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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D277/28—Radicals substituted by nitrogen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
  • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • 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
  • A61K31/415—1,2-Diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • 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
• • 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
  • A61P3/04—Anorexiants; Antiobesity agents
• • 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
• • 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
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
  • C07D231/38—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
  • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
  • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
  • C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
  • C07D285/01—Five-membered rings

Definitions

• the present invention relates generally to the field of inhibitors of stearoyl-CoA desaturase, such as heterocyclic derivatives, and uses for such com pounds in treating and/or preventing various human diseases, including those mediated by stearoyl-CoA desaturase (SCD) enzymes, preferably SCD1 , especially diseases related to elevated lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome and the like.
• SCD stearoyl-CoA desaturase
• Acyl desaturase enzymes catalyze the formation of double bonds in fatty acids derived from either dietary sources or de novo synthesis in the liver. Mammals synthesize at least three fatty acid desaturases of differing chain length specificity that catalyze the addition of double bonds at the delta-9, delta-6, and delta-5 positions.
• Stearoyl-CoA desaturases introduce a double bond in the C9-C10 position of saturated fatty acids.
• the preferred substrates are palmitoyl-CoA (16:0) and stearoyl- CoA (18:0), which are converted to palmitoleoyl-CoA (16:1 ) and oleoyl-CoA (18:1 ), respectively.
• the resulting mono-unsaturated fatty acids are substrates for incorporation into phospholipids, triglycerides, and cholesteryl esters .
• SCD1 A number of mammalian SCD genes have been cloned. For example, two genes have been cloned from rat (SCD1 , SCD2) and four SCD gen&s have been isolated from mouse (SCD1 , 2, 3, and 4). While the basic biochemical role of SCD has been known in rats and mice since the 1970's (Jeffcoat, R. et al., Elsevier Science (1984), Vol. 4, pp. 85-1 12; de Antueno, RJ, Lipids (1993), Vol. 28, No. 4, pp. 285-290), it has only recently been directly implicated in human disease processes. A single SCD gene, SCD1 , has been characterized in humans.
• SCD1 is described in Brownlie et al, PCT published patent application, WO 01/62954, the disclosure of which is hereby incorporated by reference in its entirety.
• a second human SCD isoform has recently been identified, and because it bears little sequence homology to alternate mouse or rat isoforms it has been named hum an SCD5 or hSCD5 (PCT published patent application, WO 02/26944, incorporated herein by reference in its entirety).
• sterculic acid (8-(2- octylcyclopropenyl)octanoic acid) and malvalic acid (7-(2-octylcyclopropenyl)heptanoic acid) are C18 and C16 derivatives of sterculoyl and malvaloyl fatty acids, respectively, having cyclopropene rings at their C9-C10 position.
• These agents are believed to inhibit SCD enzymatic activity by direct interaction with the enzyme, thus inhibiting delta-9 desaturation.
• Other agents that may inhibit SCD activity include thia-fatty acids, such as 9-thiastearic acid (also called 8-nonylthiooctanoic acid) and other fatty acids with a sulfoxy moiety.
• SCD inhibitor compounds are selective for SCD or delta-9 desaturases, as they also inhibit other desaturases and enzymes.
• the thia-fatty acids, conjugated linoleic acids and cyclopropene fatty acids (malvalic acid and sterculic acid) are neither useful at reasonable physiological doses, nor are they specific inhibitors of SCD1 biological activity, rather they demonstrate cross inhibition of other desaturases, in particular the delta-5 and delta-6 desaturases by the cyclopropene fatty acids.
• the present invention solves this problem by presenting new classes of compounds that are useful in modulating SCD activity and regulating lipid levels, especially plasma lipid levels, and which are useful in the treatment of SCD-mediated diseases such as diseases related to dyslipidemia and disorders of lipid metabolism, especially diseases related to elevated lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome and the like.
• the present invention provides heterocyclic derivatives that modulate the activity of stearoyl-CoA desaturase. Methods of using such derivatives to modulate the activity of stearoyl-CoA desaturase and pharmaceutical compositions comprising such derivatives are also encompassed.
• the invention provides compounds of formula (I):
• x and y are each independently 0, 1 , 2 or 3;
• W is a direct bond, -N(R 1 )C(O)-, -C(O)N(R 1 )-, -OC(O)N(R 1 )-, -N(R 1 )C(O)N(R 1 )-, -O-, -N(R 1 )-, -S(O) 1 - (where t is 0, 1 or 2), -N(R 1 )S(O) P - (where p is 1 or 2), -S(O) P N(R 1 )- (where p is 1 or 2), -C(O)-, -OS(O) 2 N(R 1 )-, -OC(O)-, -C(O)O-, or -N(R 1 )C(O)O-;
• V is -C(O)-, -C(O)CK-C(S)-, -C(O)N(R 1 )-, -S(O) 1 - (where t is O, 1 or 2), -S(O) P N(R 1 )- (where p is 1 or 2), -C(R 10 )H-, -N(R 1 )- or -0-; each R 1 is independently selected from the group consisting of hydrogen, C- ⁇ -C 12 alkyl, C 2 -C 12 hydroxyalkyl, C 4 -C 12 cycloalkylalkyl and C 7 -C 19 aralkyl; R 2 is selected from the group consisting of hydrogen, C r Ci 2 alkyl, C 2 -C 12 alkenyl, C 2 -Ci 2 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl,
• R 3 is selected from the group consisting of Ci-C 12 alkyl, C 2 -C 12 alkenyl, C 2 -Ci 2 hydroxyalkyl, C 2 -Ci 2 hydroxyalkenyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, CrC ⁇ heteroaryl and C 3 -C 12 heteroaryialkyl; or R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; each R 4 is independently selected from hydrogen, fluoro, chloro, d-Ci 2 alkyl,
• R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 and R 8a are each independently selected from hydrogen or C r C 3 alkyl; or R 5 and R 5a together, R ⁇ and R 6a together, or R 7 and R 7a together, or R 8 and R 8a together are an oxo group, provided that when V is -C(O)-, R 6 and R 6a together or R 8 and R 8a together do not form an oxo group, while the remaining R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 and R 8a are each independently selected from hydrogen or C ⁇ C 3 alkyl; or one of R 5 , R 5a , R 6 and R 6a together with one of R 7 , R 7a , R 8 and R 8a forms a direct bond or an alkylene bridge, while the remaining R 5 , R 5a , R 6 , R 6a , R 7
• R 10 is hydrogen or C r C 3 aIkyl; and each R 11 is independently selected from hydrogen, fluoro, chloro, Ci-Ci 2 alkyl or
• the invention provides compounds of formula (II):
• V is -C(O)-, -C(O)O-C(S)-, -C(O)N(R 1 )-, -S(O) 1 - (where t is O, 1 or 2), -S(O) p N(R 1 )- (where p is 1 or 2), -C(R 10 )H-, -N(R 1 )- or -O-; each R 1 is independently selected from the group consisting of hydrogen,
• R 2 is selected from the group consisting of hydrogen, d-C ⁇ alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -Ci 2 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -Ci 2 heterocyclyl, C 3 -C 12 heterocyclylalkyl, CrC- ⁇ heteroaryl, and C 3 -C 12 heteroarylalkyl; or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is selected from the group consisting of C r Ci 2 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -Ci 2 hydroxyalkenyl, C 2 -C 12 alkoxyalkyl, C 3 -C-
• R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; each R 4 is independently selected from hydrogen, fluoro, chloro, d-C ⁇ alkyl, C 1 -C ⁇ aIkOXy, haloalkyl, cyano, nitro or -N(R 9 ) 2 ; or two adjacent R 4 groups, together with the carbons to which they are attached, may form an aryl, heteroaryl or heterocyclyl ring system; R 5 , R 5a , R 6 , R
• R 12 is hydrogen, -C(O)OR 13 , -C(O)N(R 13 ) 2 , Ci-C 12 alkyl, C 2 -C 12 hydroxyalkyl, C 4 -C 12 cycloalkylalkyl or C 7 -C 19 aralkyl; and each R 13 is independently selected from hydrogen, C r C 12 alkyl, C 2 -C 12 alkenyl,
• the invention provides methods of treating an SCD-mediated disease or condition in a mammal, preferably a human, wherein the methods comprise administering to the mammal in need thereof a therapeutically effective amount of a compound of the invention as set forth above.
