Classifications

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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
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  • A61K31/4164—1,3-Diazoles
  • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
  • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
  • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/433—Thidiazoles
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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  • A61K31/4965—Non-condensed pyrazines
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  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
  • C07F7/02—Silicon compounds
  • C07F7/08—Compounds having one or more C—Si linkages
  • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
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  • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
  • C07F7/02—Silicon compounds
  • C07F7/08—Compounds having one or more C—Si linkages
  • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
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  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members

Definitions

• This invention relates to a class of chemical compounds that inhibit cholesterol ester transfer protein (CETP) and therefore may have utility in the treatment and prevention of atherosclerosis.
• CETP cholesterol ester transfer protein
• CHD coronary heart disease
• stroke and peripheral vascular disease represent a truly enormous burden to the health care systems of the industrialized world.
• CHD coronary heart disease
• stroke and peripheral vascular disease represent a truly enormous burden to the health care systems of the industrialized world.
• CHD coronary heart disease
• stroke and peripheral vascular disease represent a truly enormous burden to the health care systems of the industrialized world.
• CHD coronary heart disease
• stroke and peripheral vascular disease represent a truly enormous burden to the health care systems of the industrialized world.
• CHD coronary heart disease
• HMG-CoA Reductase inhibitors especially the statins
• LDL-C Low Density Lipoprotein cholesterol
• epidemiologic studies have demonstrated an inverse relationship between High Density Lipoprotein cholesterol (HDL-C) levels and atherosclerosis, leading to the conclusion that low serum HDL-C levels are associated with an increased risk for CHD.
• cholesteryl ester transfer protein a plasma glycoprotein that catalyzes the movement of cholesteryl esters from HDL to the apoB containing lipoproteins, especially VLDL (see Hesler, CB. , et. al. (1987) Purification and characterization of human plasma cholesteryl ester transfer protein. J. Biol. Chem. 262(5), 2275-2282)).
• CETP cholesteryl ester transfer protein
• VLDL cholesteryl ester transfer protein
• CETP plays a role in reverse cholesterol transport, the process whereby cholesterol is returned to the liver from peripheral tissues, hitriguingly, many animals do not possess CETP, including animals that have high HDL levels and are known to be resistant to coronary heart disease, such as rodents (see Guyard-Dangremont, V., et. al., (1998) Phospholipid and cholesteryl ester transfer activities in plasma from 14 vertebrate species. Relation to atherogenesis susceptibility, Comp. Biochem. Physiol. B Biochem. MoI. Biol. 120(3), 517-525).
• statins such as simvastatin (ZOCOR®) represent
• statins only achieve a risk reduction of approximately one-third in the treatment and prevention of atherosclerosis and ensuing atherosclerotic disease events.
• few pharmacologic therapies are available that favorably raise circulating levels of HDL-C.
• Certain statins and some fibrates offer modest HDL-C gains.
• Niacin which provides the most effective therapy for raising HDL-C that has been clinically documented, suffers from patient compliance issues, due in part to side effects such as flushing.
• An agent that safely and effectively raises HDL cholesterol levels can answer a significant, but as yet unmet medical need by offering a means of pharmacologic therapy that can significantly improve circulating lipid profiles through a mechanism that is complementary to existing therapies.
• Compounds having Formula I including pharmaceutically acceptable salts of the compounds, are CETP inhibitors, having the utilities described below:
• X is selected from -O-, -NH-, -N(Ci-C5alkyl)-, and -(CRR 6 )-;
• R9 is selected from the group consisting of H,-CN, and -C ⁇ -C5alkyl optionally substituted with 1-11 halogens;
• Each R is independently selected from the group consisting of H, -C1-C5 alkyl, and halogen, wherein -C1-C5 alkyl is optionally substituted with 1-11 halogens;
• B is selected from the group consisting of Al and A2, wherein Al has the structure:
• Rl and R ⁇ are each independently selected from H, -C1-C5 alkyl, halogen, and -(C(R)2)nA2, wherein -C1-C5 alkyl is optionally substituted with 1-11 halogens;
• R2 is selected from the group consisting of H, -C1-C5 alkyl, halogen, Al, and -(C(R)2)nA ⁇ , wherein -C1-C5 alkyl is optionally substituted with 1-11 halogens;
• one of B and R2 is Al; and one of B, Rl, R2, and R6 is A2 or -(C(R)2) n A 2 ; so that the compound of Formula I comprises one group Al and one group A2;
• A3 is selected from the group consisting of:
• a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6-membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and S, and optionally also having 1-2 double bonds (in addition to the double bond of the fused phenyl ring) wherein the point of attachment of A ⁇ to the phenyl ring to which A ⁇ is attached is a carbon atom;
• A2 is selected from the group consisting of:
• a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6-membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and S, and optionally also having 1-2 double bonds (in addition to the double bond of the fused phenyl ring);
• R5 is selected from the group consisting of H, -OH, -C1-C5 alkyl, and halogen, wherein -C1-C5 alkyl is optionally substituted with 1-11 halogens.
• alkyl, alkenyl, and alkynyl groups can be either linear or branched, unless otherwise stated.
• Still other compounds of the invention have a structure in accordance with Formula Id, or a pharmaceutically acceptable salt thereof:
• R ⁇ and R4 are each independently selected from H and -C1-C3 alkyl.
• p is 0-2.
• R ⁇ and R$ are each independently selected from the group consisting of H, halogen, -NR3R4, -C1-C3 alkyl, -OC1-C3 alkyl, -CN, -NO2, and pyridyl, wherein C1-C3 alkyl in all instances is optionally substituted with 1-3 halogens.
• A2 is optionally substituted with 1-2 substituent groups independently selected from halogen, -C1-C4 alkyl, and -CN, wherein -C1-C4 alkyl is optionally substituted with 1-3 halogens.
• P.? is selected from H, halogen, -NR3R4, -C1-C3 alkyl, -OC1-C3 alkyl, -CN, - NO2, and pyridyl, wherein C1-C3 alkyl in all instances is optionally substituted with 1-3 halogens; and
• R8 is selected from the group consisting of H, halogen, -CH3, -CF3, -OCH3, and -OCF3.
• A3 is phenyl which is optionally substituted with 1-3 substituents independently selected from the group consisting of Cl, F, -C1-C4 alkyl, and -OC1-C4 alkyl, wherein -Ci-C4alkyl and -OC 1-C4 alkyl are optionally substituted with 1-5 F.
• a preferred value of Y is -(CRRl)-.
• R and R ⁇ are each independently selected from the group consisting of H and -C1-C5 alkyl, wherein -C1-C5 alkyl is optionally substituted with 1-11 halogens.
• Rl is selected from the group consisting of H, -C1-C5 alkyl, and -(C(R)2)nA2, wherein -C1-C5 alkyl is optionally substituted with 1-11 halogens.
• one of B and R2 is Al; and one of B, Rl, and R ⁇ is A ⁇ or -(C(R)2)nA.2; so that the compound of Formula I comprises one group Al and one group A ⁇ .
• A3 is selected from the group consisting of:
• a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6-membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and -S(O) x - and optionally
• a ⁇ is selected from the group consisting of: (a) an aromatic ring selected from phenyl and naphthyl; (b) a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N(O)-, and optionally also comprising 1-3 double bonds and a carbonyl group;
• a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6-membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and S and optionally 1-2 double bonds;
• A3 and A ⁇ are each optionally substituted with 1- 4 substituent groups independently selected from R a .
• n is an integer from 0-2. In other subgroups, n is 1 or 2.
• R3 and R4 are each independently selected from H and -C1-C5 alkyl, wherein -C1-C5 alkyl in all instances is optionally substituted with 1-11 halogens.
• R3 and R.4 each independently selected from H and -C1-C3 alkyl, or from H and -C1-C2 alkyl.
• R.9 is selected from the group consisting of H, -CN, and CH3.
• R5 is selected from the group consisting of H, -OH, and -Cl- C5 alkyl, wherein -C1-C5 alkyl is optionally substituted with 1-11 halogens.
• R.5 is selected from H and -C1-C3 alkyl, or from H and -C1-C2 alkyl.
• each R is independently selected from the group consisting of H and C1-C3 alkyl. In other groups, R is selected from H and C1-C2 alkyl. In other groups, R is H or CH3
• R ⁇ is selected from the group consisting of H and -C1-C3 alkyl, wherein C1-C3 alkyl is optionally substituted with 1-5 halogens.
• R6 is selected from H and C1-C2 alkyl. In other groups, R6 is H or CH3,
• Rl is selected from the group consisting of H, -C1-C3 alkyl, and -(C(R)2) H A2, wherein -C1-C3 alkyl is optionally substituted with 1-5 halogens; and R2 is selected from the group consisting of H, -C1-C3 alkyl, Al, and -(C(R)2)nA2, wherein -C1-C3 alkyl is optionally substituted with 1-5 halogens, and R6 is H or alkyl.
• one of B and R2 is Al; and one of B, Rl, and R2 is A2 or -(C(R)2)nA2; SO that the compound of Formula I comprises one group Al and one group A2.
• A3 is selected from the group consisting of:
• a benzoheterocyclic ring comprising a phenyl ring fused to a 5-membered aromatic heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and -S(O) x , wherein the point of attachment of A3 to the phenyl ring to which A3 is attached is a carbon atom.
• A2 is selected from:
• a benzoheterocyclic ring comprising a phenyl ring fused to a 5-membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and S; and (d) a -C5-C6 cycloalkyl ring.
• A3 and A ⁇ are each optionally substituted with 1-4 substituent groups independently selected from R a .
• A3 is optionally substituted with 1-3 substituents R a , or with 2-3 substituents R a .
• a ⁇ is optionally substituted with 1-3 substituents R a , or with 1-2 substituents R a .
• a 2 is substituted with 2 substituents R a , or with 2-3 substituents R a .
• A3 is selected from the group consisting of phenyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, pyridyl, N-oxido-pyridyl, thiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzothienyl, benzothienyl-S-oxide, and benzothienyl-S-dioxide.
• A2 is selected from the group consisting of phenyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, pyrazolyl, 1,2,4-triazolyl, tetrazolyl, benzodioxolyl, pyridyl, N-oxido- pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, cyclopentyl, cyclohexyl, and tetrahydropyranyl.
• X is selected from the group consisting of -0-, -NH-, and -N(Ci- C3alkyl)-. X may also be selected from the group consisting of -0-, -NH-, and -N(CH3). In highly preferred subsets, X is O.
• a preferred subgroup of compounds has Formula Ie, including pharmaceutically acceptable salts thereof B
• X is selected from the group consisting of -O-, -NH-, -N(Ci-C5alkyl)- and -(CH2)-;
• Each R is independently selected from the group consisting of H and -CH3;
• Al has the structure:
• Rl is selected from the group consisting of H, -C1-C5 alkyl, and -(C(R)2)nA 2 , wherein -C1-C5 alkyl is optionally substituted with 1-11 halogens;
• R2 is selected from the group consisting of H, -C1-C5 alkyl, Al, and -(C(R)2)nA 2 , wherein -Ci-Csalkyl is optionally substituted with 1-11 halogens;
• one of B and R 2 is A 1 ; and one of B, Rl, and R 2 is A 2 or -(C(R)2) n A 2 ; so that the compound of Formula Ie comprises one group Al and one group A 2 ;
• a 2 is selected from the group consisting of phenyl, cyclohexyl, and pyridyl, wherein A 2 is optionally substituted with 1-2 substituent groups independently selected from halogen, -C1-C4 alkyl, and -CN, wherein -C1-C4 alkyl is optionally substituted with 1-3 halogens;
• Each R a is independently selected from the group consisting of -C1-C3 alkyl and halogen, wherein -C1-C3 alkyl is optionally substituted with 1-3 halogens;
• Each Rb is independently selected from the group consisting of Cl, F, -C1-C4 alkyl, and -OC1-C4 alkyl, wherein -Q-C4 alkyl and -OC1-C4 alkyl are optionally substituted with 1-5 F; n is 0 or 1; p is an integer from 0-2; and q is an integer from 0-3.
• Subsets of compounds having formula Ie include compounds of formula If, Ig, and Ih, and pharmaceutically acceptable salts thereof:
• Rl and R.2 are each independently selected from H and -C1-C5 alkyl, wherein -C1-C5 alkyl is optionally substituted with 1-11 halogens.
• Other groups are as defined previously.
• a ⁇ may be selected from the group consisting of phenyl, cyclohexyl, and pyridyl, wherein A ⁇ is optionally substituted with 1-2 substituent groups independently selected from halogen, -CH3 -CF3 , and -CN.
• each R a independently is selected from the group consisting of -CF3 and CL
• each Rb is independently selected from the group consisting of -C1-C3 alkyl, -OCH3, and F.
• Rl and R ⁇ are each independently selected from the group consisting of H and -C1-C2 alkyl.
• X is selected from -O-, -NH-, -N(CH3)-, and -CH2- .
• p is 1. In subsets of the compounds described above, q is 2 or 3.
• a subset of compounds defined previously comprises compounds having formula Ii, and pharmaceutically acceptable salts thereof:
• R7 is selected from the group consisting of Cl and -CF3 ;
• R c is selected from the group consisting of halogen, -CH3 -CF3 , and -CN; and t is an integer from 0-2.
• Other groups are as defined previously.
• a subset of compounds defined previously comprises compounds having formula Ij, or a pharmaceutically acceptable acceptable salt thereof:
• R c is selected from the group consisting of halogen, -CH3 -CF3 , and -CN; and t is an integer from 0-2.
• Other groups are as defined previously.
• Alkyl means saturated carbon chains which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise.
• alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.
• Alkylene groups are alkyl groups that are difunctional rather than monofunctional. For example, methyl is an alkyl group and methylene (-CH2-) is the corresponding alkylene group.
• alkenyl means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
• Alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-l-pentynyl, 2-heptynyl and the like.
• Cycloalkyl means a saturated carbocyclic ring having from 3 to 8 carbon atoms, unless otherwise stated (e.g., cycloalkyl may be defined as having one or more double bonds). The term also includes a cycloalkyl ring fused to an aryl group. Examples of cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. "Cycloalkenyl” means a non-aromatic carbocyclic ring having one or more double binds.
• Aryl when used to describe a substituent or group in a structure means a monocyclic or bicyclic compound in which the rings are aromatic and which contains only carbon ring atoms.
• aryl can also refer to an aryl group that is fused to a cycloalkyl or heterocycle.
• Preferred "aryls” are phenyl and naphthyl. Phenyl is generally the most preferred aryl group.
• EDC is l-ethyl-B- ⁇ -dimethylaminopropy ⁇ carbodiimide.
• Heterocyclyl means a fully or partially saturated or aromatic 5-6 membered ring containing 1-4 heteroatoms independently selected from N, S and O, unless otherwise stated.
• Benzoheterocycle represents a phenyl ring fused to a 5-6-membered heterocyclic ring having 1-2 heteroatoms, each of which is O, N, or S, where the heterocyclic ring may be saturated or unsaturated. Examples include indole, benzofuran, 2,3-dihydrobenzofuran and quinoline.
