WO2009073779A1 - Gamma secretase modulators - Google Patents

Gamma secretase modulators Download PDF

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Publication number
WO2009073779A1
WO2009073779A1 PCT/US2008/085520 US2008085520W WO2009073779A1 WO 2009073779 A1 WO2009073779 A1 WO 2009073779A1 US 2008085520 W US2008085520 W US 2008085520W WO 2009073779 A1 WO2009073779 A1 WO 2009073779A1
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Prior art keywords
group
effective amount
compound
compounds
alkyl
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PCT/US2008/085520
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French (fr)
Inventor
Xianhai Huang
Anandan Palani
Jun Qin
Robert G. Aslanian
Zhaoning Zhu
William J. Greenlee
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Schering Corporation
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Priority to CA2707722A priority Critical patent/CA2707722A1/en
Priority to JP2010537048A priority patent/JP2011506336A/en
Priority to CN2008801263971A priority patent/CN101939312A/en
Priority to EP08857874A priority patent/EP2229375A1/en
Priority to US12/746,313 priority patent/US20100298359A1/en
Priority to MX2010006244A priority patent/MX2010006244A/en
Publication of WO2009073779A1 publication Critical patent/WO2009073779A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to certain heterocyclic compounds useful as gamma secretase modulators, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat various diseases including central nervous system disorders such as, for example, neurodegenerative diseases such as Alzheimer's disease and other diseases relating to the deposition of amyloid protein. They are especially useful for reducing Amyloid beta (hereinafter referred to as A ⁇ ) production which is effective in the treatment of diseases caused by A ⁇ such as, for example, Alzheimers and Down Syndrome.
  • a ⁇ Amyloid beta
  • Alzheimer's disease is a disease characterized by degeneration and loss of neurons and also by the formation of senile plaques and neurofibrillary change.
  • treatment of Alzheimer's disease is limited to symptomatic therapies with a symptom-improving agent represented by an acetylcholinesterase inhibitor, and the basic remedy which prevents progress of the disease has not been developed.
  • a method of controlling the cause of onset of pathologic conditions needs to be developed for creation of the basic remedy of Alzheimer's disease.
  • a ⁇ protein which is a metabolite of amyloid precursor protein (hereinafter referred to as APP), is considered to be greatly involved in degeneration and loss of neurons as well as onset of demential conditions (for example, see Klein W L, et al Proceeding National Academy of Science USA, Sep. 2, 2003, 100(18), p. 10417-22, suggest a molecular basis for reversible memory loss.
  • APP amyloid precursor protein
  • a ⁇ protein A ⁇ 40 consisting of 40 amino acids and A ⁇ 42 having two additional amino acids at the C-terminal.
  • the A ⁇ 40 and A ⁇ 42 tend to aggregate (for example, see Jarrell J T et al, The carboxy terminus of the ⁇ amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease, Biochemistry, May 11 ,1993, 32(18), p.
  • senile plaques for example, (Glenner GG, et al, Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochemical and Biophysical Research Communications, May 16, 1984, 120(3), p. 885-90. See also Masters C L, et al, Amyloid plaque core protein in Alzheimer disease and Down syndrome, Proceeding National Academy of Science USA, June 1985, 82(12), p. 4245-4249.).
  • a ⁇ 40 and A ⁇ 42 are expected to be agents for controlling progress of Alzheimer's disease or for preventing the disease.
  • These A ⁇ s are produced when APP is cleaved by beta secretase and subsequently cleaved by gamma secretase.
  • beta secretase a secretase
  • gamma secretase a secretase inhibitors
  • Many of these known secretase inhibitors are peptides or peptidomimetics such as L-685,458.
  • L-685,458 an asparty! protease transition state mimic, is a potent inhibitor of ⁇ -secretase activity, (Biochemistry, Aug. 1 , 2000, 39(30), p. 8698-8704).
  • the present invention provides a novel class of heterocyclic compounds as gamma secretase modulators (including inhibitors, antagonists and the like), methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more diseases associated with the A ⁇ using such compounds or pharmaceutical compositions.
  • gamma secretase modulators including inhibitors, antagonists and the like
  • One embodiment, of the present invention is directed to compounds of formula (I): or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4 , and L are as defined below.
  • This invention also provides compounds of formula (I).
  • This invention also provides compounds of formula (I) in pure and isolated form.
  • This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas fA to IE, 1A to 4A, A1.1 to A28.1, A1.2 to A22.2, A24.2 to A28.2, 5.1, 8.1, 11.1, and A1 to A28.
  • This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas IA to IE.
  • This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas 1 A to 4A.
  • This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas A1.1 to A28.1.
  • This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas A1.2 to A22.2, and A24.2 to A28.2.
  • This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas 5.1 , 8.1 , and 11.1.
  • This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas A1 to A28.
  • This invention also provides pharmaceutical compositions comprising an effective amount of one or more (e.g., one) compounds of formula (I), or a pharmaceutically acceptable salt, ester or solvate thereof, and a pharmaceutically acceptable carrier.
  • This invention also provides pharmaceutical compositions comprising an effective amount of one or more (e.g., one) compounds of formula (I), or a pharmaceutically acceptable salt, ester or solvate thereof, and an effective amount of one or more (e.g., one) other pharmaceutically active ingredients (e.g., drugs), and a pharmaceutically acceptable carrier.
  • the compounds of formula (I) can be useful as gamma secretase modulators and can be useful in the treatment and prevention of diseases such as, for example, central nervous system disorders such as Alzheimers disease and Downs Syndrome.
  • This invention also provides combination therapies for (1) modulating gamma- secretase, or (2) treating one or more neurodegenerative diseases, or (3) inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), or (4) treating Alzheimer's disease.
  • the combination therapies are directed to methods comprising the administration of an effective amount of one or more (e.g. one) compounds of formula (I) and the administration of an effective amount of one or more (e.g., one) other pharmaceutical active ingredients (e.g., drugs).
  • This invention also provides methods for: (1) treating mild cognitive impairment; (2) treating glaucoma; (3) treating cerebral amyloid angiopathy; (4) treating stroke; (5) treating dementia; (6) treating microgliosis; (7) treating brain inflammation; and (8) treating olfactory function toss; wherein wherein each method comprises administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of such treatment.
  • each method comprises administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of such treatment.
  • This invention also provides a kit comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of a compound of formula (I) in a pharmaceutically acceptable carrier, and another container (i.e., a second container) comprises an effective amount of another pharmaceutically active ingredient (as described below), the combined quantities of the compound of formula (I) and the other pharmaceutically active ingredient being effective to treat the diseases or conditions mentioned in any of the above methods.
  • This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds of formulas IA to IE, 1 A to 4A, A1.1 to A28.1 , A1.2 to A22.2, A24.2 to A28.2, 5.1 , 8.1 , 11.1 , and A1 to A28.
  • This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds IA to IE.
  • This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from tf ⁇ e group consisting of: compounds 1 A to 4A.
  • This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds A1.1 to A28.1.
  • This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds A1.2 to A22.2, and A24.2 to A28.2.
  • This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds 5.1 , 8.1 , and 11.1.
  • This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds A1 to A28.
  • R 1 , R 2 , R 3 , R 4 and L are each independently selected;
  • R 1 is selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl (e.g., heterocycloalkyl), cycloalkenyl, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl), heterocyclenyl (i.e., heterocycloalkenyl), fused cycloalkylaryl (i.e., cycloalkyfusedlaryl-), fused heterocycloalkylaryl- (i.e., heterocycloalkylfusedaryl-), fused cycloalkylheteroaryl- (i.e., cycloalkylfusedheteroaryl-), fused heterocycloalkylheteroaryl- (
  • cycfoalkylfusedheteroarylalkyl- and fused heterocycloalkylheteroarylalkyl- (i.e., heterocycloalkylfusedheteroarylalkyl-), wherein each of said: alkyl, alkenyf, alkyny!, cycloalkyl, heterocyclyl, cycloatkenyl, aryl, heteroaryl, heterocyclenyl fused cycloalkylaryl, fused heterocycloalkylaryl-, fused cycloalkylheteroaryl-, fused heterocyctoalkylheteroaryl-, fused benzocycloalkyialkyl-, fused benzoheterocycloalkylalkyl- fused heteroarylcyctoalkylalkyl-, fused heteroarylheterocycloalkylalkyl-, fused cycloalkylarylaikyf-, fused heterocyclo
  • R 2 is the fused bicyctic ring:
  • Ring (A) is a six membered heteroaryl ring comprising atoms A 1 to A 6 , wherein:
  • a 2 , A 3 and A 4 are each independently selected from the group consisting of: N and C, and wherein each substitutable C is optionally substituted with one R 21B group and each R 2tB for each C is independently selected, and
  • Ring (B) (which comprises atoms A 5 , A 6 , and B 1 to B 4 ) is a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl or phenyl ring, and (a) A 5 and A 6 are as defined for Ring (A) above,
  • B 2 , B 3 , and B 4 are each optionally substituted with one R 21B group (and the substitution on each carbon is independent of the substitutions on the remaining carbons), (C) in said cycloalkyl Ring (B): (i) B 1 is C,
  • each substitutable B 1 to B 4 C is optionally substituted with 1 or 2 independently selected R groups (and the substitution on each carbon is independent of the substitutions on the remaining carbons, and those skilled in the art will appreciate that the total number of optional substitutents on a carbon is determined by the number bonds in the ring to the ring atom),
  • each substitutable B 1 to B 4 C is optionally substituted with 1 or 2 independently selected R groups (and the substitution on each carbon is independent of the substitutions on the remaining carbons, and those skilled in the art will appreciate that the total number of optional substitutents on a carbon is determined by the number bonds in the ring to the ring atom), and
  • said cycloalkenyl Ring (B) comprises one or two double bonds (and in one example one double bond, and in another example two double bonds),
  • B 1 is selected from the group consisting of N and C
  • B 1 to B 4 at least one (e.g., 1 to 3, or 1 to 2, or 1) of B 1 to B 4 is a heteroatom, and provided that when B 1 is a heteroatom said heteroatom is N, and the heteroatoms for B 2 to B 4 (when one or more of B 2 to B 4 are heteroatoms) are selected from the group consisting of: N 1 O, S, S(O), and S(O) 2 ,
  • each substitutable B 1 to B 4 C is optionally substituted with 1 or 2 independently selected R 21B groups (and the substitution on each carbon is independent of the substitutions on the remaining carbons, and those skilled in the art will appreciate that the total number of optional substitutents on a carbon is determined by the number bonds in the ring to the ring atom), and
  • each substitutable B 2 to B 4 N is optionally substituted with one R 21A group and each R 21A for each N is independently selected, (f) in said heterocycloalkenyl Ring (B):
  • B 1 is selected from the group consisting of N and C,
  • B 1 to B 4 at least one (e.g., 1 to 4, or 1 to 3, or 1 to 2, or 1) of B 1 to B 4 is a heteroatom, provided that when B 1 is a heteroatom said heteroatom is N, and the heteroatoms for B 2 to B 4 (when one or more of B 2 to B 4 are heteroatoms) are selected from the group consisting of: N, O, S, S(O), and S(O) 2 ,
  • each substitutabie B 1 to B 4 C is optionally substituted with 1 or 2 independently selected R groups (and the substitution on each carbon is independent of the substitutions on the remaining carbons, and those skilled in the art will appreciate that the total number of optional substitutents on a carbon is determined by the number bonds in the ring to the ring atom),
  • each substitutable B 2 to B 4 N is optionally substituted with one R 21 ⁇ group and each R 21A for each N is independently selected, and
  • said heterocycloalkenyl Ring (B) comprises one or two double bonds (and in one example one double bond, and in another example two double bonds);
  • B 2 to B 4 are each independently selected from the group consisting of C and N,
  • B 2 to B 4 is a heteroatom (e.g., at least one of B 2 to B 4 is N), and (iv) the total number of heteroatoms in said heteroaryl Ring (B) is 1 to 3 and wherein each substitutable B 2 to B 4 C is optionally substituted with one R 21B group (and the substitution on each carbon is independent of the substitutions on the remaining carbons);
  • R 3 is selected from the group consisting of: aryl- (e.g., phenyl), heteroaryl- (e.g., pyridyl), cycloalkyl-, cycloalkenyl, cycloalkylalkyl-, heterocyclyl-, heterocyclenyl-, heterocyclylalkyl-, heterocyclyalkenyl-, fused benzocycloalkyl- (i.e., benzofusedcycloalkyl-), fused benzoheterocycloalkyl- (i.e., benzofusedheterocycloalkyl-), fused heteroarylcycloalkyl- (i.e., heteroarylfusedcycloalkyl-), fused heteroarylheterocycloalkyl- (i.e., heteroarylfusedheterocycloalkyi-), fused cycloalkylaryl (i.e., cycloalkyfusedlaryl-), fused hetero
  • X is selected from the group consisting of: 0, -N(R 14 )- and -S-; and wherein each of said R 3 moieties is optionally substituted with 1 -5 independently selected R 21 groups;
  • R 4 is selected from the group consisting of: arylalkoxy-, heteroarylalkoxy-, arylalkylamino-, heteroarylalkylamino-, aryl, heteroaryl, cycloalkyl-, cycloalkenyl, heterocyclyl, heterocyclenyl, and heterocyclyalkyl-, wherein each of said R 4 arylalkoxy-, heteroarylalkoxy-, arylalkylamino-, heteroarylalkylamino-, aryl, heteroaryl, heterocyclyl, heterocyclenyl, and heterocyclyalkyl- is optionally substituted with 1 -5 independently selected R 21 groups; or R 3 and R 4 are linked together to form a fused tricyclic ring system wherein R 3 and R 4 are as defined above and the ring linking R 3 and R 4 is an alkyl ring, or a heteroalkyl ring, or an aryl ring, or a heteroaryl ring, or
  • R 6 and R 7 are each independently selected from the group consisting of: H, alky!, alkenyl, alkynyl, aryl, arylalkyl-. alkylaryl-, cycloalkyl, cycloalkylalkyl-, heteroaryl, heteroarylalkyl-, heterocyclyl (i.e., heterocycloaikyl) and heterocyclylalkyl- (i.e., heterocycloalkenyl), wherein independently each of said alkyl, alkenyl and alkynyl, aryl, arylalkyl-, alkylaryl-, cycloalkyl, cycloalkylalkyl-, heteroaryl, heteroarylalkyl-, heterocyclyl and heterocyclylalkyl- is optionally substituted with 1 to 5 independently selected R 21 groups; or
  • R 6 taken together with R 1 and the carbon to which they are bound form a cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl ring fused to said R 1 ring, said fused ring is optionally substituted with 1 to 5 independently selected R 21 groups; or R 6 and R 7 taken together with the carbon to which they are bound form a spirocycloalkyl ring, a spirocycloalkenyl ring, a spiroheterocycloalkyl ring, or a spiroheterocyclalkenyl ring, and wherein the spiro ring is optionally substituted with 1 - 5 independently selected R 21 groups;
  • R 15A and R 16A are independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocyclyl, (R 18 ) q -alkyl, (R 18 )q -cycloalkyl, (R 18 ) q -cycloalkylalkyl, (R 18 ) q -heterocyclyl, (R 18 ) q -heterocyclylalkyl, (R 18 ) q -aryl, (R 18 ) q -arylalkyl, (R 18 ) q -heteroaryl and (R 18 ) q -heteroarylalkyl, wherein q is 1 to 5 and each R 18
  • each R 18 is independently selected (and those skilled in the art will appreciate that the R 16 moieties can be bound to any available substitutabie atom); or each R 18 is independently selected from the group consisting of alkyl, alkenyl, alkynyi, aryi, arylalkyl, arylalkenyl, arylalkynyl, -NO 2 , halo, heteroaryl, HO-alkyoxyalkyl, -CF 3 , -CN, alkyl-CN, -C(O)R 19 , -C(O)OH, -C(O)OR 19 , -C(O)NHR 20 , -C(O)NH 2 , -C(O)NH 2 -C(O)N(alkyl) 2 , -C(O)N(alkyl)(aryl), -C(O)N(
  • R 19 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;
  • each R 21B group is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl,
  • R 3 is aryl and R 1 comprises a 5 or 6-membered aryl or heteroaryl ring
  • said 5 or 6-membered aryl or het ⁇ roaryl ring is not substituted with an R 21 group that is selected from the group consisting of the moieties: -O-(5 or 6 membered aryl), -S-(5 or 6 membered aryl), -S(O) 2 -(5 or 6 membered aryl), -N(R 15 )-(5 or 6 membered aryl), -C(O)-(5 or 6 membered aryl), -alkyl-(5 or 6 membered aryl), -O-(5 or 6 membered heteroaryl), -S-(5 or 6 membered heteroaryl), -S(O) 2 -(5 or 6 membered heteroaryl),
  • R 3 is aryl and R 1 comprises a 5 or 6-membered aryl or heteroaryl ring
  • said 5 or 6-membered aryl or heteroaryl ring is not substituted with -O-(5 or 6 membered aryl), -S-(5 or 6 membered aryl), -S(O) 2 -(5 or 6 membered aryl), -N(R 15 )-(5 or 6 membered aryi), -C(O)-(5 or 6 membered aryl), -alkyl-(5 or 6 membered aryl), -O-(5 or 6 membered heteroaryl), -S-(5 or 6 membered heteroaryl), -S(O) 2 -(5 or 6 membered heteroaryl), -N(R 15 )-(5 or 6 membered heteroaryl), -C(O)-(5 or 6 membered
  • R 3 is selected from the group consisting of: phenyl and pyridyl, wherein said R 3 group is optionally substituted with 1 to 4 independently selected R 21 groups.
  • R 3 is selected from the group consisting of:
  • X is selected from the group consisting of: O, -N(R 14 )- and -S-; and wherein each of said R 3 moieties is optionally substituted with 1-5 independently selected R 21 groups.
  • R 3 is selected from the group consisting of: aryi- (e.g., phenyl), heteroaryl- (e.g., pyridyl), cycloalkyl-, cycloalkenyl, cycloalkylalkyl-, heterocyclyl-, heterocyclenyl-, heterocyclylalkyl-, heterocyclyalkenyl-, fused benzocyctoalkyl- (i.e., benzofusedcycloa(kyl-), fused benzoheterocycloalkyl- (i.e., benzofusedheterocycloalkyl-), fused heteroarylcycloalkyl- (i.e., heteroarylfusedcycloalkyl-), fused heteroarylheterocycloalkyl- (i.e., heteroarylfusedheterocycloalkyl-), fused cycloalkylaryl (i.e., cycloalkyf
  • R 3 is selected from the group consisting of:
  • each of said R 3 moieties is optionally substituted with 1 -5 independently selected R 21 groups.
  • R 4 is a five membered heteroaryl ring optionally substituted with 1 to 4 independently selected R 21 groups.
  • moieties formed when R 3 and R 4 are linked together to form a fused tricyclic ring system include, but are not limited to: wherein R 3 and R 4 are as defined for formula (I), and Ring C is the ring linking R 3 and R 4 , that is Ring C is an alkyl ring, or a heteroalkyl ring, or an aryl ring, or a heteroaryl ring, or an alkenyl ring, or a heteroalkenyl ring.
  • moieties formed when R 3 and R 4 are linked together to form a fused tricyclic ring system include, but are not limited to:
  • Ring C is the ring linking R 3 and R 4 , that is Ring C is a heteroalkyl ring, or a heteroaryl ring, or a heteroalkenyl ring.
  • the fused tricyclic ring system formed when R 3 and R 4 are linked together is
  • Ring C is a heteroalkyl ring, or a heteroaryl ring, or a heteroalkenyl ring, thus, for example, the tricyclic ring system is formed by linking the atoms adjacent to the atoms by which R 3 and R 4 are bound together), and wherein said fused tricyclic ring system is optionally substituted with 1 to 5 independently selected R 21 groups.
  • moieties formed when R 3 and R 4 are linked together to form a fused tricyclic ring system include, but are not limited to:
  • R 3 is bound to A 1 and L is bound to B 1 .
  • the compound of formula (I) is a compound of the formula:
  • R 3 is bound to B 1 and L is bound to A 1 .
  • the compound of formula (I) is a compound of the formula:
  • R 4 -R 3 - moiety is:
  • the compound of formula (I) is a compound of the formula:
  • the compound of formula (I) is a compound of the formula:
  • the compound of formula (I) is a compound the formula:
  • Another embodiment of this is directed to compounds of formula (I) wherein at least one (e.g., 1 to 3, or 1-2, or 1) group selected from the group consisting of: -SF 5 , - OSF 5 , and -Si(R 15A ) 3 is present, and wherein each R 15A is independently selected, and wherein when there is more than one group, each group is independently selected.
  • at least one e.g., 1 to 3, or 1-2, or 1
  • Another embodiment of this is directed to compounds of formula (I) wherein at least one (e.g., 1 to 3, or 1-2, or 1) group selected from the group consisting of: -SF 5 and -OSF 5 is present, and wherein when there is more than one group, each group is independently selected.
  • one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 is present in the compounds of formula (I)-
  • two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I).
  • two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (!), wherein at least one group is other than -Si(R 15A ) 3 .
  • three groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I), wherein at least one group is other than -Si(R 15A ) 3 .
  • one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 is present in the compounds of formula (I).
  • two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I).
  • each R 15A is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) are present in the compounds of formula (I).
  • two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I), wherein at least one group is other than -Si(R 15A ) 3 .
  • three groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I), wherein at least one group is other than -Si(R 15A ) 3 .
  • one group selected from the group consisting of: -SF 5 , -OSF 5 , and -St(R 15A ) 3 (wherein each R 15A is independently selected from the group consisting of methyl, ethyl and phenyl) is present in the compounds of formula (I).
  • two groups selected from the group consisting of: -SF 5 , -OSF 51 and -Si(R 15A ) 3 are present in the compounds of formula (i).
  • two groups selected from the group consisting of: -SF 5> -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I), wherein at least one group is other than -Si(R 15A ) 3 .
  • three groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I) 1 wherein at least one group is other than -Si(R 15A ) 3 .
  • one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 is present in the compounds of formula (I).
  • two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I).
  • two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I), wherein at least one group is other than -Si(R 15A ) 3 .
  • three groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I), wherein at least one group is other than -Si(R 15A ) 3 .
  • one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 is present in the compounds of formula (I), and said -Si(R 15A ) 3 group is selected from the group consisting of: -Si(CH 3 ) 3 , -Si(CH 3 ) 2 phenyl, and -Si(CH 2 CH 3 ) 2 CH 3
  • two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I), and said -Si(R 15A ) 3 group is selected from the group consisting of: -Si(CH 3 ) 3 , -Si(CH 3 ) 2 phenyl, and -Si(CH 2 CH 3 ) 2 CH 3.
  • three groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I), and said -Si(R 15A ) 3 group is selected from the group consisting of: -Si(CH 3 ) 3 , - Si(CH 3 ) 2 phenyl, and -Si(CH 2 CH 3 ) 2 CH 3 .
  • two groups sefected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I), wherein at least one group is other than -Si(R 15 ⁇ ) 3 , and said -Si(R 15A ) 3 group is selected from the group consisting of: -Si(CH 3 ) 3 , -Si(CH 3 ) 2 phenyl, and -Si(CH 2 CH 3 ) 2 CH 3 .
  • three groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I), wherein at least one group is other than -Si(R 15A ) 3) and said -Si(R 15A ) 3 group is selected from the group consisting of: -Si(CH 3 ) 3 , -Si(CH 3 ) 2 phenyl, and -Si(CH 2 CH 3 ) 2 CH 3 .
  • one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 is present in the compounds of formula (I), and said -Si(R 15A ) 3 group is selected from the group consisting of: -Si(CH 3 ) 3 and -Si(CH 2 CH 3 ) 2 CH 3 ,
  • two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I), and said -Si(R 15A ) 3 group is selected from the group consisting of: -Si(CH 3 ) 3 and -Si(CH 2 CH 3 J 2 CH 3 ,
  • three groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (J), and said -Si(R 15A ) 3 group is selected from the group consisting of: -Si(CH 3 ) 3 and -Si(CH 2 CH 3 ) 2 CH 3 ,
  • two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Sf(R 15A ) 3 are present in the compounds of formula (IJ, wherein at least one group is other than -Si(R 15A ) 3 , and said -Si(R 15A ) 3 group is selected from the group consisting of: -Si(CH 3 ) 3 and -Si(CH 2 CH 3 ) 2 CH 3 , In another embodiment of this invention three groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I), wherein at least one group is other than -Si(R 15A ) 3 , and said -Si(R 15A ) 3 group is selected from the group consisting of: -Si(CH 3 ) 3 , -Si(CH 3 ) 2 phenyl, and -Si(CH 2
  • one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(CH 3 ) 3 is present.
  • two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(CH 3 ) 3 are present in the compounds of formula (I).
  • three groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(CH 3 ) 3 are present in the compounds of formula (I) .
  • two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -St(CH 3 ) 3 are present in the compounds of formula (I), wherein at least one group is other than -Si(CH 3 ) 3. .
  • three groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 24 ) 3 are present in the compounds of formula (I), wherein at least one group is other than -Si(CH 3 ) 3 .
  • one group selected from the group consisting of: -SF 5 and -OSF 5 is present in the compounds of formula (I).
  • two groups selected from the group consisting of: -SF 5 and -OSF 5 are present in the compounds of formula (I).
  • one -SF 5 group is present in the compounds of formula (I).
  • two -SF 5 groups are present in the compounds of formula (I).
  • three -SF 5 groups are present in the compounds of formula (I).
  • one -OSF 5 group is present in the compounds of formula (I).
  • two -OSF 5 groups are present in the compounds of formula (I).
  • three -OSF 5 groups are present in the compounds of formula (I).
  • one -Si(R 15a ) 3 (wherein each R 15A is independently selected) group is present in the compounds of formula (I).
  • two -Si(R 15A ) 3 (wherein each R 15A is independently selected) groups are present in the compounds of formula (I).
  • one -Si(R 15A ) 3 (wherein each R 15A is independently selected from the group consisting of alky! (e.g., methyl and ethyl) and aryl (e.g., phenyl)) is present in the compounds of formula (I).
  • two -Si(R 15A ) 3 (wherein each R 15A is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) is present in the compounds of formula (I).
  • three -Si(R 15A ) 3 (wherein each R 15A is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) is present in the compounds of formula (I).
  • one -Si(R 15A ) 3 (wherein each R 15A is independently selected from the group consisting of methyl, ethyl and phenyl) is present in the compounds of formula (I).
  • two -Si(R 15A ) 3 (wherein each R 15A is independently selected from the group consisting of methyl, ethyl and phenyl) is present in the compounds of formula (I).
  • one -Si(R 15A ) 3 (wherein each R 15A is independently selected from the group consisting of methyl and ethyl) is present in the compounds of formula (I).
  • two -Si(R 15A )s (wherein each R 15A is independently selected from the group consisting of methyl and ethyl) is present in the compounds of formula (I).
  • three -Si(R 15A ) 3 (wherein each R* 5A is independently selected from the group consisting of methyl and ethyl) is present in the compounds of formula (I).
  • one -Si(R 15A ) 3 group is present in the compounds of formula (I), and said -Si(R 15A ) 3 group is selected from the group consisting of: -Si(CH 3 ) 3l -Si(CH 3 ) 2 phenyl, and -Si(CH 2 CH 3 ) 2 CH 3.
  • two -Si(R 15A ) 3 groups are present in the compounds of formula (I), and said -Si(R 15A ) 3 groups are independently selected from the group consisting of: -Si(CH 3 ) 3 , -Si(CH 3 ) 2 phenyl, and -Si(CH 2 CH 3 ) 2 CH 3 .
  • three -Si(R 15A ) 3 groups are present in the compounds of formula (I), and said -Si(R 15A ) 3 groups are independently selected from the group consisting of: -Si(CH 3 ) 3 , -Si(CH 3 ) 2 phenyl, and -Si(CH 2 CH 3 ) 2 CH 3. .
  • one -Si(R 15A ) 3 group is present in the compounds of formula (I), and said -Si(R 15A ) 3 group is selected from the group consisting of: -Si(CH 3 ) 3 and -Si(CH 2 CH 3 ) 2 CH 3.
  • two -Si(R 15A ) 3 groups are present in the compounds of formula (I), and said -Si(R 15A ) 3 groups are independently selected from the group consisting of: -Si(CH 3 ) 3 and -Si(CH 2 CH 3 ) 2 CH 3 ..
  • three -Si(R 15A ) 3 groups are present in the compounds of formula (I), and said -Si(R 15A ) 3 groups are independently selected from the group consisting of: -Si(CH 3 ) 3 and -Si(CH 2 CH 3 ) 2 CH 3 ..
  • one -Si(R 15A ) 3 group is present in the compounds of formula (I), and said -Si(R 15A ) 3 group is -Si(CH 3 ) 3 .
  • two -Si(R 15A ) 3 groups are present in the compounds of formula (I), and said -Si(R 15A ) 3 groups are -Si(CH 3 ) 3 ..
  • three -Si(R 15A ) 3 groups are present in the compounds of formula (I), and said -Si(R 15A ) 3 groups are -Si(CH 3 ) 3 .
  • one group selected from the group consisting of: -SF 5 , -OSF 5 , -Si(CH 3 ) 3l -Si(CH 3 ) 2 phenyl, and -Si(CH 2 CH 3 ) 2 CH 3 ) is present in the compounds of formula (I).
  • one group selected from the group consisting of: -SF 5 , -OSF 5 , -Si(CH 3 ) 3 , and -Si(CH 2 CH 3 ) 2 CH 3 ) is present in the compounds of formula (I).
  • one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(CH 3 ) 3f is present in the compounds of formula (I).
  • one -SF 5 group is present in the compounds of formula (I), and one or two additional groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 (wherein each R 15A is independently selected) are also present in the compounds of formula (I).
  • one -SF 5 group is present in the compounds of formula (I), and one or two additional groups selected from the group consisting of: -OSF 5 , and -Si(R 15A ) 3 (wherein each R 15A is independently selected) are also present in the compounds of formula (I).
  • one -OSF 5 group is present in the compounds of formula (I), and one or two additional groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 (wherein each R 15A is independently selected) are also present in the compounds of formula (I).
  • one -OSF 5 group is present in the compounds of formula (I), and one or two additional groups selected from the group consisting of: -SF 5 and -Si(R 15A ) 3 (wherein each R 15A is independently selected) are also present in the compounds of formula (I).
  • one -SF 5 group is present in the compounds of formula (I), and one or two additional groups selected from the group consisting of: -SF 5 and -OSF 5 are also present in the compounds of formula (I).
  • one -OSF 5 group is present in the compounds of formula (I), and one or two additional groups selected from the group consisting of: -SF 5 and -OSF 5 are also present in the compounds of formula (I).
  • one -Si(R 15A ) 3 (wherein each R 15A is independently selected) group is present in the compounds of formula (I), and one or two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 (wherein each R 15A is independently selected) are also present in the compounds of formula (I).
  • one -Si(R 15A ) 3 (wherein each R 15A is independently selected) group is present in the compounds of formula (I), and one or two groups selected from the group consisting of: -SF 5 and -OSF 5 are also present in the compounds of formula (I).
  • at least one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 (wherein each R 15A is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) is present in the compounds of formula (I).
  • At least one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 is present in the compounds of formula (I).
  • At least one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 is present in the compounds of formula (I).
  • At least one group selected from the group consisting of: -SF 5 , -OSF 5 , -Si(CH 3 ) 3 , -Si(CH 3 ) 2 phenyl, and -Si(CH 2 CH 3 ) 2 CH 3 ) is present in the compounds of formula (I).
  • At least one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(CH 3 ) 3 is present in the compounds of formula (I).
  • one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 (wherein each R 15A is independently selected) is present in the compounds of formula (I).
  • one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 is present in the compounds of formula (I).
  • one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 (wherein each R 15A is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and phenyl) is present in the compounds of formula (I).
  • one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 is present in the compounds of formula (I).
  • one group selected from the group consisting of: -SF 5 , -OSF 5 , -Si(CH 3 ) 3 , -Si(CH 3 ) 2 phenyl f and -Si(CH 2 CH 3 ) 2 CH 3 ) is present in the compounds of formula (I).
  • one group selected from the group consisting of: -SF 5 , -OSF 5 , -Si(CH 3 ) 3 , and -Si(CH 2 CH 3 ) 2 CH 3 ) is present in the compounds of formula (I).
  • one group selected from the group consisting of: -SF 5 , -OSF 5 , and -St(CH 3 ) 3 is present in the compounds of formula (I).
  • two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I).
  • two groups independently selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I).
  • two groups independently selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I).
  • two groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 are present in the compounds of formula (I).
  • two groups independently selected from the group consisting of: -SF 5 , -OSF 5 , -Si(CH 3 ) 3 , -Si(CH 3 ) 2 phenyl, and -Si(CH 2 CH 3 ) 2 CH 3 ) is present in the compounds of formula (I).
  • two groups independently selected from the group consisting of: -SF 5 , -OSF 5 , -Si(CH 3 ) 3) and -Si(CH 2 CH 3 ) 2 CH 3 ) are present in the compounds of formula (I).
  • two groups independently selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(CH 3 ) 3 are present in the compounds of formula (I).
  • three groups selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 (wherein each R 15A is independently selected) are present in the compounds of formula (I)I.
  • each R 15 ⁇ is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) are present in the compounds of formula (I).
  • each R 15 ⁇ is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and phenyl) are present in the compounds of formula (I).
  • three groups independently selected from the group consisting of: -SF 5 , -OSF 5 , -Si(CH 3 ) 3 , -Si(CH 3 ) 2 phenyl, and -Si(CH 2 CH 3 ) 2 CH 3 ) is present in the compounds of formula (I).
  • three groups independently selected from the group consisting of: -SF 5 , -OSF 5 , -Si(CH 3 ) 3l and -Si(CH 2 CH 3 ) 2 CH 3 ) are present in the compounds of formula (I).
  • three groups independently selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(CH 3 ) 3 are present in the compounds of formula (I).
  • at least one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 is present in the compounds of formula (I).
  • At least one group selected from the group consisting of: -SF 5 , -OSF 5 , and -Si(R 15A ) 3 is present in the compounds of formula (I).
  • one -SF 5 group is present in the compounds of formula (I), and one or two groups selected from the group consisting of: -SF 5 and -OSF 5 are also present in the compounds of formula (I).
  • one -OSF 5 group is present in the compounds of formula (I), and one or two groups selected from the group consisting of: -SF 5 and -OSF 5 are also present in the compounds of formula (I).
  • L is -C(R 6 )(R 7 )-.
  • L is -C(R 6 )(R 7 )- wherein R 6 and R 7 are taken together with the carbon atom to which they are bound to form a spirocycloalkyf ring (e.g., cyclopropyl).
  • L is -C(R 6 )(R 7 )- wherein R 6 and R 7 are taken together with the carbon atom to which they are bound to form a spirocycloalkenyl ring.
  • L is -C(R 6 )(R 7 )- wherein R 6 and R 7 are taken together with the carbon atom to which they are bound to form a spiroheterocycloalkyl ring.
  • L is -C(R 6 )(R 7 )- wherein R 6 and R 7 are taken together with the carbon atom to which they are bound to form a spiroheterocycloalkenyl ring.
  • L is -C(R 6 )(R 7 )- wherein R 6 and R 7 are independently selected from the group consisting of: H, alkyl, and alkyl substituted with one R 21 group.
  • L is -C(R 6 )(R 7 )- wherein R 6 and R 7 are independently selected from the group consisting of: H, methyl, and methyl substituted with one R 21 group.
  • L is -C(R 6 )(R 7 )- wherein R 6 and R 7 are independently selected from the group consisting of: H, alkyl, and alkyl substituted with one R 21 group wherein said R 21 group is -OR 15 .
  • L is -C(R 6 ) ⁇ R 7 )- wherein R 6 and R 7 are independently selected from the group consisting of: H, alkyl, and alkyl substituted with one R 21 group wherein said R 21 group is -OR 15 , and said R 15 is H (i.e., said R 21 group is -OH).
  • L is selected from the group consisting of:
  • L is -CH 2 -. In another embodiment of this invention L is -CH(CH 3 )-. In another embodiment of this invention L is -CH(CH 2 OH)-.
  • R 1 is selected from the group consisting of: alkyl, alkenyi, alkynyl, cycloalkyl, heterocyclyl (e.g., heterocycloalkyl), cycloalkenyl, aryJ (e.g., phenyl), heteroaryi (e.g., pyridyl), heterocyclenyl (i.e., heterocycloalkenyl), wherein each of said: aikyl, alkenyi, alkynyl, cycloalkyl, heterocyciyl, cycloalkenyl, aryl, heteroaryi, and heterocyclenyl R 1 groups is optionally substituted with 1-5 independently selected R 21 groups.
  • R 1 is selected from the group consisting of: fused cycloalkylaryl (i.e., cycloalkyfusedlaryl-), fused heterocycloalkylaryl- (i.e., heterocycloalkylfusedaryl-), fused cycloalkylheteroaryl- (i.e., cycloalkylfusedheteroaryl-), fused heterocycloalkylheteroaryl- (i.e., heterocycloalkylfusedheteroaryl-), fused benzocycloalkylalkyl- (i.e., benzofusedcycloalkyialkyl-), fused benzoheterocycloalkylalkyl- (i.e., benzofusedheterocycloalkylalkyl-), fused heteroarylcycloalkylalkyl" ( ⁇ • ⁇ -.
  • fused cycloalkylaryl i.e., cycloalkyfusedlaryl-
  • heteroaryifusedcycloalkylalkyl- fused heteroarylheterocycloalkylalkyl- (i.e., heteroarylfusedheterocycloalkylalkyl-), fused cycloalkylarylalkyl- (i.e., cycloalkyfusedlarylalkyl-), fused heterocycloalkylarylalkyl- (i.e., heterocycloalkylfusedarylalkyl-), fused cycloalkylheteroarylalkyl- (i.e., cycloalkylfusedheteroarylalkyl-), and fused heterocycloalkylheteroarylalkyl- (i.e., heterocycloalkylfusedheteroarytalkyl-), wherein each of said R 1 groups is optionally substituted with 1 -5 independently selected R 21 groups
  • R ⁇ is phenyl.
  • R 1 is phenyl substituted with 1 to 3 halo atoms.
  • R 1 is phenyl substituted with 1 to 3 F atoms. In another embodiment of this invention R 1 is selected from the group consisting of: and
  • R 1 is. selected from the group consisting of:
  • R 1 is selected from the group consisting of:
  • R 1 is, selected from the group consisting of:
  • R 1 is phenyl. In another embodiment of this invention R 1 is
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 1 is:
  • R 1 is:
  • R 1 is:
  • R 1 is:
  • R 1 is. : !n another embodiment of this invention R 1 is:
  • R 1 is:
  • R 1 is:
  • R 1 is.
  • R 1 is:
  • R 1 is:
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 1 is:
  • R 1 is: In another embodiment of this invention R 1 is:
  • R 1 is:
  • R 1 is.
  • R 1 is:
  • R 1 is:
  • R 1 is:
  • R 1 is In another embodiment of this invention R 1 is
  • R 1 is phenyl substituted with 1-3 halos independently selected from the group consisting of F and Cl. In one example said phenyl is substituted with one F and one Cl.
  • R 1 is aryl (e.g., phenyl) substituted with 1 to 3 independently selected R 21 moieties wherein at least one R 21 moiety is selected from the group consisting of -SF 5 , -OSF 5 and -Si(R 15A ) 3 (and in one example each R 1SA is the same or different alkyl, and in another example the -Si(R 24 ) 3 group is -Si(CH 3 ) 3 or -Si(CH 2 CH 3 )2CH3, and in another example the -Si(R 24 ) 3 group is -Si(CH 3 ) 3 ).
  • R 1 is aryl (e.g., phenyl) substituted with 1 to 3 independently selected R 21 moieties wherein at least one R 21 moiety is selected from
  • R 1 is aryl (e.g., phenyl) substituted with 1 to 3 R 21 moieties independently selected from the group consisting of: halo (e.g., F), -SF 5 , -OSF 5 and -Si(R 15A ) 3 (and in one example each R 15A is the same or different alkyl, and in another example the -Si(R 15A ) 3 group is -Si(CH 3 ) 3 or -SKCH 2 CH 3 ) 2 CH 3 , and in another example the -Si(R 1 ⁇ ) 3 group is -Si(CH 3 ) 3 ), and wherein at least one R 21 moiety is selected from the group consisting of -SF 5 , -OSF 5 and -Si(R 15A ) 3 (and in one example each R 15A is the same or different alkyl, and in another example the -Si(R 15A ) 3 group is -Si(CH 3 ) 3 or -
  • R 1 is aryl (e.g., phenyl) substituted with 1 to 3 R 21 moieties independently selected from the group consisting of: halo (e.g., F), -SF 5 and -OSF 5 , and wherein at least one R 21 moiety is selected from the group consisting of -SF 5 and -OSF 5 .
  • R 1 is aryl (e.g., phenyl) substituted with 1 to 3 independently selected R 21 moieties wherein at least one R 21 moiety is selected from the group consisting of -SF 5 , -OSF 5 and -Si(R 15A ) 3 (and in one example each R 15A is the same or different alky!, and in another example the -Si(R l ⁇ A ) 3 group is -Si(CH 3 ) 3 or -Si(CH2CH 3 ) 2 CH 3 , and in another example the -Si(R 15A ) 3 group is -Si(CH 3 ) 3 ).
  • R 1 is phenyl substituted with 1-3 R 21 groups independently selected from the group consisting of halos, -SF 5 and -OSF 5 , wherein at least one R 21 group is -SF 5 or -OSF 5 .
  • R 1 is phenyl substituted with 1-3 R 21 groups independently selected from the group consisting of halos, -SF 5 and -OSF 5 , wherein at least one R 21 group is -SF 5 or -OSF 5 .
  • R 1 is phenyl substituted with 1-3 R 21 groups independently selected from the group consisting of F, Cl, -SF 5 and -OSF 5 . In another embodiment, R 1 is phenyl substituted with 1-3 R 21 groups independently selected from the group consisting of -SF 5 and -OSF 5 .
  • R 1 is phenyl substituted with 1-3 R 21 groups independently selected from the group consisting of F, -SF 5 and -OSF 5 , wherein at least one R 21 group is -SF 5 or -OSF 5 .
  • R 1 is phenyl substituted with one -SF 5 group. In another embodiment, R 1 is phenyl substituted with two -SF 5 groups.
  • R 1 is phenyl substituted with three -SF 5 groups. In another embodiment, R 1 is phenyl substituted with one -OSF 5 group. In another embodiment, R 1 is phenyl substituted with two -OSF 5 groups. In another embodiment, R 1 is phenyl substituted with three -OSF 5 groups. In another embodiment, R 1 is phenyl substituted with 1 F.
  • R 1 is phenyl substituted with 1 F, and also substituted with 1 to 2 groups independently selected from the group consisting of -SF 5 and -OSF 5 .
  • R 1 is phenyl substituted with 2 F. In another embodiment R 1 is phenyl substituted with 3F.
  • R 1 is selected from the group consisting of:
  • R 1 is selected from the group consisting of:
  • the compound of formula (I) is selected from the group consisting of the compounds of formulas (IA), (IB), (IC), (ID), and (IE), L is selected from the group consisting of:
  • R 1 is selected from the group consisting of:
  • the compound of formula (i) is the compounds of formula (1A), L is selected from the group consisting of;
  • R is selected from the group consisting of:
  • the compound of formula ⁇ () is the compound of formulas (IB), L is selected from the group consisting of:
  • R » i i ⁇ s selected from the group consisting of:
  • the compound of formula (I) is the compounds of formula (1C), L is selected from the group consisting of:
  • R 1 is selected from the group consisting of:
  • the compound of formula (I) is the compounds of formula (!D), L is selected from the group consisting of: and , and
  • R 1 is selected from the group consisting of:
  • the compound of formula (f) is the compounds of formula (IE), L is selected from the group consisting of:
  • R 1 is selected from the group consisting of:
  • R 5 is taken together with R 1 and the carbon to which they are bound to form a heterocycloalkyl or heterocyctoalkenyl ring fused to said R 1 ring, said fused ring is optionally substituted with 1 to 5 independently selected R 21 groups.
  • R 5 is taken together with R 1 and the carbon to which they are bound to form a 5 to 7 membered heterocycloafkyl or heterocycloalkenyl ring fused to said R 1 ring, and wherein said heterocycloaikyl and said heterocylcloalkenyl rings comprise 1 to 4 (including the atoms common to both rings) heteroatoms selected from the group consisting of: -N-, -O-, -S-, -S(O)-, and -
  • R 6 is taken together with R 1 and the carbon to which they are bound to form a cycloalkyl, cydoafkenyl, heterocycloaikyl or heterocycloalkenyl ring fused to said R 1 ring, said fused ring is optionally substituted with 1 to 5 independently selected R 21 groups.
  • R 6 is taken together with R 1 and the carbon to which they are bound to form a 5 to 7 membered cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl ring fused to said R 1 ring, and wherein said heterocycloalkyl and said heterocylcloalkenyl rings comprise 1 to 4 (including the atoms common to both rings) heteroatoms selected from the group consisting of: -N-, -O-, -S-, -S(O)-, and -S(O) 2 -, and wherein said 5 to 7 membered ring is optionally substituted with 1 to 5 independently selected R 21 groups.
  • Ring (B) is a cycloalkyl ring.
  • Ring (B) is a cycloalkenyl ring.
  • Ring (B) is a heterocycloalkyl ring.
  • Ring (B) is a heterocycloalkenyl ring.
  • Ring (B) is a phenyl ring. In another embodiment of this invention, Ring (B) is a heteroaryl ring.
  • Ring (B) is a cycloalkyl ring wherein B 1 to B 4 are carbon.
  • L is a direct bond
  • L is -O- .
  • L is -NR 3 -.
  • L is -S-. In another embodiment of this invention L is -SO-.
  • L is -S(O) 2 -.
  • B 1 is CH.
  • B 1 is C. fn another embodiment B 1 is N.
  • R 3 is phenyl
  • R 3 is phenyl substituted with 1 to 3 independently selected R 21 groups.
  • R 3 is phenyl substituted with 1 R 21 group.
  • R 3 is phenyl substituted with 1 R 21 group wherein said R 21 group is halo. In another embodiment of this invention R 3 is phenyl substituted with 1 R 21 group wherein said R 21 group is halo, and said halo is F.
  • R 3 is phenyl substituted with 1 R 21 group, wherein said R 21 group is -OR 15 .
  • R 3 is phenyl substituted with 1 R 21 group, wherein said R 21 group is -OR 15 , and wherein said R 15 is alkyl (e.g., methyl).
  • R 3 is pyridyl
  • R 3 is pyridyl substituted with 1 to 3 independently selected R 21 groups.
  • R 4 is heteroaryl. In another embodiment of this invention R 4 is heteroaryl substituted with 1 to 3 independently selected R 21 groups.
  • R 4 is heteroaryl substituted with 1 R 21 group.
  • R 4 is heteroaryl substituted with 1 to 3 independently selected R 21 groups, wherein said R 21 groups are the same or different alky! group.
  • R 4 is heteroaryl substituted with 1 R 21 group, wherein said R 21 group is alkyl (e.g., methyl).
  • R 4 is selected from the group consisting of:
  • R 4 is imidazolyl. In another embodiment of this invention R 4 is the imidazolyl:
  • R 4 is imidazotyl substituted with 1 to 3 independently selected R 21 groups.
  • R 4 is imidazolyl substituted with 1 R 21 group. In another embodiment of this invention R 4 is imidazolyl substituted with 1 to 3 independently selected R 21 groups, wherein said R 21 groups are the same or different alkyl group.
  • R 4 is imidazolyl substituted with 1 R 21 group, wherein said R 21 group is alkyl (e.g., methyl). In another embodiment of this invention R 4 is:
  • R ,4- rR->3- moiety examples include, but are not limited to:
  • the R 4 -R 3 - moiety is 1 bb. In another embodiment the R 4 -R 3 - moiety is 2bb. In another embodiment the R 4 -R 3 - moiety is 3bb. In another embodiment the R 4 -R 3 - moiety is 4bb. In another embodiment the R 4 -R 3 - moiety is 5bb. in another embodiment the R 4 -R 3 - moiety is 6bb, In another embodiment the R 4 -R 3 - moiety is 7bb. in another embodiment the R 4 -R 3 - moiety is 8bb. In another embodiment the R 4 -R 3 - moiety is 9bb. In another embodiment the R 4 -R 3 - moiety is 10bb.
  • R 4 -R 3 - moiety is 11bb. In another embodiment the R 4 -R 3 - moiety is 12bb. In another embodiment the R 4 -R 3 - moiety is 13bb. In another embodiment the R 4 -R 3 - moiety is 14bb. In another embodiment the R 4 -R 3 - moiety is 15bb. In another embodiment the R 4 -R 3 - moiety is 16bb. In another embodiment the R 4 -R 3 - moiety is 17bb. In another embodiment the R 4 -R 3 - moiety is 18bb. In another embodiment the R 4 -R 3 - moiety is 19bb. In another embodiment the R 4 -R 3 - moiety is 20bb.
  • the R 4 -R 3 - moiety is 21 bb. In another embodiment the R 4 -R 3 - moiety is 22bb. In another embodiment the R 4 -R 3 - moiety is 23bb. In another embodiment the R 4 -R 3 - moiety is 24bb. In another embodiment the R 4 -R 3 - moiety is 25bb. In another embodiment the R 4 -R 3 - moiety is 26bb. In another embodiment the R 4 -R 3 - moiety is 27bb. In another embodiment the R 4 -R 3 - moiety is 28bb. In another embodiment the R 4 -R 3 - moiety is 29bb. In another embodiment the R 4 -R 3 - moiety is 30bb.
  • the R 4 -R 3 - moiety is 31 bb. In another embodiment the R 4 -R 3 - moiety is 32bb. In another embodiment the R 4 -R 3 - moiety is 33bb. In another embodiment the R 4 -R 3 - moiety is 34bb. In another embodiment the R 4 -R 3 - moiety is 35bb. In another embodiment the R 4 -R 3 - moiety is 36bb. In another embodiment the R 4 -R 3 - moiety is 37bb. In another embodiment the R 4 -R 3 - moiety is 38bb. In another embodiment the R 4 -R 3 - moiety is 39bb. In another embodiment the R 4 -R 3 - moiety is 40bb.
  • R 3 is selected from the group consisting of: (1 ) heteroaryl and (2) hetereoaryl substituted with 1 to 3 independently selected R 21 groups;
  • R 4 is selected from the group consisting of: (1) heteroaryl (e.g., imidazolyl, such as, for example imidazol-1-yl), (2) heteroaryl (e.g., imidazolyl, such as, for example imidazol-1-yl) substituted with 1 to 3 independently selected R 21 groups, (3) heteroaryl (e.g., imidazolyl, such as, for example imidazol-1-yl) substituted with 1 R 21 group, (4) heteroaryl (e.g., imidazolyl, such as, for example imidazol-1-yl) substituted with 1 to 3 independently selected R 21 groups, wherein said R 21 groups are the same or different alkyl group, and (5) heteroaryl (e.g., imidazolyl, such as, for example imidazol-1 -yl) substituted with 1 R 21 group, wherein said R 21 group is alkyl (e.g., methyl).
  • heteroaryl e.g., imidazo
  • the -R 3 -R 4 moiety is: In another embodiment of this invention the -R % 3-R moiety is: alkyl
  • the -R 3 -R 4 moiety is:
  • the -R 3 -R 4 moiety is:
  • the -R 3 -R 4 moiety is:
  • the -R 3 -R 4 moiety is halo
  • the -R ,3- D R4 moiety is:
  • the -R i3-R moiety is: alkyl
  • the -R -.3- nR4 moiety is:
  • the -R ⁇ 3- DR4 moiety is:
  • the -R 3- D R4 moiety is: O-alkyl
  • the -R 3 -R 4 moiety is:
  • the -R i3- oR4 moiety is:
  • the -R i3- ⁇ R4 moiety is: halo
  • the -R )3- n R4 moiety is: halo
  • the -R -R moiety is: alkyl F
  • ⁇ R 3 -R 4 moiety is:
  • R 1 is H. In another embodiment of this invention R 1 is alkyl. In another embodiment of this invention R 1 is aryl. In another embodiment of this invention R 1 is aryl substituted with 1 to 3 independently selected R 21 groups. In another embodiment of this invention R 1 is aryl substituted with 1 to 3 independently selected R 21 groups wherein said R 21 groups are halo.
  • R 1 is aryl substituted with 1 to 3 independently selected R 21 groups wherein said R 21 groups are F. In another embodiment of this invention R 1 is aryl substituted with 1 R 21 group.
  • R 1 is aryl substituted with 2 R 21 groups.
  • R 1 is aryl substituted with 3 R 21 groups. In another embodiment of this invention R 1 is aryl substituted with 1 R 21 group wherein said R 21 group is halo.
  • R 1 is aryl substituted with 2 R 21 groups wherein said R 21 groups are the same or different halo.
  • R 1 is aryl substituted with 3 R 21 groups wherein said R 21 groups are the same or different halo.
  • R 1 is phenyl substituted with 1 to 3 independently selected R 21 groups.
  • R 1 is phenyl substituted with 1 to 3 independently selected R 21 groups wherein said R 21 groups are halo. In another embodiment of this invention R 1 is phenyl substituted with 1 to 3 independently selected R 21 groups wherein said R 21 groups are F.
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 1 is phenyl substituted with 1 R 21 group.
  • R 1 is phenyl substituted with 2 R 21 groups.
  • R 1 is phenyl substituted with 3 R 21 groups. In another embodiment of this invention R 1 is phenyl substituted with 1 R 21 group wherein said R 21 group is halo. In another embodiment of this invention R 1 is phenyl substituted with 2 R 21 groups wherein said R 21 groups are the same or different halo.
  • R 1 is phenyl substituted with 3 R 21 groups wherein said R 21 groups are the same or different hato.
  • R 1 is 4-F-phenyl.
  • the -L-R 1 moiety is:
  • the -L-R 1 moiety is:
  • the -L-R 1 moiety is:
  • the -L-R 1 moiety is:
  • the -L-R 1 moiety is selected from the group consisting of:
  • the -L-R 1 moiety is selected from the group consisting of:
  • R 3 is selected from the group consisting of phenyl and phenyl substituted with one or more R 21 groups
  • said R 4 group is selected from the group consisting of heteroaryl and heteroaryl substituted with one or more R 21 groups, and wherein each R 21 is independently selected.
  • L is -C(R 6 )(R 7 )- wherein R 6 and R 7 are independently selected from the group consisting of H and alkyl (e.g., methyl), and in one example one of R 6 and R 7 is H and the other is alkyl (e.g., methyl), and in another example both R 6 and R 7 are H 1
  • R 1 is aryl (e.g.
  • R 21 groups wherein said R 21 groups are halo (e.g., F), and in one example R 1 is phenyl substituted with two F 1 and in another example R 1 is phenyl substituted with 1 F, (c) R 3 is selected from the group consisting of phenyl and phenyl substituted with one or more independently selected R 21 groups, and (d) R 4 is selected from the group consisting of heteroaryl and heteroaryl substituted with one or more independently selected R 21 groups.
  • R 21 groups are halo (e.g., F)
  • R 1 is phenyl substituted with two F 1 and in another example R 1 is phenyl substituted with 1 F
  • R 3 is selected from the group consisting of phenyl and phenyl substituted with one or more independently selected R 21 groups
  • R 4 is selected from the group consisting of heteroaryl and heteroaryl substituted with one or more independently selected R 21 groups.
  • L is -C(R 6 )(R 7 )- wherein R 6 and R 7 are independently selected from the group consisting of H and alkyl (e.g., methyl), and in one example one of R 6 and R 7 is H and the other is alkyl (e.g., methyl), and in another example both R 6 and R 7 are H, (b) R 1 is aryl (e.g.
  • R 21 groups wherein said R 21 groups are halo (e.g., F), and in one example R 1 is phenyl substituted with two F, and in another example R 1 is phenyl substituted with 1 F, (c) R 3 is selected from the group consisting of phenyl and phenyl substituted with one or more independently selected R 21 groups, and (d) R 4 is selected from the group consisting of im ⁇ dazoiyl and tmidazoiyl substituted with one or more independently selected R 21 groups.
  • R 21 groups are halo (e.g., F)
  • R 1 is phenyl substituted with two F
  • R 1 is phenyl substituted with 1 F
  • R 3 is selected from the group consisting of phenyl and phenyl substituted with one or more independently selected R 21 groups
  • R 4 is selected from the group consisting of im ⁇ dazoiyl and tmidazoiyl substituted with one or more independently selected R 21 groups.
  • L is -C(R 6 )(R 7 )- wherein R 6 and R 7 are independently selected from the group consisting of H and alkyl (e.g., methyl), and in one example one of R 6 and R 7 is H and the other is alkyl (e.g., methyl), and in another example both R 6 and R 7 are H, (b) R 1 is aryl (e.g.
  • R 21 groups wherein said R 21 groups are halo (e.g., F), and in one example R 1 is phenyl substituted with two F, and in another example R 1 is phenyl substituted with 1 F 1
  • R 3 is selected from the group consisting of phenyl and phenyl substituted with one or more independently selected -OR 15 groups
  • R 4 is selected from the group consisting of imidazolyl and imidazolyl substituted with one or more independently selected alkyl groups groups.
  • L is -C(R 6 )(R 7 )- wherein R 3 and R 4 are independently selected from the group consisting of H and alkyl (e.g., methyl), and in one example one of R 6 and R 7 is H and the other is alkyl (e.g., methyl), and in another example both R 6 and R 7 are H, (b) R 1 is aryl (e.g.
  • R 21 groups wherein said R 21 groups are halo (e.g., F), and in one example R 1 is phenyl substituted with two F, and in another example R 1 is phenyl substituted with 1 F, (c) R 3 is selected from the group consisting of phenyl and phenyl substituted with one or two independently selected -OR 15 groups, wherein R 15 is alkyl, and (d) R 4 is selected from the group consisting of imidazolyl and imidazolyl substituted with one or two independently selected alkyl groups groups.
  • R 21 groups are halo (e.g., F)
  • R 1 is phenyl substituted with two F
  • R 1 is phenyl substituted with 1 F
  • R 3 is selected from the group consisting of phenyl and phenyl substituted with one or two independently selected -OR 15 groups, wherein R 15 is alkyl
  • R 4 is selected from the group consisting of imidazolyl and imidazolyl substituted with one
  • L is -C(R 6 )(R 7 )- wherein R 3 and R 4 are independently selected from the group consisting of H and alkyl (e.g., methyl), and in one example one of R 6 and R 7 is H and the other is alkyl (e.g., methyl), and in another example both R 6 and R 7 are H, (b) R 1 is aryl (e.g.
  • R 21 groups wherein said R 21 groups are halo (e.g., F), and in one example R 1 is phenyl substituted with two F, and in another example R 1 is phenyl substituted with 1 F, (c) R 3 is selected from the group consisting of phenyl and phenyl substituted with one or two independently selected -OR 15 groups, wherein R 15 is methyl , and (d) R 4 is selected from the group consisting of imidazolyl and imidazolyl substituted with one or two independently selected methyl groups groups.
  • R 21 groups are halo (e.g., F)
  • R 1 is phenyl substituted with two F
  • R 1 is phenyl substituted with 1 F
  • R 3 is selected from the group consisting of phenyl and phenyl substituted with one or two independently selected -OR 15 groups, wherein R 15 is methyl
  • R 4 is selected from the group consisting of imidazolyl and imidazolyl substituted with one or two
  • L is -C(R e )(R 7 )- wherein R 6 and R 7 are independently selected from the group consisting of H and alkyi (e.g., methyt), and in one example one of R 6 and R 7 is H and the other is alkyl (e.g., methyl), and in another example both R 6 and R 7 are H, (b) R 1 is aryl (e.g.
  • R 21 groups wherein said R 21 groups are halo (e.g., F), and in one example R 1 is phenyl substituted with two F, and in another example R 1 is phenyl substituted with 1 F, (c) R 3 is phenyl substituted with one-OR 15 group, wherein R 15 is methyl, and (d) R 4 is selected from the group consisting of imidazolyl and imidazolyl substituted with one methyl group.
  • the -L-R 1 moiety is selected from the group consisting of:
  • R 4 -R 3 - moiety is:
  • the -L-R 1 moiety is selected from the group consisting of:
  • R 3 -R 4 - moiety is:
  • L is -C(R 6 )(R 7 )- wherein R 6 and R 7 are independently selected from the group consisting of H and alkyl (e.g., methyl), and in one example one of R 6 and R 7 is H and the other is alkyl (e.g., methyl), and in another example both R 3 and R 4 are H, (b) R 1 is aryl (e.g.
  • R 21 groups wherein said R 21 groups are halo (e.g., F), and in one example R 1 is phenyl substituted with two F, and in another example R 1 is phenyl substituted with 1 F, (c) R 3 is selected from the group consisting of phenyl and phenyl substituted with one or two independently selected -OR 15 groups, wherein R 15 is methyl, and (d) R 4 is selected from the group consisting of imidazolyl and imidazolyl substituted with one or two independently selected methyf groups groups,.
  • R 21 groups are halo (e.g., F)
  • R 1 is phenyl substituted with two F
  • R 1 is phenyl substituted with 1 F
  • R 3 is selected from the group consisting of phenyl and phenyl substituted with one or two independently selected -OR 15 groups, wherein R 15 is methyl
  • R 4 is selected from the group consisting of imidazolyl and imidazolyl substituted with one
  • L is -C(R 6 )(R 7 )- wherein R 6 and R 7 are independently selected from the group consisting of H and alkyl (e.g., methyl), and in one example one of R 6 and R 7 is H and the other is alkyl (e.g., methyl), and in another example both R 6 and R 7 are H, (b) R 1 is aryl (e.g.
  • R 21 groups wherein said R 21 groups are halo (e.g., F), and in one example R 1 is phenyl substituted with two F, and in another example R 1 is phenyl substituted with 1 F, (c) R 3 is phenyl substituted with one-OR 15 group, wherein R 15 is methyf, and (d) R 4 is selected from the group consisting of imidazolyl and imidazolyl substituted with one methyl group.
  • R 21 groups are halo (e.g., F)
  • R 1 is phenyl substituted with two F
  • R 1 is phenyl substituted with 1 F
  • R 3 is phenyl substituted with one-OR 15 group, wherein R 15 is methyf
  • R 4 is selected from the group consisting of imidazolyl and imidazolyl substituted with one methyl group.
  • the -L-R 1 moiety is selected from the group consisting of:
  • R 4 -R 3 - moiety is:
  • R 15 O alkyl in another embodiment of this invention is selected from the group consisting of:
  • R 4 -R 3 - moiety is:
  • -L- R 1 moiety is selected from the group consisting of:
  • R 3 is phenyl or phenyl substituted with one or more (e.g., one or two, or one) R 21 groups (e.g., -OR 15 , wherein, for example, R 15 is alkyl, such as, for example, methyl), and R 9 is heteroaryl (e.g., imidazolyi) or heteroaryl (e.g., imidazoly! substituted with one or more (e.g., one or two, or one) R 21 groups (e.g., alkyl, such as, for example, methyl).
  • R 21 groups e.g., -OR 15 , wherein, for example, R 15 is alkyl, such as, for example, methyl
  • R 9 is heteroaryl (e.g., imidazolyi) or heteroaryl (e.g., imidazoly! substituted with one or more (e.g., one or two, or one) R 21 groups (e.g., alkyl, such as, for example,
  • alkyl (alkyl),tician 2 wherein R ⁇ 15 is alkyl (e.g., methyl), such as, for example, ORl 5
  • R 1 5 is, alkyl (e.g., methyl), such as, for example, J3 ⁇ alkyl wherein R ,15 : i,s alkyl (e.g., methyl), such as, for example,
  • Representative (A) and (B) fused rings for formula (I) include but are not limited to:
  • Compounds of formula (I) include but are not limited to:
  • R 3 , R 4 , L, R 1 and R 21 ⁇ are as defined for formula (I) and the embodiments thereof.
  • Representative (A) and (B) fused rings for formula (I) also include but are not limited to:
  • R i21A is as defined for formula (I) and the embodiments thereof.
  • Representative compounds of this invention include, but are not limited to:
  • Another embodiment of this invention is directed to a compound of formula (I) selected from the group consisting of: compounds IA to IE, 1 A to 4A, A1.1 to A28.1 , A1.2 to A22.2, A24.2 to A28.2, 5.1 , 8.1 , 11.1 , and A1 to A28.
  • Another embodiment of this invention is directed to a compound of formula (I) selected from the group consisting of: compounds iA to IE.
  • Another embodiment of this invention is directed to a compound of formula (I) selected from the group consisting of: compounds 1A to 4A.
  • Another embodiment of this invention is directed to a compound of formula (I) selected from the group consisting of: compounds A1.1 to A28.1.
  • Another embodiment of this invention is directed to a compound of formula (I) selected from the group consisting of: compounds A1.2 to A22.2, and A24.2 to A28.2.
  • Another embodiment of this invention is directed to compound 5.1.
  • Another embodiment of this invention is directed to compound 8.1.
  • Another embodiment of this invention is directed to compound 11.1.
  • Another embodiment of this invention is directed to compound A1.
  • Another embodiment of this invention is directed to compound A2.
  • Another embodiment of this invention is directed to compound A3.
  • Another embodiment of this invention is directed to compound A4. Another embodiment of this invention is directed to compound A5.
  • Another embodiment of this invention is directed to compound A6.
  • Another embodiment of this invention is directed to compound A7.
  • Another embodiment of this invention is directed to compound A8.
  • Another embodiment of this invention is directed to compound A9. Another embodiment of this invention is directed to compound A10.
  • Another embodiment of this invention is directed to compound A11.
  • Another embodiment of this invention is directed to compound A12.
  • Another embodiment of this invention is directed to compound A13.
  • Another embodiment of this invention is directed to compound A14.
  • Another embodiment of this invention is directed to compound A15.
  • Another embodiment of this invention is directed to compound A16.
  • Another embodiment of this invention is directed to compound A17.
  • Another embodiment of this invention is directed to compound A18.
  • Another embodiment of this invention is directed to compound A19. Another embodiment of this invention is directed to compound A20.
  • Another embodiment of this invention is directed to compound A21.
  • Another embodiment of this invention is directed to compound A22.
  • Another embodiment of this invention is directed to compound A23.
  • Another embodiment of this invention is directed to compound A24. Another embodiment of this invention is directed to compound A25.
  • Another embodiment of this invention is directed to compound A26.
  • Another embodiment of this invention is directed to compound A27.
  • Another embodiment of this invention is directed to compound A28.
  • Groups A, B, C, D and E are as defined as follows: (1 ) Group A: compounds tA to IE, 1 A to 4A, A1.1 to A28.1 , A1.2 to A22.2, A24.2 to A28.2, 5.1 , 8.1 , 11.1 , and A1 to A28;
  • Group B compounds IA to IE
  • Group C compounds 1 A to 4A, A1.1 to A28.1, A1.2 to A22.2, and A24.2 to A28.2;
  • Another embodiment of this invention is directed to a compound of formula (I).
  • Another embodiment of this invention is directed to a pharmaceutically acceptable salt of a compound of formula (I).
  • the salt is a salt of a compound selected from the group consisting of Group A.
  • the salt is a salt of a compound selected from the group consisting of Group B.
  • the salt is a salt of a compound selected from the group consisting of Group C.
  • the salt is a salt of a compound selected from the group consisting of Group D.
  • the salt is a salt of a compound selected from the group consisting of Group E.
  • Another embodiment of this invention is directed to a pharmaceutically acceptable ester of a compound of formula (I).
  • the ester is an ester of a compound selected from the group consisting of Group A.
  • the ester is an ester of a compound selected from the group consisting of Group B.
  • the ester is an ester of a compound selected from the group consisting of Group C.
  • the ester is an ester of a compound selected from the group consisting of Group D.
  • the ester is an ester of a compound selected from the group consisting of Group E.
  • Another embodiment of this invention is directed to a solvate of a compound of formula (J).
  • the solvate is a solvate of a compound selected from the group consisting of Group A. And in another example the solvate is a solvate of a compound selected from the group consisting of Group B. And in another example the solvate is a solvate of a compound selected from the group consisting of Group C. And in another example the solvate is a solvate of a compound selected from the group consisting of Group D. And in another example the solvate is a soivate of a compound selected from the group consisting of Group E.
  • Another embodiment of this invention is directed to a compound of formula (I) in isolated form. And in one example the compound of formula (I) is selected from the group consisting of Group A. And in one example the compound of formula (I) is selected from the group consisting of Group D. And in one example the compound of formula (I) is selected from the group consisting of Group E.
  • Another embodment of this invention is directed to a compound of formula (I) in pure form. And in one example the compound of formula (I) is selected from the group consisting of Group A. And in one example the compound of formula (I) is selected from the group consisting of Group D. And in one example the compound of formula (I) is selected from the group consisting of Group E.
  • Another embodiment of this invention is directed to a compound of formula (I) in pure and isolated form. And in one example the compound of formula (I) is selected from the group consisting of Group A. And in one example the compound of formula (I) is selected from the group consisting of Group D. And in one example the compound of formula (I) is selected from the group consisting of Group E.
  • Another embodiment of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, or ester thereof, and one or more (e.g., one) pharmaceutically acceptable carriers.
  • Another embodiment is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I) and a pharmaceutically acceptable carrier.
  • Another embodiment is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a pharmaceutically acceptable salt of one or more (e.g., one) compounds of formula (I) and a pharmaceutically acceptable carrier.
  • Another embodiment is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a pharmaceutically acceptable ester of one or more (e.g., one) compounds of formula (I) and a pharmaceutically acceptable carrier.
  • Another embodiment is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a solvate of one or more (e.g., one) compounds of formula (I) and a pharmaceutically acceptable carrier.
  • Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I) 1 and an effective amount of one or more (e.g., one) other pharmaceutically active ingredients (e.g., drugs), and a pharmaceutically acceptable carrier.
  • Examples of the other pharmaceutically active ingredients include, but are not limited to drugs selected form the group consisting of: (a) drugs useful for the treatment of Alzheimer's disease, (b) drugs useful for inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), (c) drugs useful for treating neurodegenerative diseases, and (d) drugs useful for inhibiting gamma- secretase.
  • Another embodiment of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of one or more (e.g. one) compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, or ester thereof, and one or more (e.g., one) pharmaceutically acceptable carriers, and an effective amount of one or more compounds selected from the group consisting of cholinesterase inhibitors, A ⁇ antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors.
  • Another embodiment of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more BACE inhibitors, and a pharmaceutically acceptable carrier.
  • Another embodiment of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more cholinesterase inhibitors (e.g., acetyl- and/or butyrylchlolinesterase inhibitors), and a pharmaceutically acceptable carrier.
  • one or more compounds of formula (I) e.g., one
  • cholinesterase inhibitors e.g., acetyl- and/or butyrylchlolinesterase inhibitors
  • Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I).
  • Another embodiment of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more muscarinic antagonists (e.g., mi agonist or m 2 antagonists), and a pharmaceutically acceptable carrier.
  • one or more compounds of formula (I) e.g., one
  • muscarinic antagonists e.g., mi agonist or m 2 antagonists
  • Another embodiment of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of Exelon (rivastigmine), and a pharmaceutically acceptable carrier.
  • Another embodiment of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of Cogne ⁇ (tacrine), and a pharmaceutically acceptable carrier.
  • Another embodiment of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of a Tau kinase inhibitor, and a pharmaceutically acceptable carrier.
  • Another embodiment of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more Tau kinase inhibitor (e.g., GSK3beta inhibitor, cdk5 inhibitor, ERK inhibitor), and a pharmaceutically acceptable carrier.
  • one or more compounds of formula (I) e.g., one
  • Tau kinase inhibitor e.g., GSK3beta inhibitor, cdk5 inhibitor, ERK inhibitor
  • Another embodiment of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one anti-Abeta vaccine (active immunization), and a pharmaceutically acceptable carrier.
  • Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more APP ligands, and a pharmaceutically acceptable carrier.
  • Another embodiment of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more agents that upregulate insulin degrading enzyme and/or neprilysin, and a pharmaceutically acceptable carrier.
  • Another embodiment of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more cholesterol lowering agents (for example, statins such as Atorvastatin, Ruvastatin, Lovastatin, Mevastatin, Pravastatin, Pravastatin, Rosuvastatin, Simvastatin, and cholesterol absorption inhibitor such as Ezetimibe), and a pharmaceutically acceptable carrier.
  • statins such as Atorvastatin, Ruvastatin, Lovastatin, Mevastatin, Pravastatin, Pravastatin, Rosuvastatin, Simvastatin, and cholesterol absorption inhibitor such as Ezetimibe
  • statins such as Atorvastatin, Ruvastatin, Lovastatin, Mevastatin, Pravastatin, Pravastatin, Rosuvastatin, Simvastatin, and cholesterol absorption inhibitor such as Ezetimibe
  • a pharmaceutically acceptable carrier
  • Another embodiment of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more fibrates (for example, clofibrate, Clofibricte, Etofibrate, Aluminium Ciof ⁇ brate), and a pharmaceutically acceptable carrier
  • Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more LXR agonists, and a pharmaceutically acceptable carrier.
  • Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more LRP mimics, and a pharmaceutically acceptable carrier.
  • Another embodiment of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more 5-HT6 receptor antagonists, and a pharmaceutically acceptable carrier.
  • Another embodiment of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more nicotinic receptor agonists, and a pharmaceutically acceptable carrier.
  • Another embodiment of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more H3 receptor antagonists, and a pharmaceutically acceptable carrier.
  • Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more histone deacetylase inhibitors, and a pharmaceutically acceptable carrier.
  • Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more hsp90 inhibitors, and a pharmaceutically acceptable carrier.
  • Another embodiment of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more ml muscarinic receptor agonists, and a pharmaceuticaily acceptable carrier.
  • Another embodiment of this invention is directed to combinations, i.e., a pharmaceutical composition, comprising a pharmaceuticaily acceptable carrier, an effective (i.e., therapeutically effective) amount of one or more compounds of formula
  • Another embodiment of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more 5-HT6 receptor antagonists mGluRI or mGluR ⁇ positive allosteric modulators or agonists, and a pharmaceutically acceptable carrier.
  • Another embodiment of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more one mGluR2/3 antagonists, and a pharmaceutically acceptable carrier.
  • Another embodiment of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more anti-inflammatory agents that can reduce ne ⁇ roinflammation, and a pharmaceutically acceptable carrier.
  • Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more Prostaglandin EP2 receptor antagonists, and a pharmaceutically acceptable carrier.
  • Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more PAJ-1 inhibitors, and a pharmaceutically acceptable carrier.
  • Another embodiment of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more agents that can induce Abeta efflux such as geisolin, and a pharmaceutically acceptable carrier.
  • Oth ⁇ r embodiments of this invention are directed to any one of the above embodiments directed to pharmaceutical compositions wherein the compound of formula (J) is selected from the group consisting of Group A.
  • the compounds of formula (I) can be useful as gamma secretase modulators and can be useful in the treatment and prevention of diseases such as, for example, central nervous system disorders (such as Alzheimers disease and Downs Syndrome), mild cognitive impairment, glaucoma, cerebral amyloid angiopathy, stroke, dementia, microgliosis, brain inflammation, and olfactory function loss.
  • diseases such as, for example, central nervous system disorders (such as Alzheimers disease and Downs Syndrome), mild cognitive impairment, glaucoma, cerebral amyloid angiopathy, stroke, dementia, microgliosis, brain inflammation, and olfactory function loss.
  • Another embodiment of this invention is directed to a method of treating a central nervous system disorder comprising administering a therapeutically effective amount of at least one compound of formula (I) to a patient in need of such treatment.
  • Another embodiment of this invention is directed to a method of treating a central nervous system disorder comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt, solvate, or ester thereof, and at least one pharmaceutically acceptable carrier.
  • Another embodiment of this invention is directed to a method of treating a central nervous system disorder comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula ( ⁇ ), or a pharmaceutically acceptable salt, solvate, or ester thereof, and at least one pharmaceutically acceptable carrier, and a therapeutically effective amount of one or more compounds selected from the group consisting of cholinesterase inhibitors, A ⁇ antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors.
  • another embodiment of this invention is directed to a method for modulating (including inhibiting, antagonizing and the like) gamma-secretase comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I) to a patient in need of such treatment.
  • Another embodiment of this invention is directed to a method for modulating (including inhibiting, antagonizing and the like) gamma-secretase, comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula (I) to a patient in need of treatment.
  • Another embodiment of this invention is directed to a method of treating one or more neurodegenerative diseases, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
  • Another embodiment of this invention is directed to a method of treating one or more neurodegenerative diseases, comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula (I) to a patient in need of treatment.
  • Another embodiment of this invention is directed to a method of inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
  • amyloid protein e.g., amyloid beta protein
  • neurological tissue e.g., the brain
  • Another embodiment of this invention is directed to a method of inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula (I) to a patient in need of treatment.
  • Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
  • Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula (I) to a patient in need of treatment.
  • Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula (I) to a patient in need of treatment.
  • Another embodiment of this invention is directed to a method of treating mild cognitive impairment, glaucoma, cerebral amyloid angiopathy, stroke, dementia, microgliosis, brain inflammation, or olfactory function loss, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
  • an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
  • Another embodiment of this invention is directed to a method of treating mild cognitive impairment, glaucoma, cerebral amyloid angiopathy, stroke, dementia, microgliosis, brain inflammation, or olfactory function loss, comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula (I) to a patient in need of treatment.
  • Another embodiment of this invention is directed to a method of treating mild cognitive impairment, comprising administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
  • Another embodiment of this invention is directed to a method of treating glaucoma, comprising administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
  • Another embodiment of this invention is directed to a method of treating cerebral amyloid angiopathy, comprising administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
  • Another embodiment of this invention is directed to a method of treating stroke, comprising administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
  • Another embodiment of this invention is directed to a method of treating dementia, comprising administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
  • Another embodiment of this invention is directed to a method of treating microgliosis, comprising administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
  • Another embodiment of this invention is directed to a method of treating brain inflammation, comprising administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
  • Another embodiment of this invention is directed to a method of treating olfactory function toss, comprising administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
  • Another embodiment of this invention is directed to a method of treating Downs syndrome, comprising administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
  • Another embodiment of this invention is directed to a method of treating Downs syndrome, comprising administering an effective amount of a compound of formula (I) to a patient in need of treatment.
  • Other embodiments of this invention are directed to any one of the above embodiments directed to methods of treating wherein the compound of formula (I) is selected from the group consisting of Group A.
  • inventions of this invention are directed to any one of the above embodiments directed to methods of treating wherein the compound of formula (I) is selected from the group consisting of Group E.
  • This invention also provides combination therapies for (1 ) modulating gamma- secretase, or (2) treating one or more neurodegenerative diseases, or (3) inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), or (4) treating Alzheimer's disease.
  • the combination therapies are directed to methods comprising the administration of one or more (e.g. one) compounds of formula (I) and the administration of one or more (e.g., one) other pharmaceutical active ingredients (e.g., drugs).
  • the compounds of formula (I) and the other drugs can be administered separately (i.e., each is in its own separate dosage form), or the compounds of formula (I) can be combined with the other drugs in the same dosage form.
  • other embodiments of this invention are directed to any one of the methods of treatment, or methods of inhibiting, described herein, wherein an effective amount of the compound of formula (I) is used in combination with an effective amount of one or more other pharmaceutically active ingredients (e.g., drugs).
  • the other pharmaceutically active ingredients are selected from the group consisting of: BACE inhibitors (beta secretase inhibitors), muscarinic antagonists (e.g., mi agonists or m 2 antagonists), cholinesterase inhibitors (e.g., acetyl- and/or butyrylchloltnesterase inhibitors); gamma secretase inhibitors; gamma secretase modulators; HMG-CoA reductase inhibitors; non-steroidal anti-inflammatory agents; N-methyl-D-aspartat ⁇ receptor antagonists; anti-amyloid antibodies; vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists or CB1 receptor antagonists; an antibiotic; growth hormone secretogogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABAA inverse agonists; inhibitors of amyloid aggregation; glycogen synthe
  • BACE inhibitors
  • inventions of this invention are directed to any one of the methods of treatment, or methods of inhibiting, described herein, wherein the compound of formula (I) is used in combination with an effective amount of one or more other pharmaceutically active ingredients selected from the group consisting of: BACE inhibitors (beta secretase inhibitors), muscarinic antagonists (e.g., m, agonist or r ⁇ i 2 antagonists), cholinesterase inhibitors (e.g., acetyl- and/or butyrylchlolinesterase inhibitors); gamma secretase inhibitors; gamma secretase modulators; HMG-CoA reductase inhibitors; non-steroidal anti-inflammatory agents; N-methy!-D-aspartate receptor antagonists; anti-amyloid antibodies; vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists or CB1 receptor antagonists; an antibiotic; growth hormone secretagogues; histamine
  • Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I), in combination with an effective (i.e., therapeutically effective) amount of one or more cholinesterase inhibitors (such as, for example, ( ⁇ )-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4- piperidinyl]methyl]-1 H-inden-1-one hydrochloride, i.e., donepezil hydrochloride, available as the Aricept ® brand of donepezil hydrochloride), to a patient in need of treatment.
  • an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I) in combination with an effective (i.e., therapeutically effective) amount of one or more cholinesterase inhibitors (such as, for example, ( ⁇ )-2
  • Alzheimer's disease comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula (I), in combination with an effective (i.e., therapeutically effective) amount of one or more (e.g., one) cholinesterase inhibitors (such as, for example, ( ⁇ )-2,3-dihydro-5,6-dimethoxy-2-[[1 *(phenylmethyl)-4- piperidinyl]methyl]-1 H -inden-1-one hydrochloride, i.e., donepezil hydrochloride, available as the Aricept ® brand of donepezil hydrochloride), to a patient in need of treatment.
  • an effective (i.e., therapeutically effective) amount of a compound of formula (I) in combination with an effective (i.e., therapeutically effective) amount of one or more (e.g., one) cholinesterase inhibitors (such as, for example, ( ⁇ )-2,3-dihydro-5,6-dimethoxy
  • Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I), in combination with an effective (i.e., therapeutically effective) amount of one or more compounds selected from the group consisting of A ⁇ antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors.
  • an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I) in combination with an effective (i.e., therapeutically effective) amount of one or more compounds selected from the group consisting of A ⁇ antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors.
  • Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I), in combination with an effective (i.e., therapeutically effective) amount of one or more BACE inhibitors.
  • Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of Exeion (rivastigmine).
  • Another embodiment of this invention is directed to a method of treating
  • Alzheimer's disease comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of Cognex (tacrine).
  • Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of a Tau kinase inhibitor.
  • Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more Tau kinase inhibitor (e.g., GSK3beta inhibitor, cdk ⁇ inhibitor, ERK inhibitor).
  • Tau kinase inhibitor e.g., GSK3beta inhibitor, cdk ⁇ inhibitor, ERK inhibitor.
  • This invention also provides a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one anti-Abeta vaccination (active immunization).
  • Alzheimer's disease comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more agents that upregulate insulin degrading enzyme and/or neprilysin.
  • Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more cholesterol lowering agents (for example, statins such as Atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, and cholesterol absorption inhibitor such as Ezetimibe).
  • This invention also provides a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I) 1 in combination with an effective amount of one or more fibrates (for example, clofibrate, Clofibride, Etofibrate, Aluminium Clofibrate).
  • Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more cholesterol lowering agents (for example, statins such as Atorvastatin
  • Alzheimer's disease comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more LXR agonists.
  • Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more LRP mimics.
  • Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more 5- HT6 receptor antagonists.
  • Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more nicotinic receptor agonists.
  • Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more H3 receptor antagonists.
  • This invention also provides a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more histone deacetylase inhibitors.
  • Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more hsp90 inhibitors.
  • Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (i), in combination with an effective amount of one or more ml muscarinic receptor agonists.
  • Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more 5- HT6 receptor antagonists mGiuRI or mGluR ⁇ positive allosteric modulators or agonists.
  • Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I) 1 in combination with an effective amount of one or more mGluR2/3 antagonists.
  • Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more anti-inflammatory agents that can reduce neuroinflammation.
  • Alzheimer's disease comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more PAI-1 inhibitors.
  • Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more agents that can induce Abeta efflux such as gelsolin.
  • Another embodiment of this invention is directed to a method of treating Downs syndrome, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
  • an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
  • Another embodiment of this invention is directed to a method of treating Downs syndrome, comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula (I) to a patient in need of treatment.
  • Another embodiment of this invention is directed to a method of treating Downs syndrome, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I), in combination with an effective (i.e., therapeutically effective) amount of one or more cholinesterase inhibitors (such as, for example, ( ⁇ )-2,3-dihydro-5,6-dimethoxy-2-([Hphenylmethyr)-4- piperidinyl ⁇ methyl]-1 H -inden-1 -one hydrochloride, i.e., donepezil hydrochloride, available as the Aricept ® brand of donepez ⁇ hydrochloride), to a patient in need of treatment.
  • cholinesterase inhibitors such as, for example,
  • Another embodiment of this invention is directed to a method of treating Downs syndrome, comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula (I) 1 in combination with an effective (i.e., therapeutically effective) amount of one or more (e.g., one) cholinesterase inhibitors (such as, for example, ( ⁇ )-2,3-dihydro-5,6-dimethoxy-2-[[1 - ⁇ phenylmethyl)-4- piperidinyf]methyl]-1 H -inden-1 -one hydrochloride, i.e., donepezil hydrochloride, available as the Aricept ® brand of donepezil hydrochloride), to a patient in need of treatment.
  • an effective (i.e., therapeutically effective) amount of a compound of formula (I) 1 in combination with an effective (i.e., therapeutically effective) amount of one or more (e.g., one) cholinesterase inhibitors (such as, for example, ( ⁇
  • compositions comprising an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I), in combination with an effective (i.e., therapeutically effective) amount of one or more compounds selected from the group consisting of cholinesterase inhibitors (such as, for example, ( ⁇ )-2,3- dihydro-5,6-d ⁇ rnetboxy-2-[[1 -(phenylmethyl)-4-piperidinyl]methyl]-1 H -inden-1 -one hydrochloride, i.e., donepezil hydrochloride, available as the Aricept ® brand of donepezif hydrochloride), A ⁇ antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors.
  • the pharmaceutical compositions also comprise a pharmaceutically acceptable carrier.
  • inventions of this invention are directed to any one of the above embodiments directed to combination therapies (i.e., the above methods of treating wherein compounds of formula (I) are used in combination with other pharmaceutically active ingredients, i.e., drugs) wherein the compound of formula (I) is selected from the group consisting of Group A.
  • combination therapies i.e., the above methods of treating wherein compounds of formula (I) are used in combination with other pharmaceutically active ingredients, i.e., drugs
  • the compound of formula (I) is selected from the group consisting of Group A.
  • inventions of this invention are directed to any one of the above embodiments directed to combination therapies (i.e., the above methods of treating wherein compounds of formula (I) are used in combination with other pharmaceutically active ingredients, i.e., drugs) wherein the compound of formula (I) is selected from the group consisting of Group B.
  • combination therapies i.e., the above methods of treating wherein compounds of formula (I) are used in combination with other pharmaceutically active ingredients, i.e., drugs
  • the compound of formula (I) is selected from the group consisting of Group B.
  • inventions of this invention are directed to any one of the above embodiments directed to combination therapies (i.e., the above methods of treating wherein compounds of formula (I) are used in combination with other pharmaceutically active ingredients, i.e., drugs) wherein the compound of formula (I) is selected from the group consisting of Group C.
  • combination therapies i.e., the above methods of treating wherein compounds of formula (I) are used in combination with other pharmaceutically active ingredients, i.e., drugs
  • the compound of formula (I) is selected from the group consisting of Group C.
  • inventions of this invention are directed to any one of the above embodiments directed to combination therapies (i.e., the above methods of treating wherein compounds of formula (I) are used in combination with other pharmaceutically active ingredients, i.e., drugs) wherein the compound of formula (I) is selected from the group consisting of Group D.
  • combination therapies i.e., the above methods of treating wherein compounds of formula (I) are used in combination with other pharmaceutically active ingredients, i.e., drugs
  • the compound of formula (I) is selected from the group consisting of Group D.
  • inventions of this invention are directed to any one of the above embodiments directed to combination therapies (i.e., the above methods of treating wherein compounds of formula (I) are used in combination with other pharmaceutically active ingredients, i.e., drugs) wherein the compound of formula (I) is selected from the group consisting of Group E.
  • combination therapies i.e., the above methods of treating wherein compounds of formula (I) are used in combination with other pharmaceutically active ingredients, i.e., drugs
  • the compound of formula (I) is selected from the group consisting of Group E.
  • kits comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of a compound of formula (I) in a pharmaceutically acceptable carrier, and another container (i.e., a second container) comprises an effective amount of another pharmaceutically active ingredient (as described above), the combined quantities of the compound of formula (I) and the other pharmaceutically active ingredient being effective to: (a) treat Alzheimer's disease, or (b) inhibit the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), or (c) treat neurodegenerative diseases, or (d) modulate the activity of gamma-secretase, or (e) mild cognitive impairment, or (f) glaucoma, or (g) cerebral amyloid angiopathy, or (h) stroke, or (i) dementia, or (j) microgliosis, or (k) brain inflammation, or (I) ol
  • amyloid protein e.
  • kits comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of one or more (e.g., one) compounds of formula (I) in a pharmaceutically acceptable carrier, and another container (i.e., a second container) comprises an effective amount of another pharmaceutically active ingredient (as described above), the combined quantities of the compounds of formula (I) and the other pharmaceutically active ingredient being effective to: (a) treat Alzheimer's disease, or (b) inhibit the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), or (c) treat neurodegenerative diseases, or (d) modulate the activity of gamma- secretase.
  • one container comprises an effective amount of one or more (e.g., one) compounds of formula (I) in a pharmaceutically acceptable carrier
  • another container i.e., a second container
  • another container comprises an effective amount of another pharmaceutically active ingredient (as described above)
  • kits comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of a compound of formula (I) in a pharmaceutically acceptable carrier, and another container (i.e., a second container) comprises an effective amount of another pharmaceutically active ingredient (as described above), the combined quantities of the compound of formula (I) and the other pharmaceutically active ingredient being effective to: (a) treat Alzheimer's disease, or (b) inhibit the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), or (c) treat neurodegenerative diseases, or (d) modulate the activity of gamma-secretase.
  • amyloid protein e.g., amyloid beta protein
  • kits wherein the compound of formula (I) is selected from the group consisting of Group A.
  • kits wherein the compound of formula (I) is selected from the group consisting of Group B.
  • kits wherein the compound of formula (I) is selected from the group consisting of Group D.
  • Other embodiments of this invention are directed to any one of the above embodiments directed to kits wherein the compound of formula (I) is selected from the group consisting of Group E.
  • Examples of cholinesterase inhibitors are tacrine, donepezil, rivastigmine, galantamine, pyridostigmine and neostigmine, with tacrine, donepezil, rivastigmine and galantamine being preferred.
  • Examples of agonist are known in the art.
  • Examples of m 2 antagonists are also known in the art; in particular, m 2 antagonists are disclosed in US patents
  • BACE inhibitors examples include those described in: US2005/0119227 published 06/02/2005 (see also WO2005/016876 published 02/24/2005),
  • At least one means there is at least one and there can be more than one, and examples include 1 , 2 or 3, or 1 and 2, or 1. It is noted that the carbons of formula (I) and other formulas herein may be replaced with 1 to 3 silicon atoms so long as all valency requirements are satisfied.
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
  • alkenyl means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain.
  • “Lower alkenyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • “Alkenyl” may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and -S(alkyl).
  • suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
  • Alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above.
  • Non-limiting examples of aikylene include methylene, ethylene and propylene.
  • Alkynyl means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred aikynyf groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain.
  • “Lower alkynyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl.
  • “Alkynyl” may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
  • Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
  • the aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • suitable aryl groups include phenyl and naphthyl.
  • Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms.
  • the "heteroaryl” can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • heteroaryl may also include a heteroaryl as defined above fused to an aryl as defined above.
  • suitable heteroaryls include pyridyl, pyrazinyi, furanyl, thienyl, pyrimidinyl, pyrk ⁇ one (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4- thiadiazolyl, pyrazinyi, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2- a]pyridinyl, imidazo ⁇ i -bjthiazolyl, benz
  • Aralkyl or “arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyf and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
  • Alkylaryl means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.
  • Cycloalkylalkyl means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl and the like.
  • Cycloalkenyl means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkenyls include cyciopentenyl, cyciohexenyl, cyclohepta-1 ,3-dienyl, and the like.
  • Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
  • Cycloalkenylalkyl means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable cycloaikenylalkyls include cycfopentenylmethyl, cyclohexenylmethy! and the like.
  • Halogen means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine. "Halo” refers to fluoro, chloro, bromo or iodo.
  • ting system substituent means a substituent attached to an aromatic or non- aromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • Ring system substituents may be the same or different, each being independently selected from the group consisting of alky!, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkyJheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkyisulfonyl, arylsuffonyi, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyctyl, -O-C(O)-alkyl, -OC(0)-
  • Ring system substituenf may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system.
  • Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH 3 ) 2 - and the like which form moieties such as, for example:
  • Heteroarylalkyr means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like.
  • ⁇ eterocyclyl (or heterocycloalkyl) means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclyls contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), - N(Tos) group and the like; such protections are also considered part of this invention.
  • the heterocycfyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S.S-dioxide.
  • Non-(imiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyi, thiazolidinyl, 1 ,4-dioxanyf, tetrahydrofuranyl, tetrahydrothiophe ⁇ yl, lactam, lactone, and the like.
  • Heterocyclyl may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidone:
  • He ⁇ terocyclylalkyF (or heterocycloalkylalkyl) means a heterocyclyl moiety as defined above linked via an alky! moiety (defined above) to a parent core.
  • suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like.
  • HeterocyclenyP (or heterocycloalkenyl) means a non-aromatic monocyclic or multicycltc ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon- nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclenyt rings contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • the heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituenf is as defined above.
  • the nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • heterocyclenyl groups include 1,2,3,4- tetrahydropyridinyl, 1 ,2-dihydropyridinyl, 1 ,4-dihydropyridinyf, 1 ,2,3,6- tetrahydropyridinyl, 1 ,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2- imidazoli ⁇ yl, 2-pyrazoKnyl, dihydroimidazoiyK dihydrooxazofyl, dihydrooxadiazolyl, dihydrothiazolyf, 3,4-dihydro-2H-pyranyl, dihydrofuranyi, fluorodihydrofuranyt, 7- oxabicyclo[2.2.ijheptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like.
  • Heterocyclenyl may also mean a single moiety (
  • ⁇ eterocyclenylalkyl (or heterocycloalkenylalkyl) means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • hetero-atom containing ring systems of this invention there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom.
  • N, O or S there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom.
  • Alkynylalkyl means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.
  • Heteroaralkyl means a heteroaryl-alkyi- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-fimiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3- ylmethyl. The bond to the parent moiety is through the alkyl.
  • Hydroxyalkyl means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
  • acyl means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described.
  • the bond to the parent moiety is through the carbonyl.
  • Preferred acyls contain a lower alkyl.
  • suitable acyl groups include formyl, acetyl and propanoyl.
  • Aroyl means an aryl-C(O)- group in which the aryl group is as previously described.
  • the bond to the parent moiety is through the carbonyl.
  • suitable groups include benzoyl and 1 - naphthoyl.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Aryloxy means an aryl-O- group in which the aryl group is as previously described.
  • suitable aryloxy groups include phenoxy and naphthoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Aralkyloxy means an aralkyl-O- group in which the aralkyl group is as previously described.
  • suitable aralkyloxy groups include benzyloxