S), also known as 3-trifluoromethoxyphenyl boronic acid, wherein the compound of formula (IX-S) is preferably present in an amount in the range of from about 1.0 to about 2.0 molar equivalents (relative to the moles of the compound of formula (VIII-S)), more preferably about 1.0 molar equivalent; in the presence of a suitably selected catalyst such as a palladium catalyst, such as Pd(PPh ₃ ) ₄ , Pd ₂ (OAc) ₂ , and the like, preferably Pd(PPh ₃ ) ₄ , wherein the catalyst is preferably present in an amount greater than or equal to about a catalytic amount, more preferably, about 0.5 mol%; in the presence of an organic or inorganic base such as Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ , TEA, DIPEA, pyridine, and the like, preferably 2N Na ₂ CO ₃ , more preferably, an aqueous 2N Na ₂ CO ₃ solution; wherein the base is preferably

present in an amount in the range of from about 1.0 to about 5.0 molar equivalents (relative to the moles of the compound of formula (VIII-S)), more preferably, in an amount of about 2.0 molar equivalents; in an organic solvent such as toluene, THF, 2-methyl-THF, acetonitrile, and the like, preferably toluene; at a temperature in the range of from about room temperature to about solvent reflux temperature, preferably at about 8O ⁰ C, to yield the corresponding compound of formula (X-S).

The compound of formula (X-S) is optionally reacted with a suitably selected acid such as tosic (toluenesulfonic) acid, HCI, camphorsulfonic acid, and the like, preferably tosic (toluenesulfonic) acid; optionally in an organic solvent such as toluene, THF, 2-methyl-THF, and the like, preferably toluene; to yield the corresponding acid addition salt of the compound of formula (X-S). Preferably, the acid is selected to yield a corresponding salt, which may be readily crystallized, precipitated, purified and / or isolated according to known methods.

The compound of formula (X-S) is converted to the corresponding compound of formula (XII-S), and isolated in an enantiomeric excess of the corresponding (R)-enantiomer, according to either Method A or Method B which are described in more detail below.

Method A: Alternatively, the compound of formula (X-S), also known as 2-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-5-(3-thfluoromethoxy-phenyl )- quinoline, as either its corresponding free base or corresponding acid addition salt, is reacted with a suitably selected source of hydride, such as diludine, a suitably substituted diludine derivative or a diludine-like hydride source(also known as 2,6-dimethyl-1 ,4-dihydro-pyhdine-3,5-dicarboxylic acid diethyl ester) preferably diludine; wherein the diludine is preferably present in an amount in the range of from about 2.0 to about 5.0 molar equivalents (relative to the moles of the compound of formula (X-S)), more preferably, in an amount in the range of from about 2.5 to about 3.0 molar equivalents; more preferably, in an amount of about 3.0 molar equivalents; in the presence of a suitably selected chiral acid catalyst of the formula (C-R)

wherein Z ¹ is selected from the group consisting of hydrogen, bromo, and the like, preferably hydrogen or bromo; or with a suitably selected chiral catalyst of the formula (C-S)

wherein Z ² is selected from the group consisting of 9-phenanthryl, 3,5- di(thfluoromethyl)phenyl, phenyl, 1 -naphthyl, triphenylsilyl, and the like; wherein the compound of formula (C-R) or (C-S) is present in an amount in the range of from about 0.5% mol to about 100% mol, preferably, the compound of formula (C-R) or (C-S) is present in an amount in the range of from about 3 mol% to about 100 mol %, preferably, at about 3 mol % about 6 mol%; in an organic solvent such as ethyl acetate, toluene, acetonitrile, ethanol, heptane, 2-methyl-THF, DCE, chlorophenyl, and the like, preferably ethyl acetate; at a temperature in the range of from about room temperature to about 8O ⁰ C, preferably at about 56 ⁰ C, to yield the corresponding compound of formula (XII-S), wherein the compound of formula (XII-S) is the compound of formula (Xl-S) wherein the (R)-enantiomer is present in an enantiomeric excess of greater than 0%. Preferably, the compound of formula (XII-S) is prepared with an enantiomeric enrichment of greater than or equal to about 50%ee, more preferably greater than or equal to about 75%ee, more preferably greater than or equal to about 85%ee, more preferably greater than or equal to about 90%ee, more preferably greater than or equal to about 95%ee, more preferably

greater than or equal to about 98%ee, more preferably greater than or equal to about 99%ee.

Alternatively, the compound of formula (X-S), also known as 2-[3- (1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-5-(3-trifluoromethoxy-pheny l)-quinoline, as either its corresponding free base or corresponding acid addition salt, is reacted with a suitably selected source of hydride such as diludine, a suitably substituted diludine derivative or a diludine-like hydride source (also known as 2,6-dimethyl-1 ,4-dihydro-pyhdine-3,5-dicarboxylic acid diethyl ester) preferably diludine; wherein the diludine is preferably present in an amount in the range of from about 2.0 to about 5.0 molar equivalents (relative to the moles of the compound of formula (X-S)), more preferably, in an amount of about 2.5 molar equivalents; in the presence of a chiral acid L-tartaric acid, (1 S)-(+)-10- camphorsulfonic acid, and the like; wherein the chiral acid is preferably present in an enantiomeric excess of greater than or equal to about 75%ee, more preferably in an enantiomeric excess of greater than or equal to about 80%ee, more preferably in an enantiomeric excess of greater than or equal to about 90%ee, more preferably in an enantiomeric excess of greater than or equal to about 95%ee, more preferably in an enantiomeric excess of greater than or equal to about 98%ee, more preferably in an enantiomeric excess of greater than or equal to about 99%ee; and wherein the acid is preferably present in an amount in the range of from about a catalytic amount to about 1 molar equivalent, more preferably about a catalytic amount; in an organic solvent such as ethyl acetate, benzene, DCM, acetonithle, 2-methyl-THF, and the like, preferably ethyl acetate; at a temperature in the range of from about room temperature to about solvent reflux temperature, preferably at about 58 ⁰ C, to yield the corresponding compound of formula (XII- S), wherein the compound of formula (XII-S) is present in an enantiomeric excess of greater than 0%ee. Preferably, the compound of formula (XII-S) is prepared with an enantiomeric enrichment of greater than or equal to about 75%ee, more preferably greater than or equal to about 85%ee, more preferably greater than or equal to about 90%ee, more preferably greater than or equal to

about 95%ee, more preferably greater than or equal to about 98%ee, more preferably greater than or equal to about 99%ee.

Method B: The compound of formula (X-S), also known as 2-[3-(1 ,1 ,2,2- tetrafluoro-ethoxy)-phenyl]-5-(3-thfluoromethoxy-phenyl)-qui noline, as either its corresponding free base or corresponding acid addition salt, is reacted with a suitably selected source of hydride such as diludine, a suitably substituted diludine derivative or a diludine-like hydride source (also known as 2,6- dimethyl-1 ,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester) preferably diludine; wherein the diludine is preferably present in an amount in the range of from about 2.0 to about 5.0 molar equivalents (relative to the moles of the compound of formula (X-S)), more preferably, in an amount in the range of from about 2.0 to about 3.0 molar equivalents, more preferably, in an amount of about 2.5 molar equivalents; in the presence of an acid such as HCI, tartaric acid, toluenesulfonic acid, camphorsulfonic acid (including (1S)-(+)-10- camphorsulfonic acid and (1 R)-(+)-10-camphorsulfonic acid), and the like; wherein the acid is preferably present in an amount in the range of from about a catalytic amount to about 1 molar equivalent, more preferably about a catalytic amount; in an organic solvent such as ethyl acetate, benzene, DCM, acetonitrile, 2-methyl-THF, and the like, preferably ethyl acetate; at a temperature in the range of from about room temperature to about solvent reflux temperature, preferably at about 48 ⁰ C, to yield the corresponding compound of formula (Xl-S).

Alternatively, the compound of formula (X-S), preferably as the corresponding free base, is reacted with H ₂ (g), in the presence of a catalyst such as iridium, Pd/C, Pt, and the like, preferably iridium; wherein the catalyst is present in an amount in the range of from about a catalytic amount to about 10 weight percent; in an organic solvent such as ethanol, methanol, isopropanol, and the like; at a temperature in the range of from about room temperature to about solvent reflux temperature, preferably at about 5O ⁰ C, to yield the corresponding compound of formula (Xl-S).

The compound of formula (Xl-S) is separated into its corresponding enantiomers according to known methods, for example by chiral chromatography or classical resolution, to yield the corresponding compound of formula (XII-S). Preferably the compound of formula (XII-S) is isolated as the (R)-enantiomer, in an enantiomeric excess of greater than or equal to about 85%ee, more preferably at about 90%ee, more preferably at about 95%ee, more preferably at about 98%ee, more preferably at about 99%ee.

The compound of formula (XII-S), also known as 2-[3-(1 ,1 ,2,2- tetrafluoro-ethoxy)-phenyl]-5-(3-thfluoromethoxy-phenyl)-1 ,2,3,4-tetrahydro- quinoline, is reacted with a compound of formula (XIII-S), wherein the compound of formula (XIII-S) is enantiomerically enriched with the corresponding (S)-enantiomer (also known as 2-(S)-trifluoromethyl-oxirane), wherein the (S)-enantiomer is preferably present in an enantiomeric excess of greater than of equal to about 80%ee, more preferably, in an enantiomeric excess of greater than of equal to about 90%ee, more preferably, in an enantiomeric excess of greater than of equal to about 95%ee, more preferably, in an enantiomeric excess of greater than of equal to about 98%ee, more preferably, in an enantiomeric excess of greater than of equal to about 99%ee; and wherein the compound of formula (XIII-S) is preferably present in an amount in the range of from about 1.0 to about 10.0 molar equivalents (relative to the moles of the compound of formula (XII-S)), more preferably, in an amount in the range of from about 2.0 to about 4.0 molar equivalents, more preferably, in an amount of about 3 equivalents; in an organic solvent which will act as both a solvent and a catalyst as HFIPA, 2,2,2-trifluoroethanol, 1 ,1 ,1 -trifluoroisopropanol, and the like, preferably HFIPA; preferably at a temperature in the range of from about room temperature of less than or equal to about reflux temperature, more preferably at a temperature of less than or equal to about 6O ⁰ C, more preferably still, at a temperature of less than about 48 ⁰ C, more preferably at about room temperature, to yield the corresponding compound of formula (I-S).