• DIPEA diisopropylethylamine
• Halogen includes fluorine, chlorine, bromine and iodine.
• HBT 1-Hydroxybenzotriazole
• IPAC is isopropyl acetate
• Weight amine is N,O-dimethylhydroxylamine.
• composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
• pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
• tetrazole means a 2H-tetrazol-5-yl substituent group and tautomers thereof.
• Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
• the present invention is meant to include all such isomeric forms of the compounds of Formula I and all mixtures of the compounds.
• structures are shown with a stereochemical representation, other stereochemical structures are also included individually and collectively, such as enantiomers, diastereoisomers (where diastereomers are possible), and mixtures of the enantiomers and/or diastereomers, including racemic mixtures.
• Some of the compounds described herein may contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers. Some of the compounds described herein may exist as tautomers. An example is a ketone and its enol form, known as keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of Formula I.
• enantiomers and other compounds with chiral centers may be synthesized by stereospecific synthesis using optically pure starting materials and/or reagents of known configuration.
• biphenyl and biaryl compounds herein are observed as mixtures of atropisomers (rotamers) in the NMR spectra.
• the individual atropisomers as well as mixtures thereof are encompassed with the compounds of this invention.
• salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
• Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
• Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
• basic ion exchange resins such as
• salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
• acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
• Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
• references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
• Therapeutically active metabolites where the metabolites themselves fall within the scope of the claimed invention, are also compounds of the current invention.
• Prodrugs which are compounds that are converted to the claimed compounds as they are being administered to a patient or after they have been administered to a patient, are also compounds of this invention.
• Compounds of the current invention are potent inhibitors of CETP. They are therefore useful in treating diseases and conditions that are treated by inhibitors of CETP.
• One aspect of the present invention provides a method for treating or reducing the risk of developing a disease or condition that may be treated or prevented by inhibition of CETP by administering a therapeutically effective amount of a compound of this invention to a patient in need of treatment.
• a patient is a human or mammal, and is most often a human.
• a "therapeutically effective amount” is the amount of compound that is effective in obtaining a desired clinical outcome in the treatment of a specific disease.
• Diseases or conditions that may be treated with compounds of this invention, or which the patient may have a reduced risk of developing as a result of being treated with the compounds of this invention include: atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity, endotoxemia, and metabolic syndrome.
• the compounds of this invention are expected to be particularly effective in raising HDL-C and/or increasing the ratio of HDL-C to LDL-C. These changes in HDL-C and LDL-C may be beneficial in treating atherosclerosis, reducing or reversing the development of atherosclerosis, reducing the risk of developing atherosclerosis, or preventing atherosclerosis.
• Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
• oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
• Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
• compounds of Formula I are administered orally.
• the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
• a daily dosage of from about 0.01 milligram to about 100 milligram per kilogram of animal or human body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
• the total daily dose will generally be from about 0.5 milligram to about 500 milligrams.
• the dosage for an adult human may be as low as 0.1 mg.
• the dosage regimen may be adjusted within this range or even outside of this range to provide the optimal therapeutic response.
• Oral administration will usually be carried out using tablets.
• Examples of doses in tablets are 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 250 mg, and 500 mg.
• Other oral forms can also have the same dosages (e.g. capsules).
• compositions which comprise a compound of Formula I and a pharmaceutically acceptable carrier.
• the pharmaceutical compositions of the present invention comprise a compound of Formula I or a pharmaceutically acceptable salt as an active ingredient, as well as a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
• pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
• a pharmaceutical composition may also comprise a prodrug, or a pharmaceutically acceptable salt thereof ⁇ if a prodrug is administered.
• Pharmaceutical compositions may also consist essentially of a compound of Formula I and a pharmaceutically acceptable carrier without other thereapeutic ingredients.
• the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
• the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
• any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
• oral liquid preparations such as, for example, suspensions, elixirs and solutions
• carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparation
• tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical earners are obviously employed.
• tablets may be coated by standard aqueous or nonaqueous techniques.
• Such compositions and preparations should contain at least 0.1 percent of active compound.
• the percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit.
• the amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
• the active compounds can also be administered intranasally as, for example, liquid drops or spray.
• the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
• a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
• tablets may be coated with shellac, sugar or both.
• a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
• Compounds of formula I may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
• the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
• the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
• the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
• Compounds of the invention may be used in combination with other drugs that may also be useful in the treatment or amelioration of the diseases or conditions for which compounds of Formula I are useful.
• Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I.
• a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred.
• the combination therapy also includes therapies in which the compound of Formula I and one or more other drugs are administered on different schedules.
• the drugs When oral formulations are used, the drugs may be combined into a single combination tablet or other oral dosage form, or the drugs may be packaged together as separate tablets or other oral dosage forms. It is also contemplated that when used in combination with one or more other active ingredients, the compound of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula I.
• HMG-CoA reductase inhibitors which are generally statins, including lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, pitavastatin, and other statins
• bile acid sequestrants cholesterolestyramine, colestipol, dialkylaminoalkyl derivatives of a cross-linked dextran, Colestid®, LoCholest®
• niacin and related compounds such as nicotinyl alcohol, nicotinamide, and nicotinic acid or a salt thereof,
• PP ARa agonists which are generally statins, including lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, pitavastatin, and other statins
• bile acid sequestrants cholesterol
• Preferred classes of therapeutic compounds that can be used with the compounds of this invention for use in improving a patient's lipid profile include one or both of statins and cholesterol absorption inhibitors.
• Particularly preferred are combinations of compounds of this invention with simvastatin, ezetimibe, or both simvastatin and ezetimibe.
• Also preferred are combinations of compounds of this invention with statins other than simvastatin, such as lovastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, and ZD-4522.
• compounds of this invention can be used with compounds that are useful for treating other diseases, such as diabetes, hypertension and obesity, as well as other anti-atherosclerostic compounds.
• Such combinations may be used to treat one or more of such diseases as diabetes, obesity, atherosclerosis, and dyslipidemia, or more than one of the diseases associated with metabolic syndrome.
• the combinations may exhibit synergistic activity in treating these disease, allowing for the possibility of administering reduced doses of active ingredients, such as doses that otherwise might be sub-therapeutic.
• Examples of other active ingredients that may be administered in combination with a compound of this invention include, but are not limited to, compounds that are primarily anti-diabetic compounds, including:
• PPAR gamma agonists and partial agonists including glitazones and non-glitazones (e.g. pioglitazone, englitazone, MCC-555, rosiglitazone, balaglitazone, netoglitazone, T-131, LY- 300512, and LY-818;
• glitazones and non-glitazones e.g. pioglitazone, englitazone, MCC-555, rosiglitazone, balaglitazone, netoglitazone, T-131, LY- 300512, and LY-818;
• PTP-IB protein tyrosine phosphatase- IB
• dipeptidyl peptidase IV (DP-IV) inhibitors including vildagliptin, sitagliptin, and saxagliptin;
• insulin or insulin mimetics such as for example insulin lispro, insulin glargine, insulin zinc suspension, and inhaled insulin formulations;
• sulfonylureas such as tolbutamide, glipizide, glimepiride, acetohexamide, chlorpropamide, glibenclamide, and related materials;
• ⁇ -glucosidase inhibitors such as acarbose, adiposine; camiglibose; emiglitate; miglitol; voglibose; pradimicin-Q; and salbostatin;
• PPAR ⁇ / ⁇ dual agonists such as muraglitazar, tesaglitazar, farglitazar, and naveglitazar;
• GLP-I GLP-I
• GLP-I derivatives GLP-I analogs, such as exendins, such as for example exenatide (Byetta); and non-peptidyl GLP-I receptor agonists;
• Non-sulfonylurea insulin secretagogues such as the meglitinides (e.g.nateglinide and rapeglinide).
• antiobesity compounds including 5-HT(serotonin) inhibitors, neuropeptide Y5 (NPY5) inhibitors, melanocortin 4 receptor (Mc4r) agonists, cannabinoid receptor 1 (CB-I) antagonists/inverse agonists, and ⁇ 3 adrenergic receptor agonists. These are listed in more detail later in this section.
• active ingredients also include active ingredients that are used to treat inflammatory conditions, such as aspirin, non-steroidal anti-inflammatory drugs, glucocorticoids, azulfidine, and selective cyclooxygenase-2 (COX-2) inhibitors, including etoricoxib, celecoxib, rofecoxib, and Bextra.
• active ingredients that are used to treat inflammatory conditions, such as aspirin, non-steroidal anti-inflammatory drugs, glucocorticoids, azulfidine, and selective cyclooxygenase-2 (COX-2) inhibitors, including etoricoxib, celecoxib, rofecoxib, and Bextra.
• COX-2 selective cyclooxygenase-2
• Antihypertensive compounds may also be used advantageously in combination therapy with the compounds of this invention.
• antihypertensive compounds include (1) angiotensin II antagonists, such as losartan; (2)angiotensin converting enzyme inhibitors (ACE inhibitors), such as enalapril and captopril; (3) calcium channel blockers such as nifedipine and diltiazam; and (4) endothelian antagonists.
• Anti-obesity compounds may be administered in combination with the compounds of this invention, including: (1) growth hormone secretagogues and growth hormone secretagogue receptor agonists/antagonists, such as NN703, hexarelin, and MK-0677; (2) protein tyrosine phosphatase-lB (PTP-IB) inhibitors; (3) cannabinoid receptor ligands, such as cannabinoid CBi receptor antagonists or inverse agonists, such as rimonabant (Sanofi Synthelabo), AMT-251, and SR-14778 and SR 141716A (Sanofi Synthelabo), SLV-319 (Solvay), BAY 65-2520 (Bayer); (4) anti-obesity serotonergic agents, such as fenfluramine, dexfenfluramine, phentermine, and sibutramine; (5) ⁇ 3-adrenoreceptor agonists, such as AD9677/TAK67
• Y5 antagonists such as GW-569180A, GW-594884A, GW-587081X, GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR- 120819A and JCF-104; (9) melanin-concentrating hormone (MCH) receptor antagonists; (10) melanin- concentrating hormone 1 receptor (MCHlR) antagonists, such as T-226296 (Takeda); (11) melanin- concentrating hormone 2 receptor (MCH2R) agonist/antagonists; (12) orexin-1 receptor antagonists, such as SB-334867-A; (13) melanocortin agonists, such as Melanotan II; (14) other Mc4r (melanocortin 4 receptor) agonists, such as CHIR86036 (Chiron), ME-10142,
• a patient having metabolic syndrome is characterized as having three or more symptoms selected from the following group of five symptoms: (1) abdominal obesity; (2) hypertriglyceridemia; (3) low high- density lipoprotein cholesterol (HDL); (4) high blood pressure; and (5) elevated fasting glucose, which may be in the range characteristic of Type 2 diabetes if the patient is also diabetic.
• Each of these symptoms is defined clinically in the recently released Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel DI, or ATP DI), National Institutes of Health, 2001, NEH Publication No.
• Patients with metabolic syndrome have an increased risk of developing the macrovascular and microvascular complications that are listed above, including atherosclerosis and coronary heart disease.
• the combinations described above may ameliorate more than one symptom of metabolic syndrome concurrently (e.g. two symptoms, three symptoms, four symptoms, or all five of the symptoms).
• Particles used in the assay were created from the following sources: Synthetic donor HDL particles containing DOPC (Dioleoyl Phosphatidyl Choline), BODD 3 Y ( D-CE (Molecular Probes C- 3927), triolein (a triglyceride), and apoHDL were essentially created by probe sonication as described by Epps et al, but with the addition of a non-diffusable quencher molecule, dabcyl dicetylamide, in order to reduce background fluorescence.
• DOPC Dioleoyl Phosphatidyl Choline
• BODD 3 Y D-CE (Molecular Probes C- 3927)
• triolein a triglyceride
• apoHDL a non-diffusable quencher molecule, dabcyl dicetylamide
• Dabcyl dicetylamide was made by heating dabcyl n-succinimide with dicetylamine in DMF at 95 0 C overnight in the presence of diisopropylamine catalyst.
• Native lipoproteins from human blood were used as acceptor particles. Particles having a density less than 1.063 g/ml were collected by ultracentrifugation. These particles include VLDL, DDL, and LDL. Particle concentrations were expressed in terms of protein concentration as determined by BCA assay (Pierce, USA). Particles were stored at 4°C until use.
• Assays were performed in Dynex Microfluor 2 U-bottom black 96-well plates (Cat #7205).
• An assay cocktail containing CETP, IX CETP buffer (50 mM Tris, pH 7.4, 100 mM NaCl, 1 mM EDTA), and half the final concentration of acceptor particles was prepared, and 100 ⁇ L of the assay cocktail was added to each well of the plate.
• Test compounds in DMSO were added in a volume of 3 ⁇ L. The plate was mixed on a plate shaker and then incubated at 25 0 C for 1 hour.
• a second assay cocktail containing donor particles, the remaining acceptor particles and IX CETP buffer was prepared. 47 ⁇ L of the second assay cocktail was added to the reaction wells to start the assay.
• Assays were performed at 25°C in a final volume of 150 ⁇ L. Final concentrations of materials were: 5 ng/ ⁇ L donor particles, 30 ng/ ⁇ L acceptor particles (each expressed by protein content), IX CETP buffer, 0.8 nM recombinant human CETP (expressed in CHO cells and partially purified), and up to 2% DMSO when testing compounds.
• Iodides 1-3 are prepared by treatment of 1-2 with isoamylnitrite, n-pentylnitrite, t-butyl nitrite or the like in the presence of diiodomethane (see for example: Smith et al., J. Org. Chem. 55, 2543, (1990) and references cited therein) either neat or in a solvent such as THF or acetonitrile.
• the iodide can be prepared first by diazonium formation using isoamylnitrite, n-pentylnitrite, t-butyl nitrite, sodium nitrite, nitrous acid or the like followed by heating in the presence of iodine or an iodide salt such as copper iodide, sodium iodide, potassium iodide, tetrabutylammonium iodide or the like.
• Reduction of 1-3 with DIBAL in dichloromethane affords aldehyde 1-4.
• Reduction of aldehyde 1-4 with sodium borohydride or the like in methanol or ethanol or the like gives alcohol 1-5.
• nitrile 2-2 Reduction of nitrile 2-2 is accomplished with lithium aluminum hydride in diethyl ether to afford 2-aminomethyl aniline 2-3.
• the nitrile can be reduced with palladium on carbon or Raney nickel under hydrogen atmosphere in methanol, ethanol or the like.
• Other methods for reduction of a nitrile to an aminomethyl group can be found in Smith, M. B. and March, J. "March's Advanced Organic Chemistry", 5 th Ed., John Wiley and Sons, New York, pp. 1204 (2001) and references therein.
• the reaction may be run with or without a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, or the like.
• a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, or the like.
• Reduction of the ester functionality of 3-2 affords amino alcohol 3-3.
• the preferred reducing reagent is LiAlH 4 , in a solvent such as ether, tetrahydrofuran, dimethoxyethane, dioxane, or the like.