• the invention provides compounds or pharmaceutical compositions useful in treating, preventing and/or diagnosing a disease or condition relating to SCD biological activity such as the diseases encompassed by cardiovascular disorders and/or metabolic syndrome (including dyslipidemia, insulin resistance and obesity).
• the invention provides methods of preventing or treating a disease or condition related to elevated lipid levels, such as plasma lipid levels, especially elevated triglyceride or cholesterol levels, in a patient afflicted with such elevated levels, comprising administering to said patient a therapeutically or prophylactically effective amount of a composition as disclosed herein.
• a disease or condition related to elevated lipid levels such as plasma lipid levels, especially elevated triglyceride or cholesterol levels
• the present invention also relates to novel compounds having therapeutic ability to reduce lipid levels in an animal, especially triglyceride and cholesterol levels.
• the invention provides pharmaceutical compositions comprising the compounds of the invention as set forth above, and pharmaceutically acceptable excipients.
• the present invention relates to a pharmaceutical composition comprising a compound of the invention in a pharmaceutically acceptable carrier and in an amount effective to modulate triglyceride level, or to treat diseases related to dyslipidemia and disorders of lipid metabolism, when administered to an animal, preferably a mammal, most preferably a human patient.
• the patient has an elevated lipid level, such as elevated plasma triglycerides or cholesterol, before administration of said compound and said compound is present in an amount effective to reduce said lipid level.
• the invention provides methods for treating a patient for, or protecting a patient from developing, a disease or condition mediated by stearoyl-CoA desaturase (SCD) 1 which methods comprise administering to a patient afflicted with such disease or condition, or at risk of developing such disease or condition, a therapeutically effective amount of a compound that inhibits activity of SCD in a patient when administered thereto .
• SCD stearoyl-CoA desaturase
• the invention provides methods for treating a range of diseases involving lipid metabolism utilizing compounds identified by the methods disclosed herein.
• a range of compounds having said activity based on a screening assay for identifying, from a library of test compounds, a therapeutic agent which modulates the biological activity of said SCD and is useful in treating a human disorder or condition relating to serum levels of lipids, such as triglycerides, VLDL, HDL, LDL, and/or total cholesterol.
• C 7 -C 12 alkyl describes an alkyl group, as defined below, having a total of 7 to 12 carbon atoms
• C 4 -C 12 cycloalkylalkyl describes a cycloalkylalkyl group, as defined below, having a total of 4 to 12 carbon atoms.
• the total number of carbons in the shorthand notation does not include carbons that may exist in substituents of the group described.
• Method refers to the -OCH 3 radical.
• Cyano refers to the -CN radical.
• Niro refers to the -NO 2 radical.
• Trifluoromethyl refers to the -CF 3 radical.
• “Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to twelve carbon atoms, preferably one to eight carbon atoms or one to six carbon ato ms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1 -methylethyl (/so-propyl), /i-butyl, n-pentyl, 1 ,1-dimethylethyl (f-butyl), and the like.
• an alkyl group may be optionally substituted by one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, -OR 14 , -OC(O)-R '14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)OR 14 , -C(O)N(R 14 ) 2 , -N(R 14 )C(O)OR 16 , -N(R 14 )C(O)R 16 , -N(R 14 )(S(O) t R 16 ) (where t is 1 to Z), -S(O) 1 OR 16 (where t is 1 to 2), -S(O) 1 R 16 (where t is O to 2), and -S(O) t N(R 14 ) 2 (where t is 1 to Z), -
• C r C 3 alkyl refers to an alkyl radical as defined above containing one to three carbon atoms.
• the C r C 3 alkyl radical may be optionally substituted as defined for an alkyl group.
• C r C 6 alkyl refers to an alkyl radical as defined above containing one to sbc carbon atoms.
• the C r C 6 alkyl radical may be optionally substituted as defined for an alky! group.
• Ci-Ci 2 alkyl refers to an alkyl radical as defined above containing one to twelve carbon atoms.
• the d-C 12 alkyl radical may be optionally substituted as defined for an alkyl group.
• C 2 -C 6 alkyl refers to an alkyl radical as defined above containing two to six carbon atoms.
• the C 2 -C 6 alkyl radical may be optionally substituted as defined for art alkyl group.
• C 3 -C 6 alkyl refers to an alkyl radical as defined above containing three to six carbon atoms.
• the C 3 -C 6 alkyl radical may be optionally substituted as defined for ar» alkyl group.
• C 3 -C 12 alkyl refers to an alkyl radical as defined above containing three to twelve carbon atoms.
• the C 3 -C 12 alkyl radical may be optionally substituted as defined for an alkyl group.
• C 6 -C 12 alkyl refers to an alkyl radical as defined above containing six to twelve carbon atoms.
• the C 6 -C 12 alkyl radical may be optionally substituted as defined for a n alkyl group.
• C 7 -C 12 alkyl refers to an alkyl radical as defined above containing seven to twelve carbon atoms.
• 2 alkyl radical may be optionally substituted as defined for an alkyl group.
• Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bondl, having from two to twelve carbon atoms, preferably one to eight carbon atoms and which is attached to the rest of the molecule by a single bond, e.g., ethenyl, prop-1- enyl, but-1-enyl, pent-1-enyl, penta-1 ,4-d ⁇ enyl, and the like.
• an alkenyl group may be optionally substituted by one of the following groups: alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, _ aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -OR 14 , -OC(O)-R 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)OR 14 , -C(O)N(R 14 ) 2 , -N(R 14 )C(O)OR 16 , -N(R 14 )C(O)R 16 , -N(R 14 )(S(O) t R 16 ) (where t is 1 to 2), -S(O) 1 OR 16 (where t is 1 to
• C 2 -C 12 alkenyl refers to an alkenyl radical as defined above containing two to 12 carbon atoms.
• the C 2 -C 12 alkenyl radical may be optionally substituted as defined above for an alkenyl group.
• Alkylene and “alkylene chain” refer to a straight or branched divalent hydrocarbon chain, linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, preferably having from one to eight carbons, e.g., methylene, ethylene, propylene, n-butylene, and the like.
• the alkylene chain may be attached to the rest of the molecule and to the radical group through one carbon within the chain or through any two carbons within the chain.
• the alkylene chain may be optionally substituted by one of the following groups: alkyl, alkenyl, halo, hsloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, -OR 14 , -OC(O)-R 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)OR 14 , -C(O)N(R 14 ) 2> -N(R 14 )C(O)OR 16 , -N(R 14 )C(O)R 16 , -M(R 14 )(S(O) t R 16 ) (where t is 1 to 2), -S(O) 1 OR 16 (where t is 1 to 2), -S(O) 1 R 16 (where t is O to 2), and -S(O),N(R 14 ) 2 (where t is 1 to 2) where each R 14 is independently
• alkenylene and alkenylene chain refer to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one double bond and having from two to twelve carbon atoms, e.g., ethenylene, propenylene, n-butenylene, and the like.