Preferably, the compound of formula (I-S) is isolated according to known methods, for example by solvent evaporation, precipitation, and the like. The

compound of formula (I-S) may be further optionally purified according to known methods, for example re-crystallization, column chromatography, and the like.

The present invention is further directed to a process for the preparation of compounds of formula (II) as outlined in more detail in Scheme 3, below.

(XXV)

Scheme 3

Accordingly, a suitably substituted compound of formula (XX), wherein LG ² is a first suitably selected leaving group such as Br, Cl, I, tosylate, mesylate, and the like, preferably bromo, a known compound or compound prepared by known methods, is reacted with a suitably substituted compound

of formula (XXI), wherein LG ³ is a second suitably selected leaving group such as Cl, Br, I, mesylate, tosylate, and the like, preferably Br, a known compound or compound prepared by known methods; wherein the compound of formula (XXI) is preferably present in an amount in the range of from about 0.75 to about 1.5 molar equivalents (relative to the moles of the compound of formula (XX), more preferably in an amount of from about 0.9 to about 1.1 molar equivalents; more preferably in an amount in the range of from about 0.95 to about 0.99 molar equivalents; in the presence of an inorganic base such as K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , and the like, preferably K ₂ CO ₃ ; wherein the inorganic base is present in an amount in the range of from about 1.0 to about 5.0 molar equivalents (relative to the moles of the compound of formula (XX), more preferably, in an amount in the range of from about 1.0 to about 2.0 molar equivalents, more preferably, in an amount of about 1.06 molar equivalents; in an organic solvent such as acetonithle, THF, toluene, MTBE, 2-Me- THF, and the like, preferably acetonitrile; preferably at about room temperature; to yield the corresponding compound of formula (XXII).

One skilled in the art will recognize that in the reaction of a suitably substituted compound of formula (XX) with a suitably substituted compound of formula (XXI), to yield the corresponding compound of formula (XXII), a compound of formula (T2)

may be prepared as a transient intermediate, which intermediate is preferably not isolated.

The compound of formula (XXII) is reacted to yield the corresponding compound of formula (XIII), and isolated in an enantiomeric excess of the one of its corresponding enantiomers, preferably its corresponding (S)-enantiomer,

according to either Method A or Method B, which are described in more detail below.

Method A: The compound of formula (XXII), as either its corresponding free base or corresponding acid addition salt, is reacted with a suitably selected source of hydride, such as diludine, a suitably substituted diludine derivative or a diludine-like hydride source(also known as 2,6-dimethyl-1 ,4-dihydro-pyhdine- 3,5-dicarboxylic acid diethyl ester) preferably diludine; wherein the diludine is preferably present in an amount in the range of from about 1.0 to about 5.0 molar equivalents (relative to the moles of the compound of formula (XXII)), preferably in an amount in the range of from about 1.0 to about 3.0 molar equivalents, or any range therein, more preferably about 1.2 molar equivalents; in the presence of a suitably selected chiral acid catalyst of the formula (C-R)

wherein Z ¹ is selected from the group consisting of hydrogen, bromo, and the like, preferably Z ¹ is hydrogen or bromo; or with a suitably selected chiral catalyst of the formula (C-S)

wherein Z ² is selected from the group consisting of 9-phenanthryl, 3,5- di(thfluoromethyl)phenyl, phenyl, 1-naphthyl, thphenylsilyl, and the like, preferably 9-phenanthryl or triphenylsilyl; wherein the compound of formula (C- S) is present in an amount in the range of from about 0.5% mol to about 100% mol, preferably, the compound of formula (C-S) is present in an amount in the

range of from about 3 mol% to about 100 mol %, preferably, at about 3 mol % about 6 mol%; in an organic solvent such as ethyl acetate, toluene, acetonitrile, ethanol, heptane, 2-methyl-THF, DCE, chlorophenyl, and the like, preferably ethyl acetate; at a temperature in the range of from about room temperature to about 8O ⁰ C, preferably at about room temperature, to yield the corresponding compound of formula (XXIII), wherein the desired enantiomer is present in an enantiomeric excess of greater than about 0%. Preferably, the compound of formula (XXIII) is prepared with an enantiomeric enrichment of greater than or equal to about 50%ee, more preferably greater than or equal to about 75%ee, more preferably greater than or equal to about 85%ee, more preferably greater than or equal to about 90%ee, more preferably greater than or equal to about 95%ee, more preferably greater than or equal to about 98%ee, more preferably greater than or equal to about 99%ee.

Method B: The compound of formula (XXII) is reacted with a compound of formula (L)

a known compound or compound prepared by known methods; wherein the compound of formula (L) is present in an amount in the range of from about 1.0 to about 5.0 molar equivalents (relative to the moles of the compound of formula (XXII)), preferably in an amount in the range of from about 2.0 to about 4.0 molar equivalents, more preferably in an amount of about 2.5 equivalents; in the presence of an acid such as TFA, formic acid, acetic acid, phosphoric acid, and the like, preferably TFA; wherein the acid is present in an amount in the range of from about 0.25 to about 3.0 molar equivalents, more

preferably in an amount in the range of from about 0.5 to about 2.0 molar equivalents, more preferably in an amount of about 1.05 molar equivalents; in an organic solvent such as DCM, DCE, THF, chloroform, and the like, preferably DCM; preferably at a temperature in the range of from about -78 ⁰ C to about 25 ⁰ C, preferably at a temperature in the range of from about -5O ⁰ C to about 25 ⁰ C; to yield the corresponding compound of formula (XXIII), wherein the desired enantiomer is present in an enantiomeric excess of greater than 0%. Preferably, the compound of formula (XXIII) is prepared with an enantiomeric enrichment of greater than or equal to about 50%ee, more preferably greater than or equal to about 75%ee, more preferably greater than or equal to about 85%ee, more preferably greater than or equal to about 90%ee, more preferably greater than or equal to about 95%ee, more preferably greater than or equal to about 98%ee, more preferably greater than or equal to about 99%ee.

The compound of formula (XXIII) is reacted with a suitably selected compound of formula (XXIV), a known compound or compound prepared by known methods, wherein the compound of formula (XXIV) is preferably present in an amount in the range of from about 1.0 to about 3.0 molar equivalents (relative to the moles of the compound of formula (XXIII)), more preferably about 2.0 molar equivalent; in the presence of a suitably selected catalyst such as a palladium catalyst, such as Pd(PPhS) ₂ CI ₂ , Pd(PPh ₃ ) ₄ , Pd ₂ (OAc) ₂ , and the like, preferably Pd(PPh ₃ J ₂ CI ₂ , wherein the catalyst is preferably present in an amount greater than or equal to about a catalytic amount, more preferably, about 0.5 mol%; in the presence of an organic or inorganic base such as aqueous Na ₂ COs, aqueous K ₂ CO3, aqueous NaHCO3, TEA, DIPEA, pyridine, and the like, preferably aqueous Na ₂ CO ₃ ; wherein the base is preferably present in an amount in the range of from about 1.0 to about 5.0 molar equivalents (relative to the moles of the compound of formula (XXIII)), more preferably, in an amount in the range of from about 2.0 to about 4.0 molar equivalents, more preferably, in an amount of about 3.0 molar equivalents;

in an organic solvent or mixture of solvents such as 1 ,4-dioxane, toluene, a mixture of toluene and alcohol (such as a 4:1 mixture of toluene / ethanol, a mixture of toluene/methanol, a mixture of toluene/isopropyl alcohol, and the like) THF, 2-methyl-THF, acetonitrile, 1 ,2-dimethoxyethane, and the like, preferably 1 ,4-dioxane; at a temperature in the range of from about room temperature to about solvent reflux temperature, preferably at about 8O ⁰ C, to yield the corresponding compound of formula (XXV).

The compound of formula (XXV), is reacted with a suitably substituted compound of formula (XXVI), a known compound or compound prepared by known methods, wherein the compound of formula (XXVI) is enantiomerically enriched with the corresponding (S)-enantiomer or the corresponding (R)- enantiomer, wherein the enantiomer is preferably present in an enantiomeric excess of greater than of equal to about 80%ee, more preferably, in an enantiomeric excess of greater than of equal to about 90%ee, more preferably, in an enantiomeric excess of greater than of equal to about 95%ee, more preferably, in an enantiomeric excess of greater than of equal to about 98%ee, more preferably, in an enantiomeric excess of greater than of equal to about 99%ee; and wherein the compound of formula (XXIII) is preferably present in an amount in the range of from about 1.0 to about 10.0 molar equivalents (relative to the moles of the compound of formula (XXIII)), more preferably, in an amount in the range of from about 2.0 to about 4.0 molar equivalents, more preferably, in an amount of about 3.0 molar equivalents; in an organic solvent which will act as both a solvent and a catalyst as HFIPA, 2,2,2-trifluoroethanol, 1 ,1 ,1 -trifluoroisopropanol, and the like, preferably HFIPA; preferably at a temperature of less than or equal to about reflux temperature, more preferably at a temperature of less than or equal to about 6O ⁰ C, more preferably still, at a temperature of less than about 5O ⁰ C, more preferably at about room temperature, to yield the corresponding enantiomerically enriched compound of formula (II). Thus, wherein the compound of formula (XXV) is reacted with (S) enantiomerically enriched compound of formula (XXVI) then the compound of formula (II) is prepared as its corresponding (S) enantiomerically enriched compound. Similarly, wherein the compound of formula (XXV) is reacted with (R) enantiomerically enriched

compound of formula (XXVI) then the compound of formula (II) is prepared as its corresponding (R) enantiomerically enriched compound.

Preferably, the compound of formula (II) is isolated according to known methods, for example by solvent evaporation, precipitation, and the like. The compound of formula (II) may be further optionally purified according to known methods, for example re-crystallization, column chromatography, and the like.

In an embodiment, the present invention is further directed to a process for the preparation of a compound of formula (M-S) as outlined in more detail in Scheme 4 below.

Scheme 4

Accordingly, a suitably substituted compound of formula (XX-S), wherein LG ² is a first suitably selected leaving group such as Br, Cl, I, tosylate, mesylate, and the like, preferably bromo, a known compound or compound

prepared by known methods, is reacted with a suitably substituted compound of formula (XXI-S), wherein LG ³ is a second suitably selected leaving group such as Cl, Br, I, mesylate, tosylate, and the like, preferably Br, a known compound or compound prepared by known methods; wherein the compound of formula (XXI-S) is preferably present in an amount in the range of from about 0.75 to about 1.5 molar equivalents (relative to the moles of the compound of formula (XX-S), more preferably in an amount of from about 0.9 to about 1.1 molar equivalents; more preferably in an amount in the range of from about 0.95 to about 0.99 molar equivalents; in the presence of an inorganic base such as K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , and the like, preferably K ₂ CO ₃ ; wherein the inorganic base is present in an amount in the range of from about 1.0 to about 5.0 molar equivalents (relative to the moles of the compound of formula (XX-S), more preferably, in an amount in the range of from about 1.0 to about 2.0 molar equivalents, more preferably in an amount of about 1.06 molar equivalents; in an organic solvent such as acetonithle, THF, toluene, MTBE, 2-Me- THF, and the like, preferably acetonitrile; preferably at about room temperature; to yield the corresponding compound of formula (XXII-S).

One skilled in the art will recognize that in the reaction of a suitably substituted compound of formula (XX-S) with a suitably substituted compound of formula (XXI-S), to yield the corresponding compound of formula (XXII), a compound of formula (T2-S)

may prepared as a transient intermediate, which intermediate is preferably not isolated.

The compound of formula (XXII-S) is reacted to yield the corresponding compound of formula (XXIII-S), and isolated in an enantiomeric excess of the one of its corresponding enantiomers, preferably its corresponding (S)-

enantiomer, according to either Method A or Method B, which are described in more detail below.

Method A: The compound of formula (XXII-S), as either its corresponding free base or corresponding acid addition salt, is reacted with a suitably selected source of hydride, such as diludine, a suitably substituted diludine derivative or a diludine-like hydride source(also known as 2,6-dimethyl- 1 ,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester) preferably diludine; wherein the diludine is preferably present in an amount in the range of from about 1.0 to about 5.0 molar equivalents (relative to the moles of the compound of formula (XXII-S)), preferably in an amount in the range of from about 1.0 to about 3.0 molar equivalents, or any range therein, more preferably about 1.2 molar equivalents; in the presence of a suitably selected chiral acid catalyst of the formula (C-R)

wherein Z ¹ is selected from the group consisting of hydrogen, bromo, and the like, preferably Z ¹ is hydrogen or bromo; or with a suitably selected chiral catalyst of the formula (C-S)

wherein Z ² is selected from the group consisting of 9-phenanthryl, 3,5- di(thfluoromethyl)phenyl, phenyl, 1-naphthyl, thphenylsilyl, and the like, preferably 9-phenanthryl or triphenylsilyl; wherein the compound of formula (C- S) is present in an amount in the range of from about 0.5% mol to about 100%

mol, preferably, the compound of formula (C-S) is present in an amount in the range of from about 3 mol% to about 100 mol %, preferably, at about 3 mol % about 6 mol%; in an organic solvent such as ethyl acetate, toluene, acetonitrile, ethanol, heptane, 2-methyl-THF, DCE, chlorophenyl, and the like, preferably ethyl acetate; at a temperature in the range of from about room temperature to about 8O ⁰ C, preferably at about room temperature, to yield the corresponding compound of formula (XXIII-S), wherein the (S)-enantiomer is present in an enantiomeric excess of greater than about 0%. Preferably, the compound of formula (XXIII-S) is prepared with an enantiomeric enrichment of greater than or equal to about 50%ee, more preferably greater than or equal to about 75%ee, more preferably greater than or equal to about 85%ee, more preferably greater than or equal to about 90%ee, more preferably greater than or equal to about 95%ee, more preferably greater than or equal to about 98%ee, more preferably greater than or equal to about 99%ee.

Method B: The compound of formula (XXII-S) is reacted with a compound of formula (L)

a known compound or compound prepared by known methods; wherein the compound of formula (L) is present in an amount in the range of from about 1.0 to about 5.0 molar equivalents (relative to the moles of the compound of formula (XXII-S)), preferably in an amount in the range of from about 2.0 to about 4.0 molar equivalents, more preferably in an amount of about 2.5 equivalents;

in the presence of an acid such as TFA, formic acid, acetic acid, phosphoric acid, and the like, preferably TFA; wherein the acid is present in an amount in the range of from about 0.25 to about 3.0 molar equivalents, more preferably in an amount in the range of from about 0.5 to about 2.0 molar equivalents, more preferably in an amount of about 1.05 molar equivalents; in an organic solvent such as DCM, DCE, THF, chloroform, and the like, preferably DCM; preferably at a temperature in the range of from about -78 ⁰ C to about 25 ⁰ C, preferably at a temperature in the range of from about -5O ⁰ C to about 25 ⁰ C; to yield the corresponding compound of formula (XXIII-S), wherein the desired enantiomer is present in an enantiomeric excess of greater than 0%. Preferably, the compound of formula (XXIII-S) is prepared with an enantiomeric enrichment of greater than or equal to about 50%ee, more preferably greater than or equal to about 75%ee, more preferably greater than or equal to about 85%ee, more preferably greater than or equal to about 90%ee, more preferably greater than or equal to about 95%ee, more preferably greater than or equal to about 98%ee, more preferably greater than or equal to about 99%ee.

The compound of formula (XXIII-S) is reacted with a suitably selected compound of formula (XXIV-S), a known compound or compound prepared by known methods, wherein the compound of formula (XXIV-S) is preferably present in an amount in the range of from about 1.0 to about 3.0 molar equivalents (relative to the moles of the compound of formula (XXIII-S)), more preferably about 2.0 molar equivalent; in the presence of a suitably selected catalyst such as a palladium catalyst, such as Pd(PPh ₃ ^CI ₂ , Pd(PPh ₃ ) ₄ , Pd ₂ (OAc) ₂ , and the like, preferably Pd(PPh ₃ J ₂ CI ₂ , wherein the catalyst is preferably present in an amount greater than or equal to about a catalytic amount, more preferably, about 0.5 mol%; in the presence of an organic or inorganic base such as aqueous Na ₂ CO ₃ , aqueous K ₂ CO ₃ , aqueous NaHCO ₃ , TEA, DIPEA, pyridine, and the like, preferably aqueous Na ₂ CO ₃ ; wherein the base is preferably present in an amount in the range of from about 1.0 to about 5.0 molar equivalents (relative to the moles of the compound of formula (XXIII-S)), more preferably, in an

amount in the range of from about 2.0 to about 4.0 molar equivalents, more preferably, in an amount of about 3.0 molar equivalents; in an organic solvent or mixture of solvents such as 1 ,4-dioxane, toluene, a mixture of toluene and alcohol (such as a 4:1 mixture of toluene / ethanol, a mixture of toluene/methanol, a mixture of toluene/isopropyl alcohol, and the like), THF, 2-methyl-THF, acetonithle, 1 ,2-dimethoxyethane, and the like, preferably 1 ,4-dioxane; at a temperature in the range of from about room temperature to about solvent reflux temperature, preferably at about 8O ⁰ C, to yield the corresponding compound of formula (XXV-S).

The compound of formula (XXV-S), is reacted with a suitably substituted compound of formula (XXVI-S), a known compound or compound prepared by known methods, wherein the compound of formula (XXVI-S) is enantiomerically enriched with the corresponding (S)-enantiomer, wherein the (S)-enantiomer is preferably present in an enantiomeric excess of greater than of equal to about 80%ee, more preferably, in an enantiomeric excess of greater than of equal to about 90%ee, more preferably, in an enantiomeric excess of greater than of equal to about 95%ee, more preferably, in an enantiomeric excess of greater than of equal to about 98%ee, more preferably, in an enantiomeric excess of greater than of equal to about 99%ee; and wherein the compound of formula (XXIII-S) is preferably present in an amount in the range of from about 1.0 to about 10.0 molar equivalents (relative to the moles of the compound of formula (XXIII-S)), more preferably, in an amount in the range of from about 2.0 to about 4.0 molar equivalents, more preferably, in an amount of about 3.0 molar equivalents; in an organic solvent which will act as both a solvent and a catalyst as HFIPA, 2,2,2-trifluoroethanol, 1 ,1 ,1 -trifluoroisopropanol, and the like, preferably HFIPA; preferably at a temperature of less than or equal to about reflux temperature, more preferably at a temperature of less than or equal to about 6O ⁰ C, more preferably still, at a temperature of less than about 5O ⁰ C, more preferably at about room temperature, to yield the corresponding enantiomerically enriched compound of formula (M-S).

Preferably, the compound of formula (M-S) is isolated according to known methods, for example by solvent evaporation, precipitation, and the like. The compound of formula (M-S) may be further optionally purified according to known methods, for example re-crystallization, column chromatography, and the like.

The compound of formula (XX-S) may be prepared, for example, as described in more detail in Example 9, which follows herein. The compound of formula (XXI-S) may be prepared, for example, as described in more detail in Example 8, which follows herein. The compound of formula (L) may be prepared according to known methods, for example, as described in Atarashi, S., Tsurumi, H., Fujiwara, T., and Hayakawa, I., J. Heterocyclic Chem., (1991 ), vol. 28, pp329-331 , see Compound 8b.

The compounds of formula (XXM) may alternatively be prepared according to the process outlined in Scheme 5 below.

(XXVIM) (XXX)

(XXIX)

(XXXi) (XXXM)

Scheme 5

Accordingly, a suitably substituted compound of formula (XXVIM), a known compound or compound prepared by known methods is reacted with a suitably selected activating agent; according to known methods; to yield the

corresponding compound of formula (XXIX), wherein LG ⁴ is the corresponding leaving group such as Br, Cl, I, meylate, tosylate, and the like, preferably, Br.

For example, wherein LG ⁴ is bromo, the compound of formula (XXVIII) is reacted with a suitably selected source of bromine such as bromine gas, N- bromosuccinimide, and the like, preferably bromine gas; wherein the source of bromine in present in an amount in the range of from about 0.5 to about 2.0 molar equivalents (relative to the moles of the compound of formula (XXVIII), more preferably in an amount in the range of from about 0.75 to about 1.5 molar equivalents, more preferably in an amount of about 1.05 molar equivalents; in a solvent such as water, methanol, acetic acid, and the like, preferably water; to yield the corresponding compound of formula (XXIX).

The compound of formula (XXIX) is reacted with a suitably substituted compound of formula (XXX), wherein LG ⁵ is a suitably selected leaving group such as Br, Cl, I, mesyltae, tosylate, and the like, preferably Br, a known compound or compound prepared by known methods; wherein the compound of formula (XXX) is present in an amount in the range of from about 0.5 to about 5.0 molar equivalents (relative to the amount of moles of the compound of formula (XXIX), more preferably, in an amount in the range of from about 2.0 to about 4.0 molar equivalents, more preferably, in an amount of about 3.5 molar equivalents; in an organic solvent or mixture thereof such as heptane, isobutanol, isopropanol, and the like, preferably a mixture of heptane and isobutanol; preferably at about room temperature; to yield the corresponding compound of formula (XXXI).

The compound of formula (XXXI) is reacted with sodium dithionite (Na ₂ S ₂ O ₄ ); wherein the Na ₂ S ₂ O ₄ is present in an amount in the range of from about 1.0 to about 5.0 molar equivalents, more preferably in an amount in the range of from about 3.0 to about 5.0 molar equivalents, more preferably in an amount of about 3.5 molar equivalents; in the presence of an inorganic base such as potassium phosphate, potassium carbonate, and the like, preferably potassium phosphate; wherein

the inorganic base is present in an amount in the range of from about 0.5 to about 5.0 molar equivalents, more preferably in an amount in the range of form about 2.0 to about 4.0 molar equivalents, more preferably in an amount of about 3.0 molar equivalents; in an organic solvent such as 2-methyl-THF, toluene, methanol, and the like, preferably 2-methyl-THF; preferably at a temperature in the range of from about 25 ⁰ C to about 8O ⁰ C, more preferably at about 6O ⁰ C; to yield the corresponding compound of formula (XXXII).

One skilled in the art will recognize that wherein a suitably substituted compound of formula (XXXI) is reacted to yield the corresponding compound of formula (XXXII), a compound of formula (T2)

may be prepared as a transient intermediate, which intermediate is preferably not isolated.

In an embodiment, the present invention is directed to a process for the preparation of a compound of formula (XXXII-A), as outlined in Scheme 6 below.

(XXVIII-A)

(XXIX-A)

(XXXII-A) Scheme 6

Accordingly, a compound of formula (XXVIII-A), also known as 1-(3- (1 ,1 ,2,2-tetrafluoroethoxy)phenyl)ethanone is reacted with a suitably selected source of bromine such as bromine gas, N-bromosuccinimide, and the like, preferably bromine gas; wherein the source of bromine in present in an amount in the range of from about 0.5 to about 2.0 molar equivalents (relative to the moles of the compound of formula (XXVIII-A), more preferably in an amount in the range of from about 0.75 to about 1.5 molar equivalents, more preferably in an amount of about 1.05 molar equivalents; in a solvent such as water, methanol, acetic acid, and the like, preferably water; to yield the corresponding compound of formula (XXIX-A).

The compound of formula (XXIX-A) is reacted with a compound of formula (XXX-A), also known as 2-bromo-6-nitrophenol, wherein the compound of formula (XXX-A) is present in an amount in the range of from about 0.5 to about 5.0 molar equivalents (relative to the amount of moles of the compound of formula (XXIX-A), more preferably, in an amount in the range of from about 2.0 to about 4.0 molar equivalents, more preferably, in an amount of about 3.5 molar equivalents;

in an organic solvent or mixture thereof such as heptane, isobutanol, isopropanol, and the like, preferably a mixture of heptane and isobutanol; preferably at about room temperature; to yield the corresponding compound of formula (XXXI-A).

The compound of formula (XXXI-A) is reacted with sodium dithionite (Na ₂ S ₂ O ₄ ); wherein the Na ₂ S ₂ O ₄ is present in an amount in the range of from about 1.0 to about 5.0 molar equivalents, more preferably in an amount in the range of from about 3.0 to about 5.0 molar equivalents, more preferably in an amount of about 3.5 molar equivalents; in the presence of an inorganic base such as potassium phosphate, potassium carbonate, and the like, preferably potassium phosphate; wherein the inorganic base is present in an amount in the range of from about 0.5 to about 5.0 molar equivalents, more preferably in an amount in the range of form about 2.0 to about 4.0 molar equivalents, more preferably in an amount of about 3.0 molar equivalents; in an organic solvent such as 2-methyl-THF, toluene, methanol, and the like, preferably 2-methyl-THF; preferably at a temperature in the range of from about 25 ⁰ C to about 8O ⁰ C, more preferably at about 6O ⁰ C; to yield the corresponding compound of formula (XXXII-A).

Alternatively, the nitro group on the compound of formula (XXXI-A) selectively reduced by reacting with H ₂ (gas), in the presence of a suitably selected catalyst such as Pt/C, and the like; and in the presence of a suitably selected catalyst modifier such as vanadium(V)oxide or other source of vanadium, other transition metal compounds, and the like, preferably vanadium(V)oxide; preferably the catalyst modifier is present in an amount in the range of from about a catalytic amount to about 10 mol %, more preferably about 5 mol %; in an organic solvent such as methanol, ethanol, isopropyl alcohol, ethyl acetate, and the like, preferably methanol; to yield the corresponding compound of formula (XXXII-A).

One skilled in the art will recognize that wherein a suitably substituted compound of formula (XXXI-A) is reacted to yield the corresponding compound of formula (XXXII-A), a compound of formula (T2-A)

is prepared as a transient intermediate, which intermediate is preferably not isolated.

One skilled in the art will recognize that compounds of formula (I)

wherein the stereo-center denoted by the arrow is in the (S) configuration may be prepared from the corresponding compound of formula (I) wherein the stereo-center denoted by the arrow is in the (R) configuration, according to known methods. Similarly, compounds of formula (I) wherein the stereo-center denoted by the arrow is in the (R) configuration may be prepared from the corresponding compound of formula (I) wherein the stereo-center denoted by the arrow is in the (S) configuration, according to known methods.

One skilled in the art will further recognize that compounds of formula (II)

wherein the stereo-center denoted by the arrow is the (S) configuration may be prepared from the corresponding compound of formula (I) wherein the stereo-center denoted by the arrow is in the (R) configuration, according to known methods. Similarly, compounds of formula (II) wherein the stereo-center denoted by the arrow is in the (R) configuration may be prepared from the corresponding compound of formula (II) wherein the stereo-center denoted by the arrow is in the (S) configuration, according to known methods.

Representative processes for the inter-conversion of a stereo-center which comprises a hydroxy group (-OH), such as those denoted by the arrow in the structural representations of the compounds of formula (I) and compounds of formula (II) drawn above, are as described below. In certain embodiments, the present invention is directed to processes for the preparation of compounds of formula (I), processes for the preparation of compounds of formula (II), processes for the preparation of the compound of formula (I-S) and processes for the preparation the compound of formula (N-S), which processes comprise any of the stereo-center inter-conversion methods described herein.

For example and without limitations, the following stereo-center inter- conversion methods are described for the synthesis of a compound of formula (N-S). One skilled in the art will recognize that the methods described below may be applied to the synthesis of any of the compounds of formula (I) or compounds of formula (II) described herein, regardless of whether the desired

stereo-configuration at the stereo-center comprising the hydroxy group (as denoted with the arrows in the structures listed above) is in the (R) or (S) configuration.

In an embodiment, the compound of formula (N-S) may be prepared from the corresponding compound of formula (H-R)

by oxidizing the hydroxy group (-OH) on the compound of formula (H-R) according to known methods, for example by Swern oxidation or Dess-Martin oxidation, to yield the corresponding carbonyl group (-C(O)); which carbonyl group is then reduced, preferably under chiral conditions, to yield a mixture of the corresponding the corresponding compound of formula (M-S) and the compound of formula (H-R). The mixture comprising the compounds of formula (M-S) and (M-R) may be optionally further separated, according to known methods, for example by chromatography, chiral chromatography, chirally selective precipitation, chirally selectve crystallization, chirally selective salt formation, and the like.

In another embodiment, the compound of formula (N-R) may be inter- converted to the corresponding compound of formula (N-S) according to the process comprising the following: (STEP 1) activating the hydroxy group (-OH) on the compound of formula (M-R) according to known methods, for example by reacting the compound of formula (N-R) with a suitably selected activating agent such as CH ₃ SO ₂ CI, (p-toluene)-SO ₂ CI, and the like; in the presence of a base such as thethylamine, diisopropylethylamine, and the like, in an organic solvent such as dichloromethane, and the like, to yield the corresponding activated group (for example, wherein the activating agent is CH ₃ SO ₂ CI, the

hydroxy group (-OH) is converted to the corresponding activated group -O- SO ₂ -CH ₃ ; wherein the activating agent is (p-toluene)-SO ₂ CI, the hydroxy group (-OH) is converted to the corresponding activated group -O-SO ₂ -(p-toluene)); (STEP 2) converting the activated group to the corresponding -0-C(O)-CH ₃ group, according to known methods, for example by reacting with KOC(O)CH ₃ , and the like, in an organic solvent such as DMF, and the like; and (STEP 3) hydrolyzing the -0-C(O)-CH ₃ group to the corresponding hydroxy group (-OH) according to known methods; to yield the corresponding compound of formula (M-S). Alternatively, the activated group prepared in (STEP 1 ) is reacted with a suitably selected reagent such as potassium benzoate, and the like, to yield the corresponding benzoate ester group (-O-benzoyl), which group is then hydrolyzed to the corresponding hydroxy group.

In yet another embodiment, the compound of formula (H-R) may be converted to the corresponding compound of formula (M-S) by Mitsunobu inversion, a method known in the art.

The present invention is further directed to a crystalline form of the compound of formula (N-S)

OH (M-S).

In an embodiment, the crystalline form of the compound of formula (M-S) is a non-hydrate. The crystalline form of the compound of formula (M-S) may be prepared as described in, for example, Example 13, which follows herein. In an embodiment, the crystalline form of the compound of formula (M-S) may be characterized by its corresponding powder X-ray diffraction (XRD) pattern, a representative example of which is shown in Figure 1.

The powder XRD spectra for a representative sample of the crystalline form of the compound of formula (M-S) was measured on a: Bruker AXS /Model D8 Advance equipped with a scintillation detector, parallel beam optics (Goebel Mirrors), and a Cu radiation source. The spectra was scanned 3° to 40° in 2θ using a scan rate of 3° in 2θ/min. The x-ray tube voltage and current settings were 45 KV and 40 mA, respectively. The sample was packed onto a zero background holder and scanned under ambient conditions of temperature and humidity.

The crystalline form of the compound of formula (H-S), may be characterized by its powder X-ray diffraction pattern, comprising the peaks as listed in Table 1 , below.

Table 1 : Powder XRD Peaks - Crystalline Form of Compound (M-S)

Preferably, the crystalline form of the compound of formula (N-S) is characterized by its XRD pattern, which comprises peaks having a relative intensity greater than or equal to about 10%, as listed in Table 2, below. Table 2: Powder XRD Peaks - Crystalline Form of Compound (M-S)

Preferably, the crystalline form of the compound of formula (N-S) is characterized by its XRD pattern, which comprises peaks having a relative intensity greater than or equal to about 20%, as listed in Table 3, below. Table 3: Powder XRD Peaks - Crystalline Form of Compound (M-S)

The crystalline form of the compound of formula (M-S) may alternatively be characterized by its corresponding DSC melting point. The DSC scan of a representative sample of the crystalline form of the compound of formula (H-S), sample size of 4.3 mg, loaded into a 40μl_ aluminum crucible with a hermetically sealed lid, was measured on a TA Instruments Q100 DSC, scanning from 35 ⁰ C to 35O ⁰ C with a scan rate of 10°C/min. The DSC scan showed a single peak with a melting onset of 80.78 ⁰ C and peak melting point at 83.27 ⁰ C (73.22 J/g).

A representative sample of the crystalline form of the compound of formula (M-S) was additional tested on a Mettler Toledo TGA/SDTA 851 e, scanning from 35°c to 35O ⁰ C with a scan rate of 1 O ⁰ C/ min, loading 7.9 mg of the sample onto 70 μl_ alumina crucible. The TGA scan showed no weight loss prior to decomposition beginning at 19O ⁰ C, indicating that the crystalline form of the compound of formula (M-S) is a not a hydrate or a solvate.

The present invention further comprises pharmaceutical compositions containing one or more compounds prepared according to any of the processes described herein with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing

the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral). Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives. To prepare the pharmaceutical compositions of this invention, one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable

suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.1 -1000 mg or any range therein, and may be given at a dosage of from about 0.01-100 mg/kg/day, or any range therein, preferably from about 0.5-50 mg/kg/day, or any range therein. The dosages, however, may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once- monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing

from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

The methods of treating described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.01 mg and 1000 mg of the compound, or any range therein; preferably about 10 to 500 mg of the compound, and may be constituted into any form suitable for the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixers, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders; lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.

To prepare a pharmaceutical composition of the present invention, one or more compounds prepared according to any of the processes described herein as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The

Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1 -3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1 -2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems. Volumes 1 -2, edited by Lieberman et al; published by Marcel Dekker, Inc.

Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of disorders or conditions modulated by CETP is required.

The daily dosage of the products may be varied over a wide range from 0.01 to 1 ,000 mg per adult human per day, or any range therein. For oral administration, the compositions are preferably provided in the form of tablets containing, 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 100 mg/kg of body weight per day, or any range therein. Preferably, the range is from about 0.5 to about 50.0 mg/kg of body weight per day, or any range therein. More preferably, from about 1.0 to about 5.0 mg/kg of body weight per day, or any range therein. The compounds may be administered on a regimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.

One skilled in the art will recognize that, both in vivo and in vitro trials using suitable, known and generally accepted cell and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

One skilled in the art will further recognize that human clinical trails including first-in-human, dose ranging and efficacy trials, in healthy patients and / or those suffering from a given disorder, may be completed according to methods well known in the clinical and medical arts.

Examples

The following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products are listed as having been isolated as a residue. It will be understood by one of ordinary skill in the art that the term "residue" does not limit the physical state in which the product was isolated and may include, for example, a solid, an oil, a foam, a gum, a syrup, and the like.

Examples 1 -5 represent recipes / procedures for the preparation of the titled compounds. Several batches of the title compounds were prepared using these recipes / procedures.

Example 1

(E)-3-(2-Bromo-6-nitrophenyl)-1-r3-(1,1,2,2-tetrafluoroet hoxy)phenvn propenone

A 2-L 4-neck flask equipped with an overhead stirrer, thermocouple, addition funnel, nitrogen purge, and condenser was charged with anhydrous 2- methyl THF (330 ml_). To the flask was then added 2-bromo-6- nitrobenzaldehyde (110.0 g, 478.2 mmol) and cesium carbonate (311.6 g, 956.4 mmol) and the resulting mixture stirred under nitrogen. To the reaction

mixture was then added 3-(1 ,1 ,2,2-tetrafluoroethoxyl)acetophenone (112.9 g, 478.2 mmol) slowly via an addition funnel over 40 minutes. The reaction mixture was maintained at a temperature below 45 ⁰ C and preferably below 3O ⁰ C. The resultant suspension was stirred until the reaction was complete.

To the reaction mixture was then added water (220 ml_) at room temperature, which dissolved the cesium carbonate. The resulting mixture was allowed to cool to room temperature while agitating, then transferred to a separatory funnel. The aqueous layer was removed and the organic layer which contains the title compound was used in the next step without further purification or isolation.

Note: An aliquot of the reaction mixture was purified by evaporating the solvent on a rotary evaporator to yield a dark solid, which was dissolved in CDCI3, filtered to remove any un-dissolved solid and concentrated again on a rotary evaporator to yield the title compound as a dark solid.

¹ H NMR (300 MHz, CDCI ₃ ) δ 7.93-7.82(m, 5 H), 7.55 (t, J = 8.0 Hz, 1 H), 7.46 (dd, J = 1.2, 8.3 Hz, 1 H), 7.41 (t, J = 8.1 Hz, 1 H), 7.05 (d, J = 16.1 Hz, 1 H), 5.95 (tt, J = 2.8, 53.0 Hz, 1 H);

MH ⁺ (API-ES) calculated for Ci ₇ HnBrF ₄ NO ₄ 448, measured: 448.

Example 2 5-bromo-2-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)quinoline

To a 1 L 4-neck flask equipped with agitator, thermocouple, addition funnel, and condenser was added 4N aqueous HCI (394 ml_) and tin dichloride (133.2 g, 702.8 mmol). The reaction mixture was then agitated until the tin dichloride was dissolved. To the reaction mixture was then added, via addition funnel (E)-3-(2-bromo-6-nitrophenyl)-1-[3-(1 ,1 ,2,2-tetrafluoroethoxy)phenyl] propenone (78.75 g, 175.7 mmol) as a solution in 2-methyl-THF (~197ml_

solution) (prepared as in Example 1 above) while maintaining the temperature of the reaction mixture at <35 ⁰ C (preferably <~30 ⁰ C). The resulting mixture was then heated to -78 ⁰ C and stirred until the reaction was determined complete. The resulting mixture was cooled to room temperature, then transferred to a separatory funnel. The aqueous layer (TOP) was removed and discarded. The organic layer was transferred back to the flask and 4N aqueous HCI (394 ml_) was added. The resulting mixture was agitated for 5 min, then transfer to a separatory funnel and the aqueous (TOP) layer discarded.

To the organic layer was added 2-methyl-THF (200 ml_) and the resulting mixture was cooled using an ice water bath. To the resulting mixture was then added lithium hydroxide monohydrate (98.5 g, 2340 mmol). The resulting mixture was filtered and the filter cake washed with 2-methyl-THF (80 ml_). To the filtrate was then added water (100 ml_), the mixture agitated, and the aqueous (BOTTOM) layer discarded. The organic layer containing the title compound was used in the next step without further purification or isolation.

Note: An aliquot of the solution was purified by flash chromatography to yield the title compound as a white solid.

¹ H NMR (300 MHz, CDCI ₃ ) δ 8.59 (d, J = 8.9 Hz, 1 H), 8.13 (d, J = 8.5 Hz, 1 H), 8.09-8.06 (m, 2 H), 7.93 (d, J = 8.9 Hz, 1 H), 7.81 (dd, J = 0.9, 7.5 Hz, 1 H), 7.61 -7.52 (m, 2 H), 7.34 (td, J = 0.8, 8.1 Hz, 1 H), 5.98 (tt, J = 2.8, 53.0 Hz, 1 H);

MH ⁺ (API-ES) calculated for Ci ₇ HnBrF ₄ NO 400, measured 400.

Example 3

2-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-5-(3- (trifluoromethoxy)phenyl)quinoline 4-methylbenzenesulfonate (1 :1 Salt)

To a 1 -L four-necked round bottom flask equipped with a mechanical stirrer, thermocouple and condenser was added a solution of 5-bromo-2-(3- (1 ,1 ,2,2-tetrafluoroethoxy)phenyl)quinoline (70.3g, 175.7 mmoL) in 2-methyl- THF (as prepared in Example 2 above), and toluene (349 g, 3788 mmol). The resulting mixture was agitated and heated to 98-100 ⁰ C, to distill ~ 325-330 ml_ solvent. The resulting mixture was cooled to 50-55 ⁰ C. To the resulting mixture was then added aqueous sodium carbonate (~2M, 50.9 g dissolved in 240.0 g water for a total of 291 g, 480 mmol), 3-(trifluoromethoxy)phenylboronic acid (36.2g, 175.7 mmoL) and tetrakis(triphenyl-phosphine)palladium (0) (1.02g, 0.88 mmoL). The resulting mixture was heated to reflux (82-85 ⁰ C) for 2-3 h. If the reaction was not complete, additional 3-(trifluoromethoxy)phenylboronic acid (3-5%) was added. The resulting mixture was cooled to room temperature and stirred overnight.

The aqueous (BOTTOM) layer of the resulting biphasic mixture was removed and the organic layer washed with brine (-240 ml_). The aqueous (BOTTOM) layer was removed and the resulting mixture filtered into another 1 - L 4-necked round bottom flask. The flask was washed with toluene (21.6 g, 235 mmol) and combined with the filtrate. The combined filtrate was heated to reflux to distill off ~125 ml_ of solvent, then cooled to 80-85 ⁰ C. To the resulting mixture was then added p-toluenesulfonic acid monohydrate (36.8g, 193.2 mmoL) and the resulting mixture stirred at 80-85 ⁰ C for ~1.5 hours, then cooled to room temperature and stirred overnight. To the resulting mixture was then added ethyl acetate (135.3 g, 1536 mmol) and the mixture cooled to 0-5 ⁰ C for ~2hours. The resulting slurry was filtered, washed twice with ethyl acetate (36.1 g, 409 mmol) and then dried under vacuum at 40-45 ⁰ C, 27-28"Hg

overnight to yield the title compound as crude 2-(3-(1 ,1 ,2,2- tetrafluoroethoxy)phenyl)-5-(3-(trifluoromethoxy)phenyl)quin oline 4- methylbenzenesulfonate, as a pale yellow crystalline solid. The product was used in the next step without further purification.

Example 4

2-(3-(1.1.2.2-tetrafluoroethoxy)phenyl)-5-(3-(trifluorome thoxy)phenyl)- 1,2,3,4-tetrahydroquinolium 4-methylbenzene sufonate

To a 50 L phase separator equipped with overhead mechanical stirrer was added 2-(3-(1 ,1 ,2,2-tetrafluoroethoxy)phenyl)-5-(3- (thfluoromethoxy)phenyl)quinoline 4-methylbenzenesulfonate (870 g, 1.33 mol) and ethyl acetate (4592 g) and the resulting mixture agitated. To the agitated mixture was then added a 50% saturated aqueous sodium carbonate solution (2.55 L). The resulting biphasic mixture was agitated for -15 min. and then allowed to settle. The aqueous (BOTTOM) layer was discarded. To the organic layer was added additional 50% saturated aqueous sodium carbonate solution (2.55 L). The resulting biphasic mixture was agitated for -15 min. and then allowed to settle. The aqueous (BOTTOM) layer was discarded.

The organic layer was dried with sodium sulfate (600 g, 4.22 mol), with agitation for -30 minutes. The resulting suspension was filtered to remove the sodium sulfate and the filtrate transferred to a 22L flask equipped with an overhead mechanical stirrer. To the filtrate was then added (1 S)-(+)-10- camphorsulfonic acid (92.80 g, 0.30 mol) and the resulting mixture was agitated for -10 minutes. To the resulting mixture was then added diludine (877 g, 3.46 mol) and the resulting mixture agitated at ambient temperature for 6 hours. If the reaction was not complete, additional diludine (135 g, 0.53 mol) was added and the resulting mixture agitated at ambient temperature overnight. The

resulting mixture was heated to ~ 40-50 ⁰ C to achieve a clear homogeneous solution (to decompose any remaining diludine), then cooled to ambient temperature. To the resulting mixture, at ambient temperature was then added 4N HCI (2.50 L) and the resulting biphasic mixture agitated for -15-20 minutes. The layers were allowed to split, the aqueous layer was removed and discarded. The 4N HCI wash was repeated 3-5 times to remove byproduct.

To the resulting mixture was then added a 50% saturated aqueous carbonate solution (2.55 L) and the resulting biphasic mixture agitated for -15 min. The aqueous (BOTTOM) layer was discarded, the organic layer washed a second time with a 50% saturated aqueous carbonate solution (2.55 L), the resulting biphasic mixture agitated for -15 min and the aqueous (BOTTOM) layer discarded. The organic layer was concentrated to a thick oil. To the oil was then added toluene (4444 g) and the resulting mixture agitated at ambient temperature. To the agitating mixture was then added p-toluenesulfonic acid (279 g, 1.46 mol) and the resulting suspension agitated for -2 hours. To the resulting mixture was then added heptane (2632 g), the mixture agitated for another -1.5 hours, then cooled to 0-5 ⁰ C. The resulting suspension was maintained at 0-5 ⁰ C for 1 hour, then filtered. The filter cake was washed with heptane (2.50 L) and allowed to air dry for -30-40 minutes. The resulting moist solid was transferred to a drying tray and dried under vacuum with a nitrogen bleed(~27" Hg) at ~45-50°C overnight to yield the title compound as a white crystalline solid.

Example 5

(S)-1.1.1 -trifluoro-3-((R)-2-(3-(1.1.2.2-tetrafluoroethoxy)phenvn-5-( 3- (trifluoromethoxy)phenyl)-3,4-dihydroquinolin-1(2H)-yl)propa n-2-ol

In a 2-L round bottom flask equipped with a magnetic stirrer and thermocouple, and nitrogen purge was dissolved (R)-2-(3-(1 , 1 ,2,2- tetrafluoroethoxy)phenyl)-5-(3-(trifluoromethoxy)phenyl)-1 , 2,3,4- tetrahydroquinoline (250 g) in ethyl acetate (2500 ml_). The resulting solution was transferred to a 5 L separatory flask equipped with an overhead stirrer. To the mixture was then added 4N HCI (750 ml_) and the resulting mixture stirred vigorously for 5 minutes, then allowed to split into a biphasic mixture. The aqueous (BOTTOM) layer was discarded. To the organic layer was added a second portion of 4N HCI (500 ml_), the resulting mixture stirred vigorously for 5 minutes, allowed to split into a biphasic mixture and the aqueous (BOTTOM) layer was discarded. To the organic layer was added a 50% saturated (aq.) Na2CO3 solution (550 ml_), the resulting mixture stirred vigorously for 5 minutes, allowed to split into a biphasic mixture and the aqueous (BOTTOM) layer was discarded. The organic layer was dried with Na ₂ SO ₄ (250 g), filtered to remove the desiccant and then concentrated on a rotary evaporator at <40°C in vacuo to yield a bright yellow oil.

The oil (255.3 g) was transferred to a 2-L round bottom flask, to which was then added 1 ,1 ,1 ,3,3,3-hexafluoroisopropanol (511 ml_). The flask was then flushed with nitrogen. To the resulting mixture was then added (S)-2- (thfluoromethyl)oxirane (164 g). The flask was covered with aluminum foil, the reaction mixture cooled with a room temperature water bath and slowly stirred for 4 hours and allowed to stand at room temperature for 36 hours. When the reaction was deemed complete, the solvent and any excess (S)-2- (thfluoromethyl)oxirane was removed on a rotary evaporator at 4O ⁰ C under

vacuum. To the resulting residue was added 200 proof ethanol (500 ml_) and the mixture polish filtered through a M-sintered glass filtration funnel. The solvent was removed on a rotary evaporator at 5O ⁰ C under vacuum. To the residue was added a second amount of 200 proof ethanol (500 ml_). The solvent in the resulting mixture was removed on a rotary evaporator at 50 ⁰ C under vacuum until dry to yield the title compound as a golden gel-like oil (the title compound can also have the following nomenclature as an alternative to the nomenclature described above: (2R,«S)-3,4-Dihydro-2-[3-(1 , 1 ,2,2- tetrafluoroethoxy)phenyl]-5-[3-(thfluoromethoxy)phenyl]-α-( trifluoromethyl)- 1 (2H)-quinolineethanol).

¹ H NMR (300 MHz, CDCI ₃ ) δ 7.38 (d, J = 7.6 Hz, 1 H), 7.33 (d, J = 7.5 Hz, 1 H), 7.23 (d, J = 8.3 Hz, 1 H), 7.20-7.10 (m, 5 H), 7.04 (s, 1 H), 6.73 (d, J = 8.3 Hz, 1 H), 6.67 (d, J = 7.3 Hz, 1 H), 5.89 (tt, J = 2.8, 53.0 Hz, 1 H), 4.90 (t, J = 4.5 Hz, 1 H), 4.45-4.36 (m, 1 H), 3.91 (d, J = 15.6 Hz, 1 H), 3.30 (dd, J = 9.7, 15.6 Hz, 1 H), 2.51 (d, J = 4.5 Hz, 1 H), 2.47-2.31 (m, 2 H), 2.18-2.09 (m, 1 H), 2.00-1.91 (m, 1 H);

MH ⁺ (API-ES) calculated for C ₂₇ H ₂₂ Fi ₀ NO ₃ 598, measured 598.

Example 6 - Asymmetric Reduction

2-(R)-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-5-(3-(trifluo romethoxy)phenyl)-

1.2.3.4-tetrahvdroαuinoline

To a 25 ml_ carousel tube containing diludine (1.61g, 3.0 eq., 6.36 mmoL) and the 9-phenanthrylene substituted (S)-chiral catalyst of the following structure:

(also known as 4-oxo-2,6-di-phenanthren-9-yl-3,5-dioxa-4l5-phospha- cyclohepta[2,1 -a;3,4-a']dinaphthalen-4-ol) (44.5 mg, 0.06 mmoL, 3 mol%), was added a solution made from 2-(3-(1 ,1 ,2,2-tetrafluoroethoxy)phenyl)-5-(3- (thfluoromethoxy)phenyl)quinoline (1.02g, 2.12 mmoL) and toluene (3.61g). The resulting slurry was stirred, heated to 58 ⁰ C and then stirred at 58 ⁰ C for 8 hours. The resulting mixture was then cooled to room temperature. (1 S)-(+)- 10-camphorsulfonic acid (148 mg, 0.30 eq) and additional diludine (160 mg, 0.3 eq.) were added and the resulting slurry was stirred at room temperature for 6 hours. To the resulting reaction mixture were added ethyl acetate (4 ml_) and aqueous 2N Na ₂ CO ₃ (6 ml_). The phases of the resulting biphasic mixture wEre separated. After the clear lower aqueous layer was mostly removed, the remaining organic phase and some precipitates were filtered and the filtrate was washed with 4N HCI for (3-5 times, 6 ml_ each time), followed by washing with 50% saturated aqueous Na ₂ CO ₃ solution (2X). The resulting mixture was concentrated to yield the title compound, (R)-2-(3-(1 , 1 ,2,2- tetrafluoroethoxy)phenyl)-5-(3-(trifluoromethoxy)phenyl)-1 , 2,3,4- tetrahydroquinoline, as crude product, as an oil.

Note: The crude oil may be further, optionally converted to its corresponding tosylate salt and /or further recrystallized.

Example 7

8-Bromo-3-r3-(1,1,2,2-tetrafluoro-ethoxy)-phenvn-3,4-dihv dro-2H- benzoM ,41oxazine

A 25 ml_ carousel tube was charged with 8-bromo-3-[3-(1 ,1 ,2,2- tetrafluoro-ethoxy)-phenyl]-2H-benzo[1 ,4]oxazine (202 mg, 1.0 mmol) , diludine (190 mg, 1.5 eq.) and ethyl acetate ( 1.5 ml_) and the resulting mixture stirred to effect a solution. To the resulting mixture was then added catalyst of the formula (C-S)

also known as 4-oxo-2,6-di-phenanthren-9-yl-3,5-dioxa-4λ ⁵ -phospha- cyclohepta[2,1 -a;3,4-a']dinaphthalen-4-ol (10.5 mg, 3 mol%) and the resulting mixture was stirred for at least 3 hours. Chiral HPLC on the resulting mixture showed that the title compound was prepared at an enantiomeric excess of greater than about 90%. The title compound was not further isolated in this example.

Example 8 2-Bromo-1-r3-(1,1,2,2-tetrafluoro-ethoxy)-phenvn-ethanone

A 3L 4-neck flask equipped with a thermocouple, condenser, addition funnel, overhead stirrer and argon inlet was charge with acetic acid (1.5 L; 26.18 moles; 1.50 L) and 3-(1 ,1 ,2,2-tetrafluoroethoxyl)acetophenone (199.55 g; 844.96 mmol; 149.87 ml_) at room temperature (21.3 ⁰ C). To the resulting mixture was then added bromine (46 ml_; 890.72 mmol; 46.00 ml_), at a steady rate, via addition funnel at room temperature. The resulting mixture was then stirred for 3 hours at about room temperature. The resulting mixture was concentrated to approximately half its original volume by rotovap; and the resulting mixture allowed to stand overnight. The mixture was then further concentrated to yield a thick yellow oil.

The oil was partition between dichloromethane (50OmL) and saturated sodium bicarbonate (50OmL). The phases were separated and the aqueous phase washed with additional dichloromethane(2 x 25OmL). The combined organic phases were dry over MgSO ₄ , filtered and concentrated to yield the title compound as a yellow oil.

The yellow oil was purified by loading onto a 150M Biotage (2.5kg) column eluting with heptane (6 L) and then 12.5% ethyl acetate in heptane (24L); to yield the title compound as a yellow oil.

Elemental Analysis: Calculated: C, 38.12; H, 2.24; Br, 25.36; F, 24.12; O, 10.16; Measured: C, 38.46; H, 2.31 ; Br, 25.06; F, 23.59;

Example 9 2-Amino-6-bromo-phenol

A 12L 4-neck round bottom flask equipped with an overhead mechanical stirrer, condenser, thermocouple and Argon inlet was charged with ethanol (3000 ml_; 48.95 moles; 3.00 L), 2-bromo-6-nitrophenol (251.85 g; 1.16 moles; 251.85 g) and water (2800 ml_; 155.42 moles; 2.80 L), with good agitation at room temperature, and the resulting mixture heated to 5O ⁰ C. To the resulting mixture was then slowly charged sodium dithionite (948.76 g; 4.63 moles; 948.76 g) in 100g portions (exotherm control) every 10 to 15 minutes (addition resulted in an observed exotherm). During the additions the reaction mixture was observed to change color from a yellow-orange to a red-orange. After the additions were complete, the resulting mixture was stirred at 5O ⁰ C to 6O ⁰ C for about 15 minutes, at which time the mixture was observed to turn a pale yellow color. The heat source was removed and the mixture was allowed to slowly cool to room temperature. The resulting mixture was concentrated on the rotovap to remove ethanol. The resulting yellow slurry was diluted with water (2L), then extracted with DCM (3 X 1 L). The combined organic phases were dry over MgSO ₄ filtered; and then concentrated to yield the title compound as a brown solid.

Elemental Analysis: Calculated: C 38.33; H 3.22; N 7.45; Br 42.50; Measured: C 38.20; H 2.97; N 7.33; Br 42.33;

Example 10 8-Bromo-3-r3-(1,1,2,2-tetrafluoro-ethoxy)-phenyll-2H-benzori .4loxazine

A reaction vessel was charged with acetonitrile (2600 ml_; 49.61 moles; 2.60 L), 2-amino-6-bromophenol (144 g; 765.86 mmoles; 144.00 g), α- bromoketone (240 g; 761.75 mmoles; 240.00 ml_) and potassium carbonate, 325 mesh (114 g; 808.36 mmoles; 114.00 g) at room temperature (the base was added all at once) and the resulting mixture stirred overnight. (Following addition of the potassium carbonate, the mixture temperature was observed to rise over about 30 minutes). The resulting mixture was filtered and the solids washed with DCM (0.5L). The filtrate was concentrated down using the rotovap to yield a dark brown oil. The oil was purified by loading onto 700 g silica gel using 4 L dichloromethane and eluting on 5kg Biotage column using 12L heptane followed by 36L 10% ethyl acetate in heptane; to yield the title compound as a residue which was used in the next step without further isolation or purification..

Example 11

8-Bromo-3-r3-(S)-(1,1,2,2-tetrafluoro-ethoxy)-phenvn-3,4- dihvdro-2H- benzoM ,41oxazine

A 3-L, 4-neck round bottom flask, equipped with magnetic stirrer, thermocouple, argon inlet, and two stoppers, was charged with 8-Bromo-3-[3- (1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-2H-benzo[1 ,4]oxazine (208.34 g; 515.49 mmoles; 208.34 g) as a solution in ethyl acetate (5 L/kg-bulk-LR; 10.65 moles; 1.04 L). To the resulting mixture was then added (S)-phosphonic acid, phenanthrenyl (0.03 equiv (molar); 15.46 mmoles; 10.84 g) followed by diethyl 1 ,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (1.2 equiv (molar); 618.59 mmoles; 164.93 g) and the resulting mixture stirred for about 20 hours.

The resulting mixture was then diluted with 4 M hydrochloric acid (500 mL) and ethyl acetate (400 mL) and stirred for 15 min. The resulting mixture

was filtered (Glassfiber) to remove residues and the filter cake was rinsed with minimal ethyl acetate. The filtrate was further diluted with ethyl acetate (600 ml_) and the layers separated. The organic phase was washed with 4 M hydrochloric acid (4 x 500 ml_). The combined aqueous phases were back- extracted with ethyl acetate (500 ml_). The combined organic phases were washed with saturated sodium bicarbonate (1000 ml_), brine (500 ml_), dried (MgSO ₄ ), and concentrated to yield the title compound as a residue.

Example 12

3-r3-(S)-(1,1,2,2-Tetrafluoro-ethoxy)-phenvn-8-(3-trifluo romethoxy-phenyl)-

3,4-dihvdro-2H-benzori,41oxazine

A 12 L 4-neck flask equipped with a thermocouple, stopper/addition funnel, condenser and overhead stirrer under Argon was charged with water (800 ml_; 44.41 moles; 800.00 ml_) and potassium carbonate (220.64 g; 1.58 moles; 220.64 g) and the resulting mixture stirred to dissolve the K2CO3. To the resulting mixture was then added 8-bromo-3-[3-(S)-(1 ,1 ,2,2-tetrafluoro- ethoxy)-phenyl]-3,4-dihydro-2H-benzo[1 ,4]oxazine (240 g; 525.88 mmol; 240.00 g) dissolved in 1 ,4-dioxane (5800 ml_; 67.94 moles; 5.80 L) and the mixture heated to 8O ⁰ C for 1 hour. To the resulting mixture was then added 3- (thfluoromethoxy)phenylboronic acid (216.4 g; 1.05 moles; 216.40 g) and the mixture heated to reflux (about 86-88 ⁰ C) for 15 minutes. The resulting mixture was then cooled to 8O ⁰ C and and bis(thphenylphosphine)palladium(ll) chloride (9.4 g; 13.26 mmoles; 9.40 g) was added (the red-orange solution was observed to turn very dark/black). The resulting mixture was heated to 8O ⁰ C overnight. The resulting mixture was then was cooled slowly to room

temperature. At 25 ⁰ C saturated ammonium chloride solution (4 L) was added and the resulting mixture stirred for 1 h. The mixture was then filtered through CELITE ^® and the CELITE ^® washed with ethyl acetate (500 ml_). To the filtrate was then added EtOAc (1.5 L). The phases were separated and the aqueous phase was extracted with EtOAc (3 x 1 L). The combined organic phases were washed with 4M HCI (2 x 50OmL), resulting in an emulsion, which was allowed to separate into two phases. The organic phase was separated, washed with saturated NaHCO3 (2 x 1 L), dried over MgSO ₄ , filtered and concentrate on rotovap to yield the title compound as a dark brown oil. The oil was impregnated onto 900 g silica gel and purfied by eluting on a 5 Kg Biotage silica gel column using heptane (12 L) 10% EtOAc in heptanes (30 L) to yield the title compound.

Elemental Analysis: Calculated: C 57.28; H 3.84; N 2.77; f 26.08; Measured: C 57.31 ; H 3.55; N 2.71 ; F 25.93;

Example 13

(S)-1.1.1 -Trifluoro-3-r3-(S)-r3-(1.1.2.2-tetrafluoro-ethoxy)-phenyll- 8-(3- trifluoromethoxy-phenyl)-2,3-dihvdro-benzori,41oxazin-4-vn-p ropan-2-ol

OH

A 1000-mL, three-neck flask, equipped with stopper, thermocouple, and air condenser with argon inlet was charged with 3-[3-(S)-(1 ,1 ,2,2-Tetrafluoro- ethoxy)-phenyl]-8-(3-trifluoromethoxy-phenyl)-3,4-dihydro-2H - benzo[1 ,4]oxazine (85% ee) (223.53 g; 444.13 mmol; 223.53 g) as a solution in 2-propanol, 1 ,1 ,1 ,3,3,3-hexafluoro- (9 equiv (molar); 4.00 moles; 419.28 ml_). The resulting mixture was then treated with (S)-3,3,3-trifluoro-1 ,2-

epoxypropane (2 equiv (molar); 888.26 mmol; 99.53 ml_) and heated to 5O ⁰ C for 6 hours. Additional (S)-3,3,3-trifluoro-1 ,2-epoxypropane (0.5 equiv (molar); 222.07 mmol; 24.88 ml_) was added and the mixture heated for 19 hours (25 h total). The resulting mixture was then cooled to room temperature, then diluted with acetone, concentrated, and then twice dissolved in heptane and concentrated to yield an orange oil. The orange oil was dissolved in ethyl acetate-heptane (15:85, -250 ml_) and loaded on to a Biotage 75L (800 g silica, ~3 g silica/g product) and eluted with ethyl acetate-heptane (15:85, 8 L) to yield the title compound as an oil. Recrvstallization:

The oil was dissolved in warm (-55 ⁰ C) heptane (2.4 L, ~9 vol), and the resulting mixture was then cooled. Upon cooling to 4O ⁰ C, seed crystals were added and mixture stirred. Solids began forming in -30 min, but stirring was continued for 16 hours over which time a mass of solids was observed to form. The sides of recrystallization flask were scraped down and stirring was continued for 4 hours. The resulting mixture was then chilled to 10-12 ⁰ C over 2 hours. The solids were collected by filtration and washed with heptane (250 ml_), then dried in a vacuum oven (5O ⁰ C) overnight to yield the title compound as a crystalline solid.

Optical Rotation: -81.8° (c = 1.00, CHCI ₃ , 25 ⁰ C) Elemental Analysis: Calculated: C 52.13; H 3.21 ; N 2.33; F 31.65; Measured: C 52.03; H 2.90; N 2.29; F 31.22;

Example 14 2-(2-bromo-6-nitrophenoxy)-1-(3-(1.1.2.2-tetrafluoroethoxy)p henyl)ethenone

A 250ml 5-necked flask equipped with an overhead stirrer, thermocouple, addition funnel, nitrogen purge and condenser was charged with 1 -(3-(1 ,1 ,2,2-tetrafluoroethoxy)phenyl)ethanone (2Og, 84.68 mmol). To the flask was added water (10ml), tetrabutylammoniumbromide (1.36g, 4.23 mmol)

and hydrogen bromide 48% solution in water (4.76 ml, 42.34 mmol). To the resulting mixture was then added bromine (4.57ml, 88.92 mmol) slowly via an addition funnel over 1 h. The internal temperature of the mixture was maintained below 3O ⁰ C, and preferably below 25 ⁰ C and stirred vigorously for 24 hours. The resulting mixture comprising 2-bromo-1-(3-(1 , 1 ,2,2- tetrafluoroethoxy)phenyl)ethanone was used in the next step without further isolation or purification.

To the mixture was added heptane (169ml), 2-butanol (45ml) and 2- bromo-6-nitrophenol (19.39g, 88.92 mmol). A solution of potassium carbonate (23.41 g, 169.37 mmol) in water (75ml) was prepared and added to the resulting mixture over 3 hours. The resulting mixture is stirred for 5 hours at a temperature of 23 ⁰ C, while crystallisation was observed to occur. The resulting mixture was filtered, washed with water (2 x 200ml) and a mixture of heptane (85ml) and 2-butanol (22ml). The resulting crystalline solid was dried under vacuum using a nitrogen flow to yield 2-(2-bromo-6-nitrophenoxy)-1 -(3-(1 , 1 ,2,2- tetrafluoroethoxy)phenyl)ethanone (28, 47g; 74.3%) as a white to orange product and was used in the next step without further purification.

¹ HNMR (400MHz, CDCI ₃ ) δ 5.46 (s, 2H), 5.94 (tt, J= 53.00, 2.77 Hz, 1 H), 7.21 (t, J= 8.18Hz, 1 H), 7.45-7.51 (m, 1 H), 7.54 (t, J= 7.93Hz, 1 H); 7.84 (d, J= 8.06Hz, 2H); 7.84-7.85 (m, 1 H); 7.89 (dt, J= 7.62, 1.35Hz, 1 H)

Example 15 8-bromo-3-(3-(1,1,2,2-tetrafluoroethoxy)phenvn-2H-benzorbiri .4loxazine

A 250ml 5-necked flask equipped with an overhead stirrer, thermocouple, addition funnel, nitrogen purge, and condenser was charged with 2-methyltetrahydrofuran (33ml) and 2-(2-bromo-6-nitrophenoxy)-1 -(3- (1 ,1 ,2,2-tetrafluoroethoxy)phenyl)ethanone (5g, 11.06 mmol). The resulting mixture was heated to reflux (temperature 71.5 ⁰ C).

In a separate flask potassium phosphate (7.26g, 33.17 mmol) was dissolved in water (33.17ml). Sodium dithionite (7.93g, 38.70 mmol) was added to the potassium phosphate solution. The resulting mixture was transferred to an addition funnel and added over a period of 2 hours to the 2-(2- bromo-6-nitrophenoxy)-1 -(3-(1 ,1 ,2,2-tetrafluoroethoxy)phenyl)ethanone solution. The resulting mixture was cooled to 2O ⁰ C. The layers were allowed to separate, the aqueous phase was removed and discarded. Water (20ml) and hydrochloric acid 37% solution in water (1 ml) were added to the remaining organic layer. After vigorously stirring for 5 minutes, the layers were allowed to separate, the aqueous phase was removed and discarded. Water (20ml) was added to the organic layer and the resulting mixture vigorously stirred for 5 minutes. The layers were again allowed to separate, the aqueous phase was removed and discarded. The organic layer, containing the title compound was separated and used without further purification or isolation.

Example 16 8-Bromo-3-(3-(1.1.2.2-tetrafluoroethoxy)phenyl)-2H-benzorbin .41oxazine

A 250ml 5-necked hydrogenation flask equipped with an overhead stirrer and thermocouple, was charged with methanol (26ml), 2-(2-bromo-6- nitrophenoxy)-1 -(3-(1 ,1 ,2,2-tetrafluoroethoxy)phenyl)ethanone (3g, 6.63 mmol), vanadium(V)oxide (120.67mg, 0.66mmol) and platinum on carbon (5% wet; 207mg, 0.053mmol). Hydrogen gas was added (0.15 bar) and the resulting mixture was stirred for 2 hours 20 minutes. The resulting mixture was filtered through DECALITE ^® and the filter cake was washed with methanol (10ml). The organic layer containing the title compound was used in the next step without further purification or isolation.

Example 17

1 ,1 ,1 -Trifluoro-3-r3-(S)-r3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenvn-8-(3- trifluoromethoxy-phenyl)-2,3-dihvdro-benzori,41oxazin-4-vn-p ropan-2-one

A 2 L, four neck round bottom flask, equipped with argon inlet, thermocouple and two stoppers, was charged with (S)-1 ,1 ,1-trifluoro-3-[3-(S)- [3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-8-(3-trifluoromethoxy-pheny l)-2,3- dihydro-benzo[1 ,4]oxazin-4-yl]-propan-2-ol (20 g; 33.37 mmol) and dichloromethane (1.00 L), and the resulting mixture chilled to 4 ⁰ C in a water-ice bath. 3,3,3-thacetoxy-3-iodophthalide (21.88 g, 50.05 mmoles) was then added in one portion and resulting mixture stirred at about 0-3 ⁰ C for 1.5 h. The resulting mixture was then removed from the cold bath and stirred for an additional 45 min. The reaction was quenched with saturated sodium bicarbonate (1.5 L) and solid sodium thiosulfate-sesquihydrate (-80 g) and the resulting mixture stirred for 20 min. The aqueous layer was extracted with MTBE (500 mL), the combined organic layers were dried (MgSO ₄ ), and concentrated to yield the title compound as a residue.

Example 18

(S)-1.1.1 -Trifluoro-3-r3-(S)-r3-(1.1.2.2-tetrafluoro-ethoxy)-phenyll- 8-(3- trifluoromethoxy-phenyl)-2,3-dihydro-benzori,41oxazin-4-vn-p ropan-2-ol

and (R)-1.1.1 -Trifluoro-3-r3-(S)-r3-(1.1.2.2-tetrafluoro-ethoxy)-phenyll- 8-(3- trifluoromethoxy-phenyl)-2,3-dihydro-benzori,41oxazin-4-vn-p ropan-2-ol

To a 1 L, three neck, round bottom flash, equipped with argon inlet, magnetic stirrer, thermocouple, and stopper was charged a solution of 1 ,1 ,1 - trifluoro-a-p-tSMa-ti .i ^^-tetrafluoro-ethoxy^phenyll- ^β -ta-trifluoromethoxy- phenyl)-2,3-dihydro-benzo[1 ,4]oxazin-4-yl]-propan-2-one, prepared as in Example 17 above (25.1 g; 33.88 mmol), methanol (290 ml_), and tetrahydrofuran (65 ml_). The resulting solution was chilled to O ⁰ C in a water/ice bath and then sodium tetrahydroborate (5.83 g, 152.46 mmoles) was added in one portion (an exotherm to 26 ⁰ C, and a color change from orange to light yellow were observed). The resulting mixture was stirred at about 0-3 ⁰ C for 2.5 min and then an additional charge of sodium tetrahydroborate (0.65 g, 16.94 mmoles) was added. The resulting mixture was removed from ice bath and stirred for an additional 45 min, the reaction was quenched with water (700 ml_), and the resulting mixture extracted with MTBE (2 x 400 ml_). The

combined organics were washed with brine (2 x 200 ml_), dried (MgSO ₄ ), and concentrated to yield a mixture of the two title compounds as a residue, which mixture was purified and separated by silica gel chromatography to yield the each of the two title compounds as residues.

By isolated weight, the ratio of diastereomers (S ₁ S) : (R ₁ S) diastereomer (as prepared in this example) was approximately 1 :2.

Example 19 - Prophetic Example Oral Formulation

As a specific embodiment of an oral composition, 100 mg of the compound prepared as in Example 5 (also known as (S)-1 ,1 ,1 -thfluoro-3-((f?)- 2-(3-(1 ,1 ,2,2-tetrafluoroethoxy)phenyl)-5-(3-(trifluoromethoxy)phenyl )-3,4- dihydroquinolin-1 (2H)-yl)propan-2-ol) is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.

Example 20 - Prophetic Example Oral Formulation

As a specific embodiment of an oral composition, 100 mg of the compound prepared as in Example 13 (also known as (S)-1 ,1 ,1 -Trifluoro-3-[3- (S)-[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-8-(3-thfluoromethoxy-phenyl )-2,3- dihydro-benzo[1 ,4]oxazin-4-yl]-propan-2-ol) is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.