• Other methods for reduction of an ester can be found in "March' s Advanced Organic Chemistry" 5 th Ed., John Wiley and Sons, New York, pp 1551.
• Enantiopure products may be obtained via chiral chromotography.
• the epoxide may be made from epoxidation of an olefin, cyclization of a halohydrin or 1, 2-diol, or other methods described in "March's Advanced Organic Chemistry” 5 th Ed., John Wiley and Sons, New York, pp 1051.
• the preferred solvent for this reaction is isopropanol.
• the epoxide opening may be carried out in a solvent such as acetonitrile or the like with the aid of a Lewis Acid catalyst such as Yb(OTf)3 or the like.
• a solvent such as dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane, or the like
• a base such
• aminoalcohol 4-2 can be converted to an appropriate carbamate by treatment with reagents such as dibenzyl dicarbonate or benzyl chloroformate in the presence of bases such as triethylamine, diisopropylethylamine or the like in solvents such as dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane or the like.
• bases such as triethylamine, diisopropylethylamine or the like in solvents such as dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane or the like.
• the carbamates can then be converted into oxazolidinones 4-3 by treating with bases like lithium-, sodium- or potassium hexamethyldisilazide in solvents like tetrahydrofuran, dimethoxyethane or the like.
• Enantiopure products may be obtained via chiral chromatography
• Protection of the nitrogen with a BOC or Cbz group can be carried out by reaction of 5-1 with di-t-butyldicarbonate or dibenzyldicarbonate in an appropriate solvent such as dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane, or the like.
• Alcohol 5-2 can be converted to azide 5-3 by reaction with methanesulfonyl chloride in dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane, or the like in the presence of an appropriate base such as triethylamine, diisopropylethylamine, N- methylmorpholine, or the like.
• the alcohol may be converted to an alternative leaving group, such as tosylate, iodide, bromide, or the like.
• the mesylate is then displaced by an azide source, such as NaN3, IJN3, BU4NN3 or the like in an appropriate solvent, such as DMF, DMPU, or the like.
• Azide 5-3 can also be prepared by treatment of alcohol 5-2 with diphenylphosphoryl azide, diethylazodicarboxylate and triphenylphosphine in THF. Azide 5-3 can be reduced by hydrogenation over a metal catalyst such as Pt ⁇ 2 or Pd/C or the like in an appropriate solvent, such as EtOAc, THF,
• Enantiopure products may be obtained via chiral chromatography.
• Preferred conditions for this transformation are sodium cyanoborohydride in methanol with catalytic acetic acid.
• Deprotection of 6-2 affords 6-3.
• TFA/CH2CI2 is the preferred method of deprotection.
• Enantiopure products may be obtained using chiral chromatography.
• the alcohol may be converted to an alternative leaving group, such as tosylate, iodide, bromide, or the like.
• the mesylate is then displaced by an azide source, such as NaN ⁇ , UN3, BU4NN3 or the like in an appropriate solvent, such as DMF, DMPU, or the like.
• Azide 7-3 can also be prepared by treatment of alcohol 5-2 with diphenylphosphoryl azide, diethylazodicarboxylate and triphenylphosphine in THF. Azide 7-3 can be reduced to amine 7-4 with H2 z,u over Pt ⁇ 2 with THF as a solvent when R4 is benzyl. Cyclization of 7-4 to imidazolidinones 7-5 is accomplished through the use of an appropriate base, such as lithium diisopropylamide or lithium-, sodium-, or potassium bis(trimethylsilyl)amide or the like in an appropriate solvent, such as THF, dimethoxyethane, DMF, DMA, or the like. Enantiopure products may be obtained via chiral chromatography.
• an appropriate base such as lithium diisopropylamide or lithium-, sodium-, or potassium bis(trimethylsilyl)amide or the like in an appropriate solvent, such as THF, dimethoxyethane, DMF, DMA, or the like.
• Compound 8-1 (prepared as described in Schemes 5, 6, and 7) wherein R, R a , A ⁇ , A ⁇ , p, and n are as defined in the claims can be converted to 8-2 by treatment with an appropriate alkylating agent such as an alkyl halide, alkyl tosylate, alkyl mesylate, or the like (for example methyl iodide) in an appropriate solvent such as THF, dimethoxyethane, DMF, DMA, or the like, in the presence of an appropriate base, such as lithium diisopropylamide or lithium-, sodium-, or potassium bis(trimethylsilyl)amide or the like.
• an appropriate alkylating agent such as an alkyl halide, alkyl tosylate, alkyl mesylate, or the like (for example methyl iodide) in an appropriate solvent such as THF, dimethoxyethane, DMF, DMA, or the like
• an appropriate base such as lithium diisopropy
• Benzoic acids 9-2 can be reduced to benzyl alcohols 9-3 with reducing agents such as borane in solvents such as tetrahydrofuran or the like(See: Smith, M. B. and March, J. "March's Advanced Organic Chemistry", 5 th Ed., John Wiley and Sons, New York, pp. 1549 (2001) and references therein).
• 9-2 can be esterified by known methods including treatment with trimethylsilyldiazomethane and the resulting ester reduced to alcohol 9-3 with L1AIH4 or the like.
• Intermediates 9-3 can be transformed into benzyl bromides 9-4 using reagents such as triphenylphosphine and carbon tetrabromide in solvents such as dichloromethane, dichloroethane or the like (See: Smith, M. B. and March, J. "March's Advanced Organic Chemistry", 5 th Ed., John Wiley and Sons, New York, pp. 518-519 (2001) and references therein).
• solvents such as dichloromethane, dichloroethane or the like
• Nitroalcohols 10-2 can be reduced to aminoalcohols 10-3 with reductants such as Raney nickel, palladium on activated carbon or platinum oxide in the presence of hydrogen gas and aqueous acid in alcoholic solvents such as methanol, ethanol or the like (See: Langer, O., et al., Bioorg. Med. Chem., 2001, 9, 677-694).
• reductants such as Raney nickel, palladium on activated carbon or platinum oxide
• bases such as triethylamine, diisopropylethylamine or the like in solvents like dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane or the like.
• Compounds 13-4 are then prepared via a Suzuki or Stille reaction or variation thereof employing palladium catalyzed cross coupling of iodide 13-3 with an appropriately substituted aryl- or heteroaryl-boronic acid, -boronate ester or -trialkyl tin as described in Miyaua et al., Chem. Rev. 95, 2457 (1995) and references cited within and as described in Smith, M. B. and March, J. "March's Advanced Organic Chemistry", 5 th Ed., John Wiley and Sons, New York, pp. 868-869 (2001) and references cited therein.
• 2-Amino-l-phenylethanols 14-3 can be prepared from 14-2 via the corresponding silylated cyanohydrin by treatment with trimethylsilyl cyanide and catalytic zinc iodide followed by reduction with lithium aluminum hydride or the like reducing agent.
• 2-amino-l-phenylethanols 14-3 can be prepared from 14-2 via the corresponding cyanohydrin by treatment with potassium cyanide followed by reduction.
• Oxazolidinones 14-4 can be alkylated with alkyl, heteroalkyl, aryl, or heteroaryl bromides using bases such as sodium hexamethyldisiliazide or sodium hydride in solvents like tetrahydrofuran, dimethoxyethane, diethyl ether or the like to afford products 14-5.
• Enantiopure products may be obtained via chiral chromatography.
• Nitroalcohols 15-2 can be reduced to aminoalcohols 15-3 with reductants such as Raney nickel, palladium on activated carbon, or platinum oxide in the presence of hydrogen gas and aqueous acid in alcoholic solvents such as methanol, ethanol or the like (See: Langer, O., et al., Bioorg. Med. Chem., 2001, 9, 677-694).
• reductants such as Raney nickel, palladium on activated carbon, or platinum oxide
• bases such as triethylamine, diisopropylethylamine or the like in solvents like dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane or the like.
• Oxazolidinones 15-5 are prepared via a Suzuki or Stille reaction or variation thereof employing palladium catalyzed cross coupling of iodides 15-4 with appropriately substituted aryl- or heteroaryl- boronic acids, -boronate esters or -trialkyl tin compounds, as described in Miyaura et al., Chem. Rev. 95, 2457 (1995) and references cited within, and as described in Smith, M. B. and March, J. "March's Advanced Organic Chemistry", 5 th Ed., John Wiley and Sons, New York, pp. 868-869 (2001) and references cited therein.
• Oxazolidinones 15-5 can be alkylated with alkyl, heteroalkyl, aryl, or heteroaryl bromides using bases such as sodium hexamethyldisiliazide or sodium hydride in solvents like tetrahydrofuran, dimethoxyethane, diethyl ether or the like to afford products 15-6.
• Enantiopure products may be obtained via chiral chromatography.
• Compounds 16-2 can be hydrolyzed to the corresponding acids and then treated with diphenylphosphorazidate and a trialkylamine base to effect a Curtius rearrangement, affording chiral oxazolidinones 16-3.
• Oxazolidinones 16-4 are prepared via a Suzuki or Stille reaction or variation thereof employing palladium catalyzed cross coupling of iodides 16-3 with appropriately substituted aryl- or heteroaryl-boronic acids, -boronate esters or -trialkyl tin compounds, as described in Miyaura et al., Chem. Rev. 95, 2457 (1995) and references cited within, and as described in Smith, M. B. and March, J.
• Oxazolidinones 16-4 can be alkylated with alkyl, heteroalkyl, aryl, or heteroaryl bromides using bases such as sodium hexamethyldisiliazide or sodium hydride in solvents like tetrahydrofuran, dimethoxyethane, diethyl ether or the like to afford products 16-5.
• oxazolidinones 16-3 are alkylated with the appropriate bromides to afford compounds 16-6, which are subjected to a Suzuki or Stille reaction or variation thereof with appropriately substituted aryl- or heteroaryl-boronic acids, -boronate esters or -trialkyl tin compounds to afford products 16-5.
• Step A methyl r3,5-bis(trifluoromethyl)phenyll(hydroxy)acetate
• Step B methyl r3,5-bis(trifluoromethyl)phenyll(bromo)acetate
• Step C methvirS.S-bisftrifluoromethvDphenylKirS'-isopropyl ⁇ '-methoxy ⁇ -CtrifluoromethvDbiphenyl ⁇ - ylimethyl I amino)acetate
• Step D 2-r3,5-bis(trifluoromethyl)phenyll-2-(ir5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- ylimethyl I amino)ethanol
• Step E 4-r3,5-bis(trifluoromethyl)phenyn-3-( r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- yllmethy ⁇ -l,3-oxazolidin-2-one
• phosgene 21 ⁇ L of a 20% solution in toluene, ⁇ 0.0535 mmol
• CH2CI2 0.5 mL
• 2-[3,5-bis(trifluoromethyl)phenyl]-2-( ⁇ [5'-iso ⁇ ropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- yl]methyl ⁇ amino)ethanol 3. mg, 0.00535 mmol) in CH2CI2 (0.5 mL), followed by DIPEA (19 ⁇ L,
• Step B l-r3,5-bis(trifluoromethyl)phenyll-2-( ⁇ r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- ylimethyl I amino)ethanol
• Step C 5-r3,5-bis(trifluoromethyl)phenyll-3- ⁇ r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- yllmethyl ) -1 ,3-oxazolidin-2-one
• the 2 enantiomers could be separated by chiral HPLC using 15% IP A/heptanes and an AD chiral column.
• Step A 2-(ir5'-isopropyl-2'-methoxy-4-( ' trifluoromethyl)biphenyl-2-yllmethyllamino)-l-pyridin-2- ylethanol
• Step B Benzyl (2-hvdroxy-2-pyridin-2-ylethyl) ⁇ r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- yllmethyl 1 carbamate
• Step C 3- ⁇ r5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yllmethyll-5-pyridin-2-yl-l,3- oxazolidin-2-one
• This compound was separated into its two enantiomers (4S, 5R)-5-[3,5- bis(trifluoromethyl)phenyl]-4-methyl-l,3-oxazolidin-2-one and (4R, 5S)-5-[3,5- bistrifluoromethyl)phenyl]-4-methyl-l,3-oxazolidin-2-one using chiral HPLC (AS column, 20 x 250 mm, 15% z-PrOH in heptane).
• the Weinreb amide from Step 1 (6kg, 22.5 mol) and 3,5-bis(trifluoromethyl)bromobenzene (4.85L, 28.1 mol) are dissolved in anhydrous THF (24L).
• the solution is purged with nitrogen to remove oxygen.
• the water content should be ⁇ 500ppm at this point.
• Atmospheric distillation can be carried out to azeotropically remove water if necessary.
• the solution is cooled to -10 0 C and iso-PrMgCl in THF (56.4 mol) is slowly added (2 hours) to the reaction via addition funnel, maintaining a reaction temperature ⁇ -5 0 C.
• the solution is allowed to warm to 20°C and aged overnight at 20° C, until the amide is ⁇ 0.5 LCAP.
• the reaction is then cooled to -10°C under nitrogen and is quenched slowly over 2 hours into 5N HCl (14L) that is maintained at 0-5 0 C.
• MTBE (12L) is added and the biphasic mixture is agitated for 5 min. After warming to 20°-25°C, it is allowed to settle for 30 min, and then the layers are separated.
• the organic layer is washed with water twice (12L).
• the organic layer is vacuum transferred through a 1 -micron in-line PTEE filter into a distillation flask and is then concentrated to ⁇ 12L under vacuum (internal temperature ⁇ 40°C) to a minimum agitated volume.
• the solution is then azeotropically dried with toluene and taken to a minimum agitated volume again. The solution is used directly in the next step.
• heptane is added to the organic layer after it has been concentrated to a minimum agitated volume.
• the distillation is continued under vacuum at 40°-55°C until the final volume is 4OL.
• the solution is cooled to 35°-37°C , seeded (-0.5%, 30gms) and then aged for 30min to allow for a full seed bed to grow.
• the slurry is cooled to 10°C over 2-3 hrs.
• the slurry is then filtered, washed with 5°C heptane (18L), and allowed to dry fully on the filter pot using a vacuum/nitrogen sweep overnight.
• the dried solid is obtained with >99.9ee%.
• the amide can be recrystallized from straight heptane if the optical purity is not sufficient.
• TFA (9L) is added to a 100 L Buchi reactor under an inert atmosphere and is cooled to -5°C.
• the ketone product from Step 2 (5.50 kg, 13.1 mol) is added as a solid followed by a TFA rinse (2 L).
• the solution is cooled to -5°C and is stirred until all the solid dissolves.
• the silane (2.18 kg, 15.7 mol) is added slowly over ⁇ 1 h (in two portions) while keeping the temperature at ⁇ 0°C.
• the reaction is aged at -2 to -6°C for 15-20 h, at which time LC reveals ⁇ 2% of the ketone remains.
• a 50w/w% KOH solution is prepared by adding 13.6kg of KOH pellets (87w%) slowly to 10 L water while keeping the highly exothermic dissolution at ⁇ 30 0 C.
• the solution is stored in a refrigerator.
• the reaction is quenched with ⁇ 2 L of the 50w/w% KOH solution with vigorous stirring and cooling, keeping temp at -20 °C.
• Cold THF (16.5L, previously stored in freezer) is added, followed by slow addition of the remainder of the KOH solution (-13.7 L), followed by a 2 L water rinse while keeping temp ⁇ 20 0 C.
• the reaction is aged at room temperature.
• the reaction is quenched after 3 h with 27.5 L PAC and 20 L 20%w/v aq NaCl.
• the aqueous and organic layers are separated.
• the organic layer is washed with 26 L of 20%w/v aq NaCl, then with 36 L water, then with 31 L 0.5 N HCl, and finally with 32 L of water.
• the organic layer is concentrated to -10 L.
• Heptane (20 L) is added, yielding crystals.
• the organic layer is concentrated to -10 L.
• Heptane (20L) is added again, and the organic layer is concentrated to -10 L.
• Heptane (22 L) is added and the slurry is aged at rt.
• the solid is filtered and washed with 24 L heptane.
• a solid product is obtained (98.8% purity, >99.95%ee, by LC).
• the solid is then re-dissolved in 12.5 L MeOH (endothermic). At rt, 3 L water is added, and the mixture is aged to initiate crystallization. Water (9.5 L) is added over ⁇ 60min at rt. After aging for 60min, the slurry is filtered and the solid is washed with 5 L MeOH/water (1/1.5), 5 L MeOH/water (1/4) and then 4 L water. The solid product is dried at 50° C under vacuum (99.9% pure by LC, >99.95%ee).
• the reaction in Step 3 can also be carried out using Al(O-i-Pr)3 as the reducing agent.
• the ketone (6 kg) is heated at 5O 0 C with 0.3 eq of Al(O-i-Pr)3 (79Og) in 12L IPA and 18 L of toluene for 15.5 hours.
• the solution is cooled to ambient temperature, and solid KOH pellets (1.35 kg) are added slowly with vigorous stirring, while keeping the temperature at ⁇ 25 °C.
• 33L of IN HCl solution is added to quench the reaction, which is kept at ⁇ 25 0 C.
• a rag layer of solids forms, it should be filtered off to upgrade the enantiomeric excess.
• the organic layer is then washed first with 36L of 0.5N HCl, then with 6L IPA combined with 45L water, and finally with 6L IPA combined with 36L water.
• the organic layer is transferred via an inline filter.
• the solvent is switched to heptane (target volume is ⁇ 42L) at -40 0 C until ⁇ 2 v% toluene is left. Aging at rt for 2 h gives the solid product.
• Step A fer ⁇ -butyl
• Step B l-r3,5-bis(trifluoromethyl)phenyll-2-((fer?-butoxycarbonyl ' ) ⁇ r5'-isopropyl-2'-methoxy-4-
• Step C ferf-butyl 12-azido-2-r3,5-bis(trifluoromethvDphenyllethyl 11 r5'-isopropyl-2'-methoxy-4- (trifluoromethyl)biphenyl-2-yllmethyl
• Step D mixture of fert-butyl f2-amino-2-r3,5-bis(trifluoromethyl)phenyl1ethyllir5'-isopropyl-2'- methoxy-4-(trifluoromethvDbiphenyl-2-yllmethyl I carbamate and fe/t-butyl ri-F3,5- bisftrifluoromethyDphenyli -2-( I [5 '-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- yllmethyl I amino)ethy ⁇ carbamate
• Step E l-r3.5-bis(trifluoromethyl)phenyll- N 2 - ⁇ r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- y I] methyl I ethane- 1 ,2-diamine
• Step F 4-r3,5-bis(trifluoromethyl)phenvn-l-ir5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- ylimethyl limidazolidin-2-one
• Step B fert-butyl r(lR)-2-oxo-l-phenylethyricarbamate
• Step C fert-butvirdi?)-2-( ' ( r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yllmethyl ⁇ amino)-l- phenylethyll carbamate
• Step D (lJ?)-N2-(r5'-isopropyl-2'-methoxy-4-( * trifluoromethyl)biphenyl-2-ynmethyll-l-phenylethane- 1,2-diamine
• Step E (4R)-I-I r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-vnmethyll-4- phenylimidazolidin-2-one.
• Step A l-(4-chlorophenyl)-2-( ⁇ r5'-isopropyl-2'-methoxy-4-( ' trifluoromethyl)biphenyl-2- yl1methyl ⁇ ammo)ethanol
• Step B benzyl r2-(4-chlorophenyl)-2-hydroxyethylli r5'-isopropyl-2'-methoxy-4-
• Step C benzyl r2-azido-2-(4-chlorophenyl)ethyll 115'-iso ⁇ ropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-
• Step D benzyl r2-amino-2-(4-chlorophenyl)ethyl] I r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl- 2-yllmethyl 1 carbamate
• Step E 4-(4-chlorophenyl)-l-l r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- vHmethyl limidazolidin-2-one
• Step B 5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde
• Step C 2-amino-l-r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-ynethanol
• a solution of 0.679 g of 5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde in 1.5 mL of CH2CI2 was added ca. 5 mg of Znl2, then 0.23 g of trimethylsilyl cyanide.
• the mixture was stirred at room temperature for 3 h, and then partitioned between 15 mL of water and 10 mL of Et2 ⁇ . The aqueous phase was extracted with 2 x 10 mL of Et2 ⁇ .
• Step D 5-r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-vn-1.3-oxazolidin-2-one
• Step B (45)-4-benzyl-3- ⁇ r5'-isopropyl-2'-methoxy-4-(trifluoromehtyl)biphenyl-2-yllmethyl
• the ether layer was then dried over anhydrous MgSO 4 , filtered and concentrated.
• the material is chromatographed on SiO 2 using a step gradient of 1:3 CH 2 Cl 2 /hexanes, then 1:1 CH 2 Cl 2 /hexanes, then 100% CH 2 Cl 2 to afford [2-iodo-5-(trifluoromethyl)phenyl]methanol as a white solid.
• Carbon tetrabromide (1.86 g; 5.6 mmol) and triphenylphosphine (1.47 g; 5.6 mmol) were added successively to a stirred solution of [2-iodo-5-(trifluoromethyl)phenyl]methanol (1.13 g; 3.74 mmol) in CH2CI2 (25 mL) at 0°C under N2.
• the reaction was stirred at room temperature for 48 h.
• a second equivalent of carbon tetrabromide (1.2 g; 3.74 mmol) and triphenylphosphine (0.98 g; 3.74 mmol) was added and the reaction was stirred an additional 14 h.
• the racemic material was separated by chiral HPLC using 15% IP A/heptane and an OD column into its two enantiomers.
• Step 1 (45.5J?)-5-r3.5-bisftrifluoromethyl)phenvn-3-r2-iodo-5-( ' trifluoromethyl)benzvn-4-methyl-l,3- oxazolidin-2-one
• Step 2 (4S,5J?)-5-r3,5-bis(trifluoromethyl)phenyll-3-( r4'-fluoro-5'isopropyl-2'-methoxy-4- (trifluoromethyl)biphenyl-2-yllmethyl ) -4-methyl-l ,3-oxazolidin-2-one
• a stirred mixture of (45,5i?)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4- methyl-l,3-oxazolidin-2-one (4.29 g; 7.19 mmol)
• (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (Example 78) (4.57 g; 21.57 mmol), te£r ⁇ £zs(triphenylphosphine)palladium (0) (1.0 g; 0.86 mmol), and sodium carbonate
• Step A (4S,5S)-5-r3,5-bis(Mfluoromethyl)phenyri-3- ⁇ r5'-isopropyl-2'-methoxy-4- (trifluoromethvDbiphenyl-2-vnmethyl)-4-methyl-l,3-oxazolidin-2-one.
• Step B (lS,2S)-l-r3,5-bis(trifluoromethyl)phenyri-2-( " ⁇ r5'-isopropyl-2'-methoxy-4-
• Step C ⁇ -butyl((15,2S)-2-r3,5-bis(trifluoromethyl)phenyll-2-hvdroxy-l-methylethylH r5'-isopropyl- 2'-methoxy-4-( ' trifluoromethyl)biphenyl-2-yllmethyl lcarbamate .
• Step D ter?-butyl ⁇ (l l S.2j?)-2-azido-2-r3,5-bis(trifluoromethyl)phenvn-l-methylethyl ⁇ I r5'-isopropyl-2'- methoxy-4-(trifluoromethyl)biphenyl-2-yllmethyl
• PI13P (18.3 mg, 0.0698 mmol) was added. The reaction was stirred at room temperature for 30 min, and then additional DEAD (11 ⁇ L, 0.0698 mmol), DPPA (15 ⁇ L, 0.0698 mmol), and PI13P
• Step E (Ii?. 2y)-l-azido-l-r3.5-bis(trifluoromethyl)phenyll-N-( r5'-isopropyl-2'-methoxy-4-
• Step F (1R.2SV l-r3.5-bis(trifluoromethyl)phenyl1-N 2 -f r5'-isopropyl-2'-methoxy-4-
• Step G (4i?,5Sy4-r3,5-bis(trifluoromethyl)phenyl1-l- ⁇ r5'-isopropyl-2'-methoxy-4-
• Step B 2-fluoro- l-isopropenyl-4-methoxybenzene
• the boronic acid intermediate can also be made by the following 4-step process: MeMgCI
• THF 24 L
• CeCl 3 2.75 kg
• the resultant slurry was aged at room temperature for 1.5 hours.
• a sample was then examined under a microscope to confirm that the desired form change had occurred.
• the slurry was cooled to 9 0 C and MeMgCl was added. The rate of addition was adjusted to maintain internal temperature below 19 0 C.
• the mixture was cooled to -11 0 C, and a solution of acetophenone 1 (4.0kg diluted to 1OL with THF) was added dropwise, maintaining the internal temperature below O 0 C.
• the reaction mixture was then aged at a temperature below O 0 C for an hour.
• the reaction was quenched with 5.7L of 3N HCl in a dropwise fashion, maintaining the internal temperature below 15 0 C.
• the quenched reaction mixture was then aged at 5-1O 0 C for 1.5 hours and was filtered through a plug of Solka Floe.
• the THF solution of 2 was solvent switched into ethanol ( ⁇ 18L volume), and 1.9L HCl was added, followed by 190gm of 10% Pd/C (50% water).
• the mixture was placed under 15 psi hydrogen at 4O 0 C until the reaction was complete based on HPLC analysis.
• the mixture was cooled to room temperature.
• the catalyst was removed by filtration using Solka-Flok as a filter aid.
• the anisole product in ethanol was then solvent switched into acetonitrile for the next step.
• Anisole 3 is diluted in acetonitrile (1.72 L, 4mL MeCN/ mMol 3). This mixture is warmed to 35 0 C, and NBS (1.1 eq, 84 g) is added in a single solid addition. The reaction is complete in 2-4 hours. The solution is concentrated to 400 mL total volume and diluted with IL of toluene. The solution is then washed with sodium thiosulfate and water to remove the succinimide by-product. The organic layer is then concentrated and solvent switched to toluene.
• a 75 L glass reaction vessel was charged with 1.87 kg of aryl bromide 4 (7.6 MoI), which was added as 6.4 kg of a 29.1 wt% solution of 4 in toluene. This solution was diluted with 5.6 L of THF. The vessel was flushed with nitrogen, and tri-isopropylborate (1.35 eq, 2.35 L, 10.3 MoI) was added. The mixture was cooled to ⁇ -70 0 C. Then 5. 9L of 1.6 M n-BuLi in hexanes (9.5 MoI) was added slowly over 4 hours, maintaining a temperature of ⁇ -55 0 C. Thirty minutes after completion of the n-BuLi addition, the reaction was complete by LC analysis.
• the reaction was warmed to -35 0 C and quenched into 3.0 M H 2 SO 4 solution (5.6 L).
• the aqueous phase after the quench should be acidic (pH ⁇ 2).
• MTBE 7.5 L was added to the mixture to dilute the organic layer.
• the mixture was stirred (15 min) and the aqueous layer was cut away.
• the organic layer was washed with another 5.6 L of a 3.0 M H 2 SO 4 solution (15 min).
• the organic MTBE/Toluene layer was extracted twice with 1 M KOH (15.1 L first and then 7.6 L). The two KOH extractions were combined, diluted with 2- propanol (6.4 L), and cooled to 15 0 C.
• Step A l-bromo-2-(bromomethyl)-4-chlorobenzene
• Step B (45,5J?)-5-F3,5-bis(trifluoromethyl)phenyll-3-(2-bromo-5-chlorobenzyl)-4-methyl-l,3-oxazolidin-
• Step C (4S,5J?)-5-r3,5-bis(trifluoromethyl)phenyll-3-r(4-chloro-4'-fluoro-5'-isopropyl-2'- methoxybiphenyl-2-yl)methyll-4-methyl-l,3-oxazolidin-2-one
• TLC analysis indicates imine still present and an additional 100 mL 2N aqueous was added and the reaction stirred overnight. Imine was still present by TLC analysis and 200 mL 2N aqueous HCl was added and the mixture stirred 2 hours. The layers were separated and the aqueous layer back extracted with ether. The ether extracts were combined, washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated. The product was purified by silica gel chromatography eluting with 95:5 hexanes/EtOAc to give 2-Iodo-5-(trifluoromethyl)benzaldehyde as a white solid.
• Step B 5-r2-iodo-5-(trifluoromethyl)phenyl1-l,3-oxazolidin-2-one
• Step A (45)-4-benzyl-3- ⁇ (2i?,35)-3-hydroxy-3-[2-iodo-5-(trifluoromethyl)phenyl] -2-methylpropanoyl ⁇ - 1 ,3-oxazolidin-2-one
• Step B (4i?,5/?)-5-[2-iodo-5-(trifluoromethyl)phenyl] -4-methyl- 1 ,3-oxazolidin-2-one
• Step A (4i?)-4-benzyl-3- ⁇ (25,3R)-3-hydroxy-3-[2-iodo-5-(trifluoromethyl)phenyl]-2-methylpropanoyl ⁇ - 1 ,3-oxazolidin-2-one
• Step B (45,55)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-l,3-oxazolidin-2-one
• Step A benzyl r(lS)-2-(3,5-difluoiOphenyl)-l-methyl-2-oxoethyl1carbamate
• Step B benzyl fd 1 S',25 l V2-(3.5-difluorophenyl)-2-hvdroxy-l-methylethyllcarbamate
• Step C (45.5J?)-5-(3.5-difluorophenyl)-4-methyl-l,3-oxazolidin-2-one
• Step A 4-( ⁇ rtgrt-butyl(dimethyl)silyl1 oxy 1 methyl)-2-iodo- 1 ,3 -thiazole.
• Step A 4-(j rfert-butyl(diniethyl)silylloxy ⁇ methyl)-l,3-thiazole
• the mixture was degassed with N 2 , and then heated at 80 0 C for 16 hours.
• the reaction was then cooled to room temperature, diluted with EtOAc (200 mL), and washed with saturated NaHCO 3 and brine (80 mL each).
• the organic layer was dried over Na 2 SO 4 , filtered through a plug of silica, and concentrated.

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