• the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double bond or a sing Ie bond.
• the points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.
• the alkenylene chain may be optionally substituted by one of the following groups: alkyl, alkenyl, halo, haloalken;yl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, -OR 14 , -OC(O)-R 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)OR 14 , -C(O)N(R 14 ) 2j -N(R 14 JC(O)OR 16 , -N(R 14 )C(O)R 16 , -N(R 14 )(S(O) t R 16 ) (where t is 1 to 2), -S(O) 1 OR 16 (where t is 1 to 2), -S(O) 1 R 16 (where t is 0 to 2), and -S(O) t N(R 14 ) 2 (where t is 1 to 2) where each R 14
• Alkylene bridge refers to a straight or branched divalent hydrocarbon bridge, linking two different carbons of the same ring structure, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, preferably having from one to eight carbons, e.g., methylene, ethylene, propylene. n-butylene, and the like.
• the alkylene bridge may link any two carbons within the ring structure.
• Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined above.
• R a is an alkyl radical as defined above.
• the alkyl part of the alkoxy radical may be optionally substituted as defined above for an alkyl radical.
• C ⁇ C 6 alkoxy refers to an alkoxy radical as defined above containing one to six carbon atoms.
• the alkyl part of the CVC ⁇ alkoxy radical may be optionally substituted as defined above for an alkyl group.
• C-rCi 2 alkoxy refers to an alkoxy radical as defined above containing one to twelve carbon atoms.
• the alkyl part of the (VC- ⁇ alkoxy radical may be optionally substituted as defined above for an alkyl group.
• C 3 -C 12 alkoxy refers to an alkoxy radical as defined above containing three to twelve carbon atoms.
• the alkyl part of the C 3 -C 12 alkoxy radical may be optionally substituted as defined above for an alkyl group.
• Alkoxyalkyl refers to a radical of the formula -R a -O-R a where each R a is independently an alkyl radical as defined above. The oxygen atom may be bonded to any carbon in either alkyl radical.
• Each alkyl part of the alkoxyalkyl radical may be optionally substituted as defined above for an alkyl group.
• C 2 -C 12 alkoxyalkyl refers to an alkoxyalkyl radical as defined above conta ining two to twelve carbon atoms. Each alkyl part of the C 2 -C 12 alkoxyalkyl radical may be optionally substituted as defined above for an alkyl group.
• C 3 alkoxyalkyl refers to an alkoxyalkyl radical as defined above containing three carbon atoms. Each alkyl part of the C 3 alkoxyalkyl radical may be optionally substituted as defined above for an alkyl group.
• C 3 -C 12 alkoxyalkyl refers to an alkoxyalkyl radical as defined above containing three to twelve carbon atoms. Each alkyl part of the C 3 -C 12 alkoxyalkyl radical may be optionally substituted as defined above for an alkyl group.
• Alkylsulfonyl refers to a radical of the formula -S(O) 2 R a where R a is an alkyl group as defined above.
• R a is an alkyl group as defined above.
• the alkyl part of the alkylsulfonyl radical may be optionally substituted as defined above for an alkyl group.
• C- ⁇ -C 6 alkylsulfonyl refers to an alkylsulfonyl radical as defined above having one to six carbon atoms.
• the C- ⁇ -C 6 alkylsulfonyl group may be optionally substituted as defined above for an alkylsulfonyl group.
• Aryl refers to aromatic monocyclic or multicyclic hydrocarbon ring system consisting only of hydrogen and carbon and containing from 6 to 19 carbon atoms, preferably 6 to 10 carbon atoms, where the ring system may be partially or fully saturated.
• Aryl groups include, but are not limited to groups such as fluorenyl, phenyl and naphthyl.
• aryl or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R 15 -OR 14 , -R 15 -OC(O)-R 14 , -R 15 -N(R 14 ) 2 , -R 15 -C(O)R 14 , -R 15 -C(O)OR 14 , -R 15 -C(O)N(R 14 ) 2) -R 15 -N(R 14 )C(O)OR 16 , -R 15
• each R 14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R 15 is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R 16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and where each of the above substituents is unsubstituted.
• Alkyl refers to a radical of the formula -R a R b where R 3 is an alkyl radical as defined above and R b is one or more aryl radicals as defined above, e.g., benzyl, diphenylmethyl and the like.
• the aryl part of the aralkyl radical may be optionally substituted as described above for an aryl group.
• the alkyl part of the aralkyl radical may be optionally substituted as defined above for an alkyl group.
• C 7 -Ci 2 aralkyl refers to an aralkyl group as defined above containing seven to twelve carbon atoms.
• the aryl part of the C 7 -C 12 aralkyl radical may be optionally substituted as described above for an aryl group.
• the alkyl part of the C 7 -C 12 aralkyl radical may be optionally substituted as defined above for an alkyl group.
• C 7 -C 19 aralkyl refers to an aralky! group as defined above containing seven to nineteen carbon atoms.
• the aryl part of the C 7 -C 19 aralkyl radical may be optionally substituted as described above for an aryl group.
• the alkyl part of the C 7 -C 19 aralkyl radical may be optionally substituted as defined above for an alkyl group.
• C 13 -C 1 garalkyl refers to an aralkyl group as defined above containing thirteen to nineteen carbon atoms.
• the aryl part of the C 13 -C 19 aralkyl radical may be optionally substituted as described above for an aryl group.
• the alkyl part of the C 13 -C 19 aralkyl radical may be optionally substituted as defined above for an alkyl group.
• alkenyl refers to a radical of the formula -R 0 R b where R c is an alkenyl radical as defined above and R b is one or more aryl radicals as defined above, which may be optionally substituted as described above.
• the aryl part of the aralkenyl radical may be optionally substituted as described above for an aryl group.
• the alkenyl part of the aralkenyl radical may be optionally substituted as defined above for an alkenyl group.
• Aryloxy refers to a radical of the formula -OR b where R b is an aryl group as defined above. The aryl part of the aryloxy radical may be optionally substituted as defined above.
• Aryl-C-rC 6 alkyl refers to a radical of the formula -R h -R 1 where R h is an unbranched alkyl radical having one to six carbons and R 1 is an aryl group attached to the terminal carbon of the alkyl radical.
• Cycloalkyl refers to a stable non-aromatic monocyclic or bicycl ⁇ c hydrocarbon radical consisting solely of carbon and hydrogen atoms, having from three to fifteen carbon atoms , preferably having from three to twelve carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl and the like.
• cycloalkyl is meant to include cycloalkyl radicals which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R 15 -OR 14 , -R 15 -OC(O)-R 14 , -R 15 -N(R 14 ) 2l -R 15 -C(O)R 14 , -R 15 -C(O)OR 14 , -R 15 -C(O)N(R 14 ) 2 , -R 15 -N(R 14 )C(O)OR 16 , -R 15 -N(R 14 )C
• C 3 -C 6 cycloalkyr' refers to a cycloalkyl radical as defined above having three to six carbon atoms.
• the C 3 -C 6 cycloalkyl radical may be optionally substituted as defined above for a cycloalkyl group.
• C 3 -C 12 cycloalkyl refers to a cycloalkyl radical as defined above having three to twelve carbon atoms.
• the C 3 -C 12 cycloalkyl radical may be optionally substituted as defined above for a cycloalkyl group.
• Cycloalkylalkyl refers to a radical of the formula -R 3 R d where R 3 is an alkyl radical as defined above and R d is a cycloalkyl radical as defined above.
• the cycloalkyl part of the cycloalkyl radical may be optionally substituted as defined above for an cycloalkyl radical.
• the alkyl part of the cycloalkyl radical may be optionally substituted as defined above for an alkyl radical.
• C 4 -C 12 cycloalkylalkyl refers to a cycloalkylalkyl radical as defined above having four to twelve carbon atoms.
• the C 4 -C 12 cycloalkylalkyl radical may be optionally substituted as defined above for a cycloalkylalkyl group.
• Halo refers to bromo, chloro, fluoro or iodo.
• Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl,
• alkyl part of the haloalkyl radical may be optionally substituted as defined above for an alkyl group.
• Haloalkenyl refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 2-bromoethenyl, 3-bromoprop-1- enyl, and the like.
• the alkenyl part of the haloalkenyl radical may be optionally substituted as defined above for an alkyl group.
• Heterocyclyl refers to a stable 3- to 18-membered non-aromatic ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
• the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized; and the heterocyclyl radical may be partially or fully saturated.
• heterocyclyl radicals include, but are not limited to, dioxolanyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazo ⁇ dinyl, isoxiazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thionnorpholinyl
• heterocyclyl is meant to include heterocyclyl radicals as defined above which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R 15 -OR 14 , -R 15 -OC(O)-R 14 , -R 15 -N(R 14 ) 2 , -R 15 -C(O)R 14 , -R 15 -C(O)OR 14 , -R 15 -C(O)N(R 14 ) 2 , -R 15 -N(R 14 )C(O)OR 16 , -R 15 -C(O)N(R
• each R 14 is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R 15 is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R 16 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkyl,
• C 3 -C 12 heterocyclyl refers to a heterocyclyl radical as defined above having three to twelve carbons.
• the C 3 -C 12 heterocyclyl may be optionally substituted as defined above for a heterocyclyl group.
• Heterocyclylalkyl refers to a radical of the formula -R a R e where R 3 is an alkyl radical as defined above and R 6 is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at the nitrogen atom.
• the alkyl part of the heterocyclylalkyl radical may be optionally substituted as defined above for an alkyl group.
• the heterocyclyl part of the heterocyclylalkyl radical may be optionally substituted as defined above for a heterocyclyl group.
• C 3 -C 12 heterocyclylalkyl refers to a heterocyclylalkyl radical as defined above having three to twelve carbons.
• the C 3 -C 12 heterocyclylalkyl radical may be optionally substituted as defined above for a heterocyclylalkyl group.
• Heteroaryl refers to a 5- to 18-membered aromatic ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
• the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized.
• Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazx>[1 ,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, isox
• heteroaryl is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroa ryl, heteroarylalkyl, -R 15 -OR 14 , -R 15 OC(O)-R 14 , -R 15 -N(R 14 ) 2 , -R 15 -C(O)R 14 , -R 15 -C(0)OR 14 , -R 15 -C(O)N(R 14 ) 2 , -R 15 -N(R 14 )C(O)OR 16 , -R
• C r C 12 heteroaryl refers to a heteroaryl radical as defined above having one to twelve carbon atoms.
• the CrC 12 heteroaryl group may be optionally substituted as defined above for a heteroaryl group.
• C 5 -C 12 heteroaryl refers to a heteroaryl radical as defined above having five to twelve carbon atoms.
• the C 5 -Ci 2 heteroaryl group may be optiontally substituted as defined above for a heteroaryl group.
• Heteroarylalkyl refers to a radical of the formula -R 3 R f where R a is an alkyl radical as defined above and R f is a heteroaryl radical as defined above.
• the heteroaryl part of the heteroarylalkyl radical may be optionally substituted as defined above for a heteroaryl group.
• the alkyl part of the heteroarylalkyl radical may be optionally substituted as defined above for an alky! group.
• C 3 -C 12 heteroarylalkyl refers to a heteroarylalkyl radical as defined above having three to twelve carbon atoms.
• 2 heteroarylalkyl group may be optionally substituted as defined above for a heteroarylalkyl group.
• Heteroarylcyclo alkyl refers to a radical of the formula -R d R f where R d is a cycloalkyl radical as defined above and R f is a heteroaryl radical as defined above.
• the cycloalkyl part of the heteroarylcycloalkyl radical may be optionally substituted as defined above for a cycloalkyl group.
• the heteroaryl part of the heteroarylcycloalkyl radical may be optionally substituted as defined above for a heteroaryl group.
• Heteroarylalkenyl refers to a radical of the formula -R b R f where R b is an alkenyl radical as defined above and R f is a heteroaryl radical as defined sbove.
• the heteroaryl part of the heteroarylalkenyl radical may be optionally substituted as defined above for a heteroaryl group.
• the alkenyl part of the heteroarylalkenyl radical may be optionally substituted as defined above for an alkenyl group.
• Hydroalkyl refers to a radical of the formula -R 3 -OH where R 3 is an alkyl radical as defined above.
• the hydroxy group may be attached to the alkyl radical on any carbon within the alkyl radical.
• the alkyl part of the hydroxyalkyl group may be optionally substituted as defined above for an alkyl group.
• C 2 -C 12 hydroxyalkyr' refers to ahydroxyalkyl radical as defined above containing two to twelve carbon atoms.
• the alkyl part of the C 2 -C 12 hydroxyalkyl radical may be optionally substituted as defined above for an alkyl group.
• C 3 -C 12 hydroxyalkyl refers to a hydroxyalkyl radical as defined above containing three to twelve carbon atoms.
• the alkyl part of the C 3 -C 12 hydroxyalkyl radical may be optionally substituted as defined above for an alkyl group.
• C 7 -C 12 hydroxyalkyl refers to a hydroxyalkyl radical as defined above containing seven to twelve carbon atoms.
• the alkyl part of the C 7 -C 12 hydroxyalkyl radical may be optionally substituted as defined above for an alkyl group.
• “Hydroxyalkenyl” refers to a radical of the formula -R 0 -OH where R 0 is an alkenyl radical as defined above.
• the hydroxy group may be attached to the alkenyl radical on any carbon within the alkenyl radical.
• the alkenyl part of the hydroxyalkenyl group may be optionally substituted as defined above for an alkenyl group.
• C 2 -C 12 hydroxyalkenyl refers to a hydroxyalkenyl radical as defined above containing two to twelve carbon atoms.
• the alkenyl part of the C 2 -C 12 hydroxyalkenyl radical may be optionally substituted as defined above for an alkenyl group.
• C 3 -C 12 hydroxyalkenyl refers to a hydroxyalkenyl radical as defined above containing three to twelve carbon atoms. The alkenyl part of the C 3 -C 12 hydroxyalkenyl radical may be optionally substituted as defined above for an alkenyl group.
• “Hydroxyl-C r C 6 -alkyl” refers to a radical of the formula -R h -OH where R h is an unbranched alkyl radical having one to six carbons and the hydroxy radical is attached to the terminal carbon.
• Trihaloalkyl refers to an alkyl radical, as defined above, that is substituted by three halo radicals, as defined above, e.g., trifluoromethyl.
• the alkyl part of the trihaloalkyl radical may be optionally substituted as defined above for an alkyl group.
• Ci-C 6 trihaloalkyl refers to a trihaloalkyl radical as defined above havi ng one to six carbon atoms.
• the Ci-C 6 trihaloalkyl may be optionally substituted as defined above for a trihaloalkyl group.
• Trihaloalkoxy refers to a radical of the formula -OR 9 where R 9 is a trihialoalkyl group as defined above.
• the trihaloalkyl part of the trihaloalkoxy group may be optionally substituted as defined above for a trihaloalkyl group.
• CrC ⁇ trihaloalkoxy refers to a trihaloalkoxy radical as defined above .having one to six carbon atoms.
• the d-C 6 trihaloalkoxy group may be optionally substituted as defined above for a trihaloalkoxy group.
• a multi-ring structure refers to a multicyclic ring system comprised ot two to four rings wherein the rings are independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl as defined above.
• Each cycloalkyl may be optional Iy substituted as defined above for a cycloalkyl group.
• Each aryl may be optionally substituted as defined above for an aryl group.
• Each heterocyclyl may be optionally substituted as defined above for a heterocyclyl group.
• Each heteroaryl may be optionally substituted as defined above for a heteroaryl group.
• the rings may be attached to other through direct bonds or some or all of the rings may be fused to each other. Examples include, but are not limited to a cycloalkyl radical substituted by aryl group; a cycloalkyl group substituted by an aryl group, which, in turn, is substituted by another aryl group; and so forth.
• Prodrugs is meant to indicate a compound that may be converted under physiological conditions or by solv ⁇ lysis to a biologically active compound of the invention.
• prodrug refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable.
• a prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention.
• Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood.
• the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H ., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
• prodrugs are also meant to include any covalently bonded carriers which release the active compound of the invention in vivo when such prodrug is ad ministered to a mammalian subject.
• Prodrugs of a compound of the invention may be prepared by modifying functional groups present in trie compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention.
• Prodrugs include compounds of the invention wh erein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
• Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the compounds of thie invention and the like.
• Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
• “Mammal” includes humans and domestic animals, such as cats, dogs, swine, cattle, sheep, goats, horses, rabbits, and the like.
• Optional or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
• optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
• “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in hurnans or domestic animals.
• “Pharmaceutically acceptable salt” includes both acid and base addition salts.
• “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biolog ⁇ cally or otherwise undesirable, and which are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroaceticacid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disul
• “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologi cally or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
• Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, cinoline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucarnine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, ⁇ /-ethylpiperidine, polyamine resins and the like.
• Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. Often crystallizations produce a solvate of the compound of the invention.
• the term "solvate" refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent.
• Th e solvent may be water, in which case the solvate may be a hydrate.
• the solvent may be an organic solvent.
• the compounds of the present invention may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms.
• Th-e compound of the invention may be true solvates, while in other cases, the compound of the invention may merely retain adventitious water or be a mixture of water plus some adventitious solvent.
• a "pharmaceutical composition” refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.
• “Therapeutically effective amount” refers to that amount of a compound of the invention which, when administered to a mammal, preferably a human, is sufficient to effect treatment, as defined below, of an SCD-mediated disease or condition in the mammal, preferably a human.
• the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowled-ge and to this disclosure.
• Treating covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or disorder o»f interest, and includes: (i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition but has not yet been diagnosed as having it;
• disease and “condition” may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.
• the compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomer ⁇ forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
• the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
• Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as HPLC using a chiral column.
• the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
• stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
• the present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
• a “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule.
• the present invention includes tautomers of any said compounds.
• a compound of formula (I) where x and y are both 1 ; G is -S-; L and M are both -N ; J and K are both N; W is -N(H)C(O)-; V is -C(O)-; R 2 is ⁇ -hexyl; R 3 is 2-trifluoromethylphenyl; and R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 and R 8a are each hydrogen, i.e., a compound of the following formula:
• W is described, for example, as being -N(R 1 )C(O)-, -C(O)N(R 1 )-, or-N(R 1 )C(O)N(R 1 )-; and V is described as -C(O)-, -C(S)- or -C(R 10 )H-.
• This description is meant to describe a W group attached to the R 2 group as follows: R 2 -N(R 1 )C(O)-, R 2 -C(O)N(R 1 )-, or R 2 -N(R 1 )C(O)N(R 1 )-; and meant to describe a V group attached to the R 3 group as follows: -C(O)-R 3 , -C(R 10 )(H)-R 3 , or -C(S)-R 3 .
• the description of the W and V linkage groups are meant to be read from left to right in view of formula (I) as depicted above.
• one embodiment of the compounds of formula (I) is that embodiment wherein J and K are both N, i.e., compound having the following formula (Ia):
• this subset of compounds include the following: 5-[4-(2-Trifluoromethylbenzoyl)piperazin-1 -yl]-[1 ,3,4]thiadiazole-2-carboxylic acid ethyl ester;
• this subset of compounds include the following: 5-[4-(2-Trifluoromethyl benzoyl) piperazin-1-yl] [1 ,3,4]oxadiazole-2-carboxylic acid pentylamide;
• R 3 is other than substituted phenylene, substituted phenyl and substituted thiazolyl.
• a group of compounds of formula (I) is directed to compounds where K is N, and V is -C(O)-, -C(0)0-,-C(S)-, -C(O)N(R 1 )-, -S(O)p- (where p is 1 or 2), -S(O) P N(R 1 )- (where p is 1 or 2), or -C(R 10 )H-.
• a group of compounds of formula (I) is directed to compounds where K is -C(R 11 )-, V is -C(O)-, -C(0)0-,-C(S)-, -C(O)N(R 1 )-, -S(O) 1 - (where t is 1 or 2), -S(O) P N(R 1 )- (where p is 1 or 2), -C(R 10 )H-, - N(R 1 )- or -O-;
• K is -C(R 11 )-
• V is -C(O)-, -C(0)0-,-C(S)-, -C(O)N(R 1 )-, -S(O) 1 - (where t is 1 or 2), -S(O) P N(R 1 )- (where p is 1 or 2), -C(R 10 )H-, - N(R 1 )- or -O-;
• one embodiment are those compounds of formula (II) where J and K are N, i.e., compounds of the following formula (Ha):
• R 12 is hydrogen,-C(O)OR 13 , -C(O)N(R 1 3 ) 2 , d-C 12 alkyl, C 2 -C 12 hydroxyalkyl, C 4 -C 12 cycloalkylalkyl or C 7 -C 1g aralkyl; and each R 13 is independently selected from hydrogen, d-C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C-i 2 hydroxyalkyl, C 2 -d 2 hydroxyalkenyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, Cs-C ⁇ heterocyclylalkyl, C-i-d 2 heteroaryl, and C 3 -d 2 heteroarylalkyl.
• a group of compounds of formula (II) is directed to compounds where K ⁇ s N, and V is -C(O)-, -C(O)O-,-C(S)-, -C(O)N(R 1 )-, -S(O) p - (where p is 1 or 2), -S(O) P N(R 1 )- (where p is 1 or 2), or -C(R 10 )H-.
• a group of compounds of formula (II) is directed to compounds where K ⁇ s N, and V is -C(O)-, -C(O)O-,-C(S)-, -C(O)N(R 1 )-, -S(O) p - (where p is 1 or 2), -S(O) P N(R 1 )- (where p is 1 or 2), or -C(R 10 )H-.
• a group of compounds of formula (II) is directed to compounds where
• (II) is directed to compounds where K is -C(R 11 )-, V is -C(O)-, -C(O)O-,-C(S)-, -C(O)N(R 1 )-, -S(O) 1 - (where t is 1 or 2), -S(O) P N(R 1 )- (where p is 1 or 2), -C ⁇ R 10 )H-, - N(R 1 )- or -O-;
• the methods of the invention are directed towards the treatment and/or prevention of diseases mediated by stearoyl-CoA desaturase (SCD), especially human SCD (hSCD), preferably diseases related to dyslipidem ia and disorders of lipid metabolism, and especially a disease related to elevated plasma lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome and the like by administering an effective amount of a compound of the invention.
• SCD stearoyl-CoA desaturase
• hSCD human SCD
• diseases related to dyslipidem ia and disorders of lipid metabolism preferably diseases related to dyslipidem ia and disorders of lipid metabolism, and especially a disease related to elevated plasma lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome and the like by administering an effective amount of a compound of the invention.
• the present invention also relates to pharmaceutical composition containing the compounds of the invention.
• the invention relates to a composition comprising compounds of the invention in a pharmaceutically acceptable carrier and in an amount effective to modulate triglyceride level or to treat diseases related to dyslipidemia and disorders of lipid metabolism, when administered to an animal, preferably a mammal, most preferably a human patient.
• the patient has an elevated lipid level, such as elevated triglycerides or cholesterol, before administration of said compound of the invention and the compound of the invention is present in an amount effective to reduce said lipid level.
• the present invention relates to compounds, pharmaceutical compositions and methods of using the compounds and pharmaceutical compositions for the treatment and/or prevention of diseases mediated by stearoyl-CoA desaturase (SCD), especially human SCD (hSCD), preferably diseases related to dyslipidemia and disorders of lipid metabolism, and especially a disease related to elevated plasma lipid levels, especially cardiovascular disease, diabetes, obesity, metabolic syndrome and the like, by administering to a patient in need of such treatment an effective amount of an SCD- modulating, especially inhibiting, agent.
• SCD stearoyl-CoA desaturase
• hSCD human SCD
• diseases related to dyslipidemia and disorders of lipid metabolism preferably diseases related to dyslipidemia and disorders of lipid metabolism, and especially a disease related to elevated plasma lipid levels, especially cardiovascular disease, diabetes, obesity, metabolic syndrome and the like, by administering to a patient in need of such treatment an effective amount of an SCD- modulating, especially inhibiting, agent.
• the present invention provides a method for treating a patient for, or protecting a patient from developing, a disease related to dyslipidemia and/or a disorder of lipid metabolism, wherein lipid levels in an animal, especially a human being, are outside the normal range (i.e., abnormal lipid level, such as elevated plasma lipid levels), especially levels higher than normal, preferably where said lipid is a fatty acid, such as a free or complexed fatty acid, triglycerides, phospholipids, or cholesterol, such as where LDL-cholesterol levels are elevated or HDL-cr*olesterol levels are reduced, or any combination of these, where said lipid-related condition or disease is an SCD-mediated disease or condition, comprising administering to an animal, such as a mammal, especially a human patient, a therapeutically effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention wherein the compound modulates the activity of SCD, preferably human SCD1.
• the compounds of the invention modulate
• the general value of the compounds of the invention in modulating , especially inhibiting, the activity of SCD can be determined using the assay described below in Example 8.
• the general value of the compounds in treating disorders and diseases may be established in industry standard animal models for demo nstrating the efficacy of compounds in treating obesity, diabetes or elevated triglyceride or cholesterol levels or for improving glucose tolerance.
• Such models include Zucker obese fa/fa rats (available from Harlan Sprague Dawley, Inc. (Indianapolis , Indiana)), or the Zucker diabetic fatty rat (ZDF/GmiCrl-/a//aj (available from Charles River Laboratories (Montreal, Quebec)).
• the compounds of the instant invention are inhibitors of delta-9 desaturases and are useful for treating diseases and disorders in humans and other organisms, including all those human diseases and disorders which are the result of aberrant delta-9 desaturase biological activity or which may be ameliorated by mod ulation of delta-9 desaturase biological activity.
• an SCD-mediated disease or condition includes but is not limited to a disease or condition which is, or is related to, cardiovascular d isease, dyslipidemias (including but not limited to disorders of serum levels of triglycerides, hypertriglyceridemia, VLDL, HDL, LDL, fatty acid Desaturation Index (e.g.
• compounds of the invention will, in a patient, increase HDL levels and/or decrease triglyceride levels and/or decrease LDL or non-HD L-cholesterol levels.
• An SCD-mediated disease or condition also includes metabolic syndrome (including but not limited to dyslipidemia, obesity and insulin resistance, hypertension, microalbuminemia, hyperuricaemia, and hypercoagulability), Syndrome X, diabetes, insulin resistance, decreased glucose tolerance, non-insulin-dependent diabetes mellitus, Type Il diabetes, Type I diabetes, diabetic complications, body weight disorders (including but not limited to obesity, overweight, cachexia and anorexia), weight loss, body mass index and leptin related diseases.
• metabolic syndrome including but not limited to dyslipidemia, obesity and insulin resistance, hypertension, microalbuminemia, hyperuricaemia, and hypercoagulability
• Syndrome X diabetes, insulin resistance, decreased glucose tolerance, non-insulin-dependent diabetes mellitus, Type Il diabetes, Type I diabetes, diabetic complications, body weight disorders (including but not limited to obesity, overweight, cachexia and anorexia), weight loss, body mass index and leptin related diseases.
• compounds of the invention will be used to treat diabetes mellitus and obesity.
• metabolic syndrome is a recognized clinical term used to describe a condition comprising combinations of Type Il diabetes, impaired glucose tolerance, insulin resistance, hypertension, obesity, increased abdominal girth, hypertriglyceridemia, low HDL, hyperuricaemia , hypercoagulability and/or microalbuminemia.
• An SCD-mediated disease or condition also includes fatty liver, hepatic steatosis, hepatitis, non-alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, acute fatty liver, fatty liver of pregnancy, drug-induced hepatitis, erythrohepatic protoporphyria, iron overload disorders, hereditary hemochromatosis, hepatic fibrosis, hepatic cirrhosis, hepatoma and conditions related thereto.
• NASH non-alcoholic steatohepatitis
• An SCD-mediated disease or condition also includes but is not limited to a disease or condition which is, or is related to primary hypertriglyceridemia, or hypertriglyceridemia secondary to another disorder or disease, such as hyperlipoproteinemias, familial histiocytic reticulosis, lipoprotein lipase deficiency, apolipoprotein deficiency (such as ApoCII deficiency or ApoE deficiency), and the like, or hypertriglyceridemia of unknown or unspecified etiology.
• a disease or condition which is, or is related to primary hypertriglyceridemia, or hypertriglyceridemia secondary to another disorder or disease, such as hyperlipoproteinemias, familial histiocytic reticulosis, lipoprotein lipase deficiency, apolipoprotein deficiency (such as ApoCII deficiency or ApoE deficiency), and the like, or hypert
• An SCD-mediated disease or condition also includes a disorder of polyunsaturated fatty acid (PUFA) disorder, or a skin disorder, including but not limited to eczema, acne, psoriasis, keloid scar formation or prevention, diseases related to production or secretions from mucous membranes, such as monounsaturated fatty acids, wax esters, and the like.
• PUFA polyunsaturated fatty acid
• An SCD-mediated disease or condition also includes inflammation, sinusitis, asthma, pancreatitis, osteoarthritis, rheumatoid arthritis, cystic fibrosis, and pre ⁇ menstrual syndrome.
• An SCD-mediated disease or condition also includes but is not limited to a disease or condition which is, or is related to cancer, neoplasia, malignancy, metastases, tumours (benign or malignant), carcinogenesis, hepatomas and the like.
