WO2008141077A1 - Procédé de préparation de dérivés de tétrahydroquinolinyle, de benzoxazine et de benzothiazine - Google Patents

Procédé de préparation de dérivés de tétrahydroquinolinyle, de benzoxazine et de benzothiazine Download PDF

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Publication number
WO2008141077A1
WO2008141077A1 PCT/US2008/063035 US2008063035W WO2008141077A1 WO 2008141077 A1 WO2008141077 A1 WO 2008141077A1 US 2008063035 W US2008063035 W US 2008063035W WO 2008141077 A1 WO2008141077 A1 WO 2008141077A1
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formula
compound
alkyl
yield
reacting
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PCT/US2008/063035
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English (en)
Inventor
Kirk L. Sorgi
Fuqiang Liu
Yanping Chen
Hongfeng Chen
Mitul N. Patel
Xun Li
Aihua Wang
Scott A. Ballentine
Derek A. Beauchamp
John-Michael Macphee
Thomas Joachim Landewald Rammeloo
Tim Joeri Vanhoegaerden
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Janssen Pharmaceutica N.V.
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Priority to TW097117071A priority Critical patent/TW200911268A/zh
Priority to ARP080101983A priority patent/AR066519A1/es
Priority to CL2008001377A priority patent/CL2008001377A1/es
Publication of WO2008141077A1 publication Critical patent/WO2008141077A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring

Definitions

  • 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).
  • CETP cholesteryl ester transfer protein
  • 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.
  • CETP cholesteryl ester transfer protein
  • HDL cardioprotective High Density Lipoprotein
  • VLDL Very Low Density Lipoprotein
  • 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).
  • BPI Bacillicidal/permeability increasing protein
  • 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.
  • HDL-C HDL cholesterol
  • the CETP concentration is around 1 -3 ⁇ g/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.
  • 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 present invention is directed to a process for the preparation of a compound of formula (I)
  • 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
  • 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,
  • Z 1 is selected from the group consisting of hydrogen and bromo; or a chiral catalyst of the formula (C-S)
  • 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;
  • the present invention is further directed to a process for the preparation of a compound of formula (I)
  • 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
  • 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,
  • the present invention is directed to a process for the preparation of the compound of formula (I-S)
  • 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);
  • Z 1 is selected from the group consisting of hydrogen and bromo; and the compound of formula (C-S)
  • 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).
  • the present invention is directed to a process for the preparation of a compound of formula (I-S)
  • 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);
  • the present invention is further directed to a process for the preparation of compounds of formula (II)
  • 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
  • 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, diastere
  • Z 1 is selected from the group consisting of hydrogen and bromo; or with a chiral catalyst of the formula (C-S)
  • 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%;
  • 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
  • the present invention is further directed to a process for the preparation of a compound of formula (M-S) (M-S)
  • 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%;
  • the present invention is further directed to a process for the preparation of a compound of formula (M-S)
  • 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.
  • the present invention is directed to processes for the preparation of the compound of formula (XII-S)
  • the present invention is further directed to processes for the preparation of the compounds of formula (XXIII)
  • the present invention is further directed to processes for the preparation of the compounds of formula (XXXII)
  • 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).
  • 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 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.
  • 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),
  • 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.
  • 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)
  • the present invention is directed to processes for the preparation of compound of formula (II)
  • the present invention is directed to processes for the preparation of the compound of formula (I-S)
  • 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.
  • dyslipidemia including hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, and hypo- HDL-cholesterolemia
  • hyper-LDL-cholesterolemia hyperbetaliproteinemia hypoalphalipoproteinemia
  • familial-hypercholesterolemia familial-hypercholesterolemia
  • cardiovascular disorders angina
  • 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.
  • M-S compound of formula (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 ,
  • 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.
  • dyslipidemia including hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, and hypo-HDL-cholesterolemia
  • hyper-LDL-cholesterolemia hyperbetaliproteinemia hypoalphalipoproteinemia
  • familial- hypercholesterolemia familial- hypercholesterolemia
  • cardiovascular disorders angina, isch
  • 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.
  • 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.
  • 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.
  • 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)
  • 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.
  • the present invention is directed to processes for the preparation of the compound of formula (XII-S)
  • the present invention is further directed to processes for the preparation of the compounds of formula (XXIII)
  • the present invention is further directed to processes for the preparation of the compounds of formula (XXXII)
  • the present invention features a compound of Formula (I) wherein m is O.
  • the present invention features a compound of Formula (I) wherein n is 1 or 2.
  • the present invention features a compound of Formula (I) wherein Li is a covalent bond.
  • the present invention features a compound of Formula (I) wherein Q 1 is phenyl.
  • the present invention features a compound of Formula (I) wherein Qi is thienyl or pyridinyl.
  • 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.
  • 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
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • 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
  • the present invention is directed to a compound of
  • the present invention is directed to a compound of Formula (I) as shown above wherein m is 0, and R 4 is -CF 3 .
  • 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-
  • 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,
  • Ri is Ci- ⁇ alkyl or C 3- iocycloalkyl, preferably -CH 2 CH 3 or
  • 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;
  • Ri is 5- or 6-membered heteroaryl, preferably ⁇ - J ;
  • Qi is C 6- IO aryl, and preferably Q1 is phenyl
  • Qi is 5- or 6-membered heteroaryl; preferably thienyl, oxazolyl, thiazolyl, isoxazolyl, pyridinyl, and pyridazinyl; and more preferably thienyl and pyridinyl;
  • 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 ;
  • n O, 1 , or 2;
  • 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;
  • 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,
  • 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.
  • 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 ,
  • 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
  • R 4 is
  • the compounds of formula (I) are compounds of Formula (Ia):
  • 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 al
  • 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.
  • the present invention features a compound of Formula (Ia) wherein m is O.
  • the present invention features a compound of Formula (Ia) wherein n is 1 or 2.
  • the present invention features a compound of Formula (Ia) wherein Li is a covalent bond.
  • the present invention features a compound of Formula (Ia) wherein Qi is phenyl.
  • the present invention features a compound of Formula (Ia) wherein Qi is thienyl or pyridinyl.
  • 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.
  • 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
  • Ri is phenyl substituted with -OCF 2 CF 2 H, -CF 3 , or -OCF 3
  • 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
  • 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.
  • 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.
  • 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.
  • 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!
  • R 4 is halogenated Ci -2 alkyl optionally substituted with hydroxy, Ci -4 alkoxy, oxo, or cyano.
  • 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.
  • 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
  • the present invention is directed to a compound of
  • the present invention is directed to a compound of Formula (Ia) as shown above wherein m is 0, and R 4 is -CF 3 .
  • 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 alk
  • 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
  • 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 ,
  • R 1 is d- ⁇ alkyl or C 3-1 ocycloalkyl, preferably -CH 2 CH 3 or
  • 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;
  • R 1 is phenyl
  • Ri is 5- or 6-membered heteroaryl, preferably ⁇ - J ;
  • Qi is a heteroaryl selected from the group consisting of thienyl, oxazolyl, thiazolyl, isoxazolyl, pyridinyl, and pyridazinyl; and more preferably thienyl and pyridinyl;
  • 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 ;
  • n O, 1 , or 2;
  • 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;
  • 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.
  • 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 ,
  • 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
  • Q1 is phenyl., , or .
  • the present invention is further directed to a compound of Formula (Ia) wherein
  • n 1 , 2, or 3;
  • R 1 is -CH 2 CH 3 , , or phenyl;
  • Q 1 is phenyl or naphthalenyl;
  • Qi is phenyl;
  • Qi is a selected from the group consisting of thienyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, and pyridizinyl;
  • R 2 is -0-CF 3 ;
  • R 2 is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 ;
  • R 2 is -O-CH(CH 3 ) 2 , F, Cl, Or -CF 3 ;
  • R 2 is -0-CH 3 , -0-CF 3 , or -O-CH(CH 3 ) 2 ;
  • R 4 is Ci -3 alkyl optionally substituted with 1 or 2 members independently selected from oxo, hydroxy, and — O- CH 3 ;
  • R 4 is halogenated Ci -2 alkyl optionally substituted with oxo, hydroxy, or -0-CH 3 ;
  • R 4 is -CF 3 ;
  • R 4 is -CH 2 CF 3 ;
  • R 4 is -CH(CH 3 ) 2 ; O
  • n 1
  • L 1 is a bond
  • Q 1 is phenyl
  • R 1 is or
  • R 2 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 ,
  • (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.
  • the compounds of formula (I) are compounds of Formula (Ib):
  • 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
  • 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.
  • 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.
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • 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!
  • R 4 is halogenated Ci -2 alkyl optionally substituted with hydroxy, Ci -4 alkoxy, oxo, or cyano.
  • 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.
  • Ri is Ci -6 alkyl or C 3- i 0 cycloalkyl, preferably -CH 2 CH 3 or
  • 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;
  • Ri is 5- or 6-membered heteroaryl, preferably ⁇ —- ⁇ ;
  • 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 ;
  • 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;
  • 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.
  • 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.
  • the present invention is directed to a compound of Formula (Ic) wherein R 2a is absent or halo, preferably R 2a is absent.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ..
  • 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.
  • 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.
  • the present invention is directed to a compound of Formula (I) selected from the group consisting of:
  • the present invention is directed to a compound of Formula (I) selected from the group consisting of
  • the present invention is directed to a compound of Formula (I) selected from the group consisting of
  • the present invention features a compound of Formula (II) wherein q is O.
  • the present invention features a compound of Formula (II) wherein p is 1 or 2.
  • the present invention features a compound of Formula (II) wherein L 2 is a covalent bond.
  • the present invention features a compound of Formula (II) wherein Q 2 is phenyl.
  • the present invention features a compound of Formula (II) wherein Q 2 is thienyl or pyridinyl.
  • the present invention features a compound of Formula (II) wherein X is O.
  • 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.
  • 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.
  • 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
  • the present invention features a compound of Formula (II) wherein Rn is d- ⁇ alkyl substituted with hydroxy, Ci -4 alkoxy, oxo, halo, or cyano.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • the present invention is directed to a compound of
  • the present invention is directed to a compound of Formula (II) as shown above wherein q is 0, and Ri 4 is -CF 3 .
  • 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;
  • 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.
  • 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.
  • Rn is Ci -6 alkyl substituted with hydroxy, oxo, or Ci -3 alkoxy;
  • Rn is thienyl optionally substituted with Ci -3 alkyl or Ci -3 alkoxy;
  • 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,
  • Rn is optionally substituted 5- or 6-membered heteroaryl, preferably,
  • Q 2 is C ⁇ -io aryl, and preferably Q 2 is phenyl;
  • Q 2 is 5- or 6-membered heteroaryl; preferably thienyl, oxazolyl, thiazolyl, isoxazolyl, pyridinyl, and pyridazinyl; and more preferably thienyl and pyridinyl;
  • 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;
  • R 14 is -C(O)O-Ci -4 alkyl, preferably -C(O)O-CH 3 or -C(O)O-CH 2 CH 3 ;
  • 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 ,
  • 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.
  • 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
  • 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.
  • the present invention features a compound of Formula (Ma) wherein X is O.
  • the present invention features a compound of Formula (Ma) wherein q is O.
  • the present invention features a compound of Formula (Ma) wherein p is 1 or 2.
  • the present invention features a compound of Formula (Ma) wherein L 2 is a covalent bond.
  • the present invention features a compound of Formula (Ma) wherein Q 2 is phenyl.
  • the present invention features a compound of Formula (Ma) wherein Q 2 is thienyl or pyridinyl.
  • 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.
  • 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
  • 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.
  • 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.
  • Rn is furanyl or thienyl optionally substituted with Ci- 3 alkyl, Ci -3 alkoxy, hydroxy, or cyano.
  • 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 .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • the present invention is directed to a compound of Formula (Ma) as shown above, wherein
  • the present invention is directed to a compound of Formula (Ma) as shown above, wherein
  • the present invention is directed to a compound of Formula (Ma) as shown above wherein q is 0, and Ri 4 is -CF 3 .
  • 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
  • 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.
  • the present invention is directed to a compound of Formula (Na) as shown above wherein:
  • Rn is Ci- ⁇ alkyl substituted with hydroxy, oxo, or Ci-3alkoxy;
  • Rn is thienyl optionally substituted with Chalky! or Ci-3alkoxy
  • 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,
  • Rn is optionally substituted 5- or 6-membered heteroaryl, preferably,
  • Q 2 is thienyl, oxazolyl, thiazolyl, isoxazolyl, pyridinyl, and pyridazinyl; and more preferably thienyl and pyridinyl;
  • 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;
  • R 14 is -C(O)O-Ci -4 alkyl, preferably -C(O)O-CH 3 or -C(O)O-CH 2 CH 3 ;
  • 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,
  • 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 ,
  • 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.
  • 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 ,
  • the present invention is further directed to a compound of Formula (Ma) wherein
  • (C) p is 1 , 2, or 3;
  • R 11 is -CH 2 CH 3 , u ⁇ , or phenyl; (o) R 11 Js -CH 2 CH 2 CH 2 OH;
  • Q 2 is phenyl or naphthalenyl; (s) Q 2 is phenyl;
  • Q 2 is a selected from the group consisting of thienyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, and pyridizinyl;
  • Ri 2 is -0-CF 3 ;
  • R 12 is -CF 3 (CC) Ri 2 is F;
  • Ri 2 is -CH 3 , -CH 2 CH 3, or -CH(CH 3 ) 2 ;
  • Ri 2 is -C(O)H, CN, OH,
  • Rif) is -O-CH(CH 3 ) 2j F, Cl, Or -CF 3 ;
  • R 12 is -0-CH 3 , -0-CF 3 , or -O-CH(CH 3 ) 2 ;
  • 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
  • Ri 4 is Ci -3 alkyl substituted with substituted heterocyclyl selected from
  • Ri 4 is halogenatedCi -2 alkyl optionally substituted with oxo, hydroxy, or -0-CH 3 ;
  • R 14 is -CF 3 ;
  • R 14 is -CH 2 CH 3 , or -CH 2 CH 2 CH 3 ;
  • R 14 is -CH 2 CI or R 14 is -CF 3 ;
  • 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
  • each Ri 2 is independently selected from F, -CF 3 , and -0-CF 3 ;
  • the compounds of formula (II) are compounds of Formula (Mb):
  • 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 al
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • Rn is furanyl or thienyl optionally substituted with Ci- salkyl, Ci -3 alkoxy, hydroxy, or cyano.
  • 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 .
  • 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.
  • 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.
  • the present invention features a compound of Formula (Mb) wherein Ri 4 is C h alky!
  • 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.
  • 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.
  • 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.
  • Rn is Ci- ⁇ alkyl substituted with hydroxy, oxo, or Ci -3 alkoxy
  • Rn is thienyl optionally substituted with Ci -3 alkyl or Ci -3 alkoxy;
  • 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;
  • Rn is phenyl
  • Rn is an optionally substituted 5- or 6-membered heteroaryl
  • 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 ;
  • Ri 4 is -C(O)O-Ci -4 alkyl, preferably -C(O)O-CH 3 or -C(O)O-CH 2 CH 3 ;
  • 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,
  • 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 ,
  • 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.
  • the compounds of formula (II) are compounds of Formula (lie):
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 .
  • 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.
  • the present invention is directed to a compound of Formula (II) selected from the group consisting of:
  • the present invention is directed to a compound of Formula (II) selected from the group consisting of
  • the present invention is directed to a compound of Formula (II) selected from the group consisting of
  • substituted refers to a radical in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • halogen 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.
  • alkoxy refers to an -Oalkyl substituent group, wherein alkyl is defined supra.
  • 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.
  • 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.
  • 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.
  • halo F, Cl, Br, or I
  • oxo oxo
  • cyano amino, alkoxy, cycloalkyl, carboxy, hydroxy, heterocyclyl, and halogenatedalkyl
  • one group selected from optionally substituted aryl and optionally substituted heteroaryl selected from optionally substituted aryl and optionally substituted hetero
  • 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.
  • 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.
  • phthalimide and saccharin are examples of compounds with oxo substituents.
  • 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.
  • the aryl ring is a C 6- ioaryl.
  • Ph when used herein refers to phenyl.
  • 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.
  • arylalkyl means an alkyl group substituted with an aryl group (e.g., benzyl, phenylethyl, naphthylmethyl).
  • arylalkoxy indicates an alkoxy group substituted with an aryl group (e.g., benzyloxy).
  • the alkyl moiety of the arylalkyl group is (Ci-3) and the aryl moiety is (C ⁇ -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.
  • 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.
  • the "heterocyclyl” or “heterocycle” can be substituted with, one, two or three groups independently selected from Ci- ⁇ alkyl, halogenatedd- ⁇ alkyl, 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
  • 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.
  • 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.
  • the heteroaryl ring contains one member of nitrogen, oxygen or sulfur and, in addition, may contain up to three additional nitrogens.
  • the heteroaryl ring may contain from one to three nitrogen atoms.
  • 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.
  • the point of attachment is through the heteroaryl ring portion of the compound.
  • 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, quinoxal
  • 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.
  • 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., CrC ⁇
  • 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.
  • d- ⁇ 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.).
  • phenylCr C 6 alkylaminocarbonylCi-C 6 alkyl refers to a group of the formula
  • DIPEA or DIEA Diisopropylethylamine DMF N,N-Dimethylformamide EtOAc Ethyl Acetate HFIPA Hexafluoroisopropyl alcohol HPLC High Pressure Liquid Chromatography
  • 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.
  • the compounds according to this invention 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.
  • 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%.
  • 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%.
  • 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.
  • 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.
  • 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.
  • subject refers to an animal, preferably a mammal, most preferably a human, who is the object of treatment, observation or experiment.
  • terapéuticaally effective amount 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.
  • reaction step(s) is performed under suitable conditions, according to known methods, to provide the desired product.
  • reagent or reagent class/type e.g. base, solvent, etc.
  • the individual reagents are independently selected for each reaction step and may be the same of different from each other.
  • 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.
  • 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.
  • 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.
  • 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.
  • prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound.
  • 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.
  • 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.
  • 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.
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands e.g., quaternary ammonium salts.
  • 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, ole
  • 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-glu
  • the present invention is directed to processes for the preparation of compounds of formula (I), as described in more detail in Scheme 1 , below.
  • 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, T
  • the compound of formula (VII) is not isolated.
  • 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
  • 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
  • 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).
  • 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)
  • a suitably selected source of hydride such as diludine
  • 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,
  • 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.
  • 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
  • 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)-
  • 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).
  • a catalyst such as iridium, Pd/C, Pt, and the like, preferably iridium
  • an organic solvent such as ethanol, methanol, isopropanol, and the like
  • 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).
  • 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 (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.
  • 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.
  • 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
  • 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
  • the compound of formula (VII-S) is not isolated.
  • 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
  • transient intermediate may be prepared as a transient intermediate, which intermediate is preferably not isolated.
  • 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).
  • 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
  • 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
  • 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.
  • the compound of formula (X-S) also known as 2-[3- (1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-5-(3-trifluoromethoxy-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 of about 2.5 molar equivalents; in the presence of a chirality
  • 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)-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-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
  • 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).
  • a catalyst such as iridium, Pd/C, Pt, and the like, preferably iridium
  • an organic solvent such as ethanol, methanol, isopropanol, and the like
  • 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).
  • 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 (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.
  • transient intermediate 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)
  • 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)
  • 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
  • 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 (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
  • 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, DI
  • 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
  • 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.
  • 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.
  • transient intermediate may be 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)
  • 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)
  • 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
  • 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 (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
  • 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 , aque
  • 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
  • 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.
  • 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.
  • 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).
  • a suitably selected source of bromine such as bromine gas, N- bromosuccinimide, and the like, preferably bromine gas
  • 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 (XXV
  • 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).
  • LG 5 is
  • 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
  • transient intermediate may be prepared as a transient intermediate, which intermediate is preferably not isolated.
  • the present invention is directed to a process for the preparation of a compound of formula (XXXII-A), as outlined in Scheme 6 below.
  • 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).
  • a suitably selected source of bromine such as bromine gas, N-bromosuccinimide, and the like, preferably bromine gas
  • 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).
  • a compound of formula (XXX-A) also known as 2-bromo-6-nitrophenol
  • 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
  • a suitably substituted compound of formula (XXXI-A) is reacted to yield the corresponding compound of formula (XXXII-A)
  • stereo-center denoted by the arrow is in the (S) configuration
  • 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.
  • 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.
  • 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.
  • 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.
  • stereo-center inter- conversion methods are described for the synthesis of a compound of formula (N-S).
  • N-S a compound of formula
  • 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.
  • the compound of formula (N-S) may be prepared from the corresponding 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.
  • 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 process comprising the
  • 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.
  • a suitably selected reagent such as potassium benzoate, and the like
  • 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)
  • 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.
  • 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.
  • XRD powder X-ray diffraction
  • the spectra was scanned 3° to 40° in 2 ⁇ using a scan rate of 3° in 2 ⁇ /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.
  • 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)
  • 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 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 ⁇ l_ 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).
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
  • 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.
  • 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.
  • a pharmaceutical 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.
  • any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • a pharmaceutical carrier e.g.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • 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
  • 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.
  • 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.
  • 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.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • 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.
  • suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like.
  • sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • a pharmaceutical 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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)
  • 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.
  • 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.
  • diludine 877 g, 3.46 mol
  • 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 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]- ⁇ -(trifluoromethyl)- 1 (2H)-quinolineethanol).
  • the crude oil may be further, optionally converted to its corresponding tosylate salt and /or further recrystallized.
  • Example 7 The crude oil may be further, optionally converted to its corresponding tosylate salt and /or further recrystallized.
  • 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.
  • 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.
  • 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).
  • reaction mixture was observed to change color from a yellow-orange to a red-orange.
  • 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.
  • 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), ⁇ - 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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_).
  • 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.
  • 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.

Abstract

L'invention concerne un nouveau procédé de préparation de dérivés de tétrahydroquinolinyle utilisés dans le traitement de troubles et états modulés par la protéine de transfert des esters de cholestéryle (CETP).
PCT/US2008/063035 2007-05-10 2008-05-08 Procédé de préparation de dérivés de tétrahydroquinolinyle, de benzoxazine et de benzothiazine WO2008141077A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
TW097117071A TW200911268A (en) 2007-05-10 2008-05-09 Process for the preparation of tetrahydroquinolinyl derivatives
ARP080101983A AR066519A1 (es) 2007-05-10 2008-05-09 Proceso para la preparacion de derivados de tetrahidroquinolinilo
CL2008001377A CL2008001377A1 (es) 2007-05-10 2008-05-09 Proceso para la preparacion de compuestos derivados de tetrahidroquinolinilo.

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US91713507P 2007-05-10 2007-05-10
US60/917,135 2007-05-10

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CN115448876A (zh) * 2022-09-16 2022-12-09 哈尔滨工业大学（深圳） 一种喹啉不对称转移氢化方法

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Publication number Priority date Publication date Assignee Title
CN115448876A (zh) * 2022-09-16 2022-12-09 哈尔滨工业大学（深圳） 一种喹啉不对称转移氢化方法
CN115448876B (zh) * 2022-09-16 2023-10-31 哈尔滨工业大学（深圳） 一种喹啉不对称转移氢化方法

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