• An SCD-mediated disease or condition also includes a condition where increasing lean body mass or lean muscle mass is desired, such as is desirable in enhancing performance through muscle building.
• Myopathies and lipid myopathies such as carnitine palmitoyltransferase deficiency (CPT I or CPT " II) are also included herein.
• Such treatments are useful in humans and in animal husbandry, including for administration to bovine, porcine or avian domestic animals or any other animal to reduce triglyceride production and/or provide leaner meat products and/or healthier animals.
• An SCD-mediated disease or condition also includes a disease or condition which is, or is related to, neurological diseases, psychiatric disorders, multiple sclerosis, eye diseases, and immune disorders.
• An SCD-mediated disease or condition also includes a disease or condition which is, or is related to, viral diseases or infections including but not limited to all positive strand RNA viruses, coronaviruses, SARS virus, SARS-associated coronavirus, Togaviruses, Picomaviruses, Coxsackievirus, Yellow Fever virus, Flaviviridae, ALPHAVIRUS (TOGAVIRIDAE) including Rubella virus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Sindbis virus, Semliki forest virus, Chikungunya virus, O'nyong'nyong virus, Ross river virus, Mayaro virus, Alphaviruses; ASTROVIRIDAE including Astrovirus, Human Astroviruses; CALICIVIRIDAE including Vesicular exanthema of swine virus, Norwalk virus, Calicivirus, Bovine calicivirus, Pig calcivirus, Hepatitis E;
• Treatable viral infections include those where the virus employs an RNA intermediate as part of the replicative cycle (hepatitis or HIV); additionally it can be a disease or infection caused by or linked to RNA negative strand viruses such as influenza and parainfluenza viruses.
• the compounds identified in the instant specification inhibit the desaturation of various fatty acids (such as the C9-C10 desaturation of stearoyl-CoA) which is accomplished by delta-9 desaturases, such as stearoyl-CoA desaturase 1 (SCD1). As such these compounds inhibit the formation of various fatty acids and downstream metabolites thereof. This may lead to an accumulation of stearoyl-CoA or palmitoyl- CoA and other upstream precursors of various fatty acids; whi ich may possibly result in a negative feedback loop causing an overall change in fatty a cid metabolism. Any of these consequences may ultimately be responsible for the overall therapeutic benefit provided by these compounds.
• various fatty acids such as the C9-C10 desaturation of stearoyl-CoA
• SCD1 stearoyl-CoA desaturase 1
• a successful SCD inhibitory therapeutic ag&nt will meet some or all of the following criteria.
• Oral availability should be at or above 20%.
• Animal model efficacy is less than about 2 mg/Kg, 1 mg/Kg, or 0.5 mg/Kg and the target human dose is between 50 and 250 mg/70 Kg, although doses outside of this range may be acceptable.
• mg/Kg means milligrams of compound per kilogram of body mass of the subject to whom it is being administered).
• the therapeutic index or ratio of toxic dose to therapeutic dose
• the potency should be less than 10 ⁇ M, preferably below 1 ⁇ M anct most preferably below 50 nlvi.
• the IC 50 is a measure of the amount of compound required to achieve 50% inhibition of SCD activity, over a specific time period, in an SCD biological activity assay. Any process for measuring the activity of SCD enzymes, preferably mouse or human SCD enzymes, may be utilized to assay the activity of the compounds useful in the methods of the invention in inhibiting said SCD activity.
• Compounds of the invention demonstrate an IC 50 in a 15 minute microsomal assay of preferably less than 10 ⁇ M, less than 5 ⁇ M, less than 2.5 ⁇ M, less than 1 ⁇ M, less than 750 nM, less than 500 nM, less than 25O nM, less than 100 nM, less than 50 nM, and most preferably less than 20 nM.
• the compound of the invention may show reversible inhibition (i.e., competitive inhibition) and preferably does not inhibit other iron binding proteins.
• the required dosage should preferably be no more than about once or twice a day or at meal times.
• the identification of compounds of the invention as SCD inhibitors was readily accomplished using the SCD enzyme and microsomal assay procedure described in Brownlie et al, supra.
• compounds of the invention When tested in this assay, compounds of the invention had less than 50% remaining SCD activity at 10 ⁇ M concentration of the test compound, preferably less than 40% remaining SCD activity at 10 ⁇ M concentration of the test compound, more preferably less than 30% remaining SCD activity at 10 ⁇ M concentration of the test compound, and even more preferably less than 20% remaining SCD activity at 10 ⁇ M concentration of the test compound, thereby demonstrating that the compounds of the invention are potent i nhibitors of SCD activity.
• SAR structure-activity relationship
• said contacting may be accomplished in vivo.
• said contacting in step (a) is accomplished by administering said chemical agent to an animal afflicted with a triglyceride (TG)- or very low density lipoprotein (VLDL)-related disorder and subsequently detecting a change in plasma triglyceride level in said animal thereby identifying a therapeutic agent useful in treating a triglyceride (TG)- or very low density lipoprotein (VLDL)-related disorder.
• the animal may be a human, such as a human patient afflicted with such a disorder and in need of treatment of said disorder.
• said change in SCD1 activity in said animal is a decrease in activity, preferably wherein said SCD1 modulating agent does not substantially inhibit the biological activity of a delta-5 desaturase, delta-6 desaturase or fatty acid synthetase.
• the model systems useful for compound evaluation may include, but are not limited to, the use of liver microsomes, such as from mice that have been maintained on a high carbohydrate diet, or from human donors, including persons suffering from obesity.
• Immortalized cell lines, such as HepG2 (from human liver), MCF-7 (from human breast cancer) and 3T3-L1 (from mouse adipocytes) may also be used.
• mice used as a source of primary hepatocyte cells may also be used wherein the mice have been maintained on a high carbohydrate diet to increase SCD activity in mirocrosomes and/or to elevate plasma triglyceride levels (i.e., the 18:1/18:0 ratio); alternatively mice on a normal diet or mice with normal triglyceride levels may be used.
• Mouse models employing transgenic mice designed for hypertriglyceridemia are also available as is the mouse phenome database. Rabbits and hamsters are also useful as animal models, especially those expressing CETP (cholesteryl ester transfer protein).
• Another suitable method for determining the in vivo efficacy of the compounds of the invention is to indirectly measure their impact on inhibition of SCD enzyme by measuring a subject's Desaturation Index after administration of the compound.
• Desaturation Index as employed in this specification means the ratio of the product over the substrate for the SCD enzyme as measured from a given tissue sample. This may be calculated using three different equations 18:1n-9/18:0 (oleic acid over stearic acid); 16:1n-7/16:0 (palmitoleic acid over palmitic acid); and/or 1S:1 n-7 + 18:1 n-7/16:0 (measuring all reaction products of 16:0 desaturation over 16:0 substrate).
• Desaturation Index is primarily measured in liver or plasma triglycerides, but may also be measured in other selected lipid fractions from a variety of tissues. Desaturation Index, generally speaking, is a tool for plasma lipid profiling. A number of human diseases and disorders are the result of aberrant SCD1 biological activity and may be ameliorated by modulation of SCD 1 biological activity using the therapeutic agents of the invention.
• Inhibition of SCD expression may also affect the fatty acid composition of membrane phospholipids, as well as production or levels of triglycerides and cholesterol esters.
• the fatty acid composition of phospholipids ultimately determines membrane fluidity, while the effects on the composition of triglycerides and cholesterol esters can affect lipoprotein metabolism and adiposity.
• the present invention also relates to pharmaceutical composition containing the compounds of the invention disclosed herein.
• the present invention relates to a composition comprising compounds of the invention in a pharmaceutically acceptable carrier and in an amount effective to modulate triglyceride level or to treat diseases related to dyslipidemia and disorders of lipid metabolism, when administered to an animal, preferably a mammal, most preferably a human patient.
• the patient has an elevated lipid level, such as elevated triglycerides or cholesterol, before administration of said compound of the invention and the compound of the invention is present in an amount effective to reduce said lipid level.
• compositions useful herein also contain a pharmaceutically acceptable carrier, including any suitable diluent or excipient, which includes any pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.
• Pharmaceutically acceptable carriers include, but are not limited to, liquids, such as water, saline, glycerol and ethanol, and the like.
• Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side-effects for the patient.
• the preferred dosage range for an animal is 0.001 mg/Kg to 10,000> mg/Kg, including 0.5 mg/Kg, 1.0 mg/Kg and 2.0 mg/Kg, though doses outside this ra nge may be acceptable.
• the dosing schedule may be once or twice per day, although more often or less often may be satisfactory.
• the compounds of the invention can be used in in vitro or in vivo studies as exemplary agents for comparative purposes to find other compounds also useful in treatment of, or protection from, ttie various diseases disclosed herein.
• Suitable protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., f-butyldimethylsilyl, f-butyldiphe nylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like.
• Suitable protecting groups for amino, amidino and guanidino include f-butoxycarbonyl, benzyloxycarbonyl, and the like.
• Suitable protecting groups for mercapto include -C(O)-R" (v ⁇ -here R" is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like.
• Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters.
• Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.VV. and P. G. M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., WWey.
• the protecting group may also be a polymer resin such as a Wang resin or a 2-chlorotrityl-chloride resin.
• protected derivatives of compounds of this invention may not possess pharmacological activity as such, they may be administered to a mammal and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All prodrugs of compounds of this invention are included within the scope of the invention.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a and V are defined as in the Specification unless specifically defined otherwise.
• a base such as, but not limited to, triethylamine
• a solvent such as, but not limited to, ⁇ /,/V-dimethylforrnamide
• the final product 106 can be achieved by reacting ester 105 with an appropriate amine (excess amount) directly in the presence of sodium cyanide, or via its acid or acyl chloride derivative after hydrolysis of ester 105 with a base such as, but not limited to, lithium hydroxide.
• a base such as, but not limited to, diisopropylethylamine in a solvent such as, but not limited to, dichloromethane.
• bromothiodiazole 1 08 Bromination of 2-aminothiadiazole 107 with bromi ne in acetic acid in the presence of sodium acetate gives the bromothiodiazole 1 08, which can react with piperazine 101 in the presence of a base such as, but not limited to, triethyl amine in a solvent such as, but not limited to, 2-propanol to generate compound 109.
• the final product 110 can be achieved by reacting the amino thiadiazole 109 with an appropriate acid or acyl chloride.
• the reaction is performed in the presence of a base such as, but not limited to, diisopropylethylamine, 1-hydroxyl-1H-benzotriazole and 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide in a solvent such as, but not limited to, dichloromethane.
• a base such as, but not limited to, diisopropylethylamine, 1-hydroxyl-1H-benzotriazole and 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide
• a solvent such as, but not limited to, dichloromethane.
• the compounds of formula (II) of the invention where M is -N ; VM is -N(H)C(O)-; R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 and R 8a are each hydrogen and V is -C(O)- can be synthesized following the general procedure as described in Reaction Scheme 3.
• the pyrazole ester 112 can be obtained from acid 111 by any skilled in the art.
• a protecting group such as f-butyloxycarbonyl or benzyloxycarbonyl can be introduced by reacting with di-feit-butyl dicarbonate or benzyl chloroformate, respectively.
• the nitro group in compound 113 can be reduced by a method such as, but not limited to, using tin(ll) chloride in a refluxing 1 ,2-dimethoxyethane media.
• Compound 117 can be achieved by reacting ester 116 with an appropriate amine (excess amount) directly in the presence of sodium cyanide, or via its acid or acyl chloride derivative after hydrolysis of ester 116 with a base such as, but not limited to, lithium hydroxide.
• the protecting group can be removed to give the final product 1 18 by using acidic conditions (for f-Boc) or hyd rogenation conditions (for Cbz) as described in Green, T.W. and P. G. M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley.
• Ethyl chlorooxoacetate (0.84 ml_, 7.54 mmol) was added dropwise to a stirred solution of 4-(2-trifluoromethylbenzoyl)piperazine-1-carbothioic acid hydrazide (2.18 g, 6.56 mmol) and triethylamine in 8 mL of DM F at 0 0 C over 15 minutes. The mixture was stirred for 1 hour, then 100 ml_ of ethyl scetate was added.
• Oxo- ⁇ /'-[4-(2-trifluoromethylbenzoyl)piperazine>-1-carbothioyl]hydrazino ⁇ -acetic acid ethyl ester (2.88 g, 6.56 mmol) was dissolved in a mixture of 50 mL of toluene and 10 mL of ⁇ /-methyl-2-pyrrolidone. Methanesulfonic acid (0.723 mL, 11.15 mmol) was then added dropwise over 5 minutes to the stirred solution. The mixture was refluxed for 1.5 hours, then evaporated to 10 ml_, and then 20 mL of water was added. The pH of the solution was adjusted to 8 by saturated NaHCO 3 .
• CDCI 3 ⁇ 174.5, 167.6, 163.3, 160.0, 158.3, 155.6, 134.1 , 133.9, 132.4, 130.2, 130.1 , 129.7, 129.1 , 126.9, 126.7, 126.8, 125.4, 121 .8, 115.6, 1 15.3, 49.5, 48.9, 45.9, 40.9, 40.7, 34.9.
• reactions are started by adding 2 mg of microsomal protein to pre-incubated tubes containing 0.20 ⁇ Ci of the substrate fatty acid (1- 14 C palmitic acid) at a final concentration of 33.3 ⁇ M in 1.5 ml of homogenization solution, containing 42 mM NaF, 0.33 mM niacinamide, 1.6 mM ATP, 1.0 mM NADH, 0.1 rnM coenzyme A and a 10 ⁇ M concentration of test compound.
• the tubes are vortexed vigorously and after 15 min incubation in a shaking water bath (37 0 C), the reactions are stopped and fatty acids are analyzed.
• Fatty acids are analyzed as follows: The reaction m ixture is saponified with 10% KOH to obtain free fatty acids which are further methylated using BF 3 in methanol.
• the fatty acid methyl esters are analyzed by high performance liquid chromatography (HPLC) using a Hewlett Packard 1090, Series Il chromatograph equipped with a diode array detector set at 205 nm, a radioisotope detector (Model 171 , Beckman, CA) with a solid scintillation cartridge (97% efficiency for 14 C-detection) and a reverse-phase ODS (C-18) Beckman column (250 mm x 4.6 mm i.d.; 5 ⁇ m particle size) attached to a pre- column with a ⁇ Bondapak C-18 (Beckman) insert.
• HPLC high performance liquid chromatography
• Fatty acid methyl esters are separated isocratically with acetonitrile/water (95:5 v:v) at a flow rate of 1 mL/min and are identified by comparison with authentic standards.
• fatty acid methyl esters may be analyzed by capillary column gas-chromatography (GC) or Thin Layer Chromatography (TLC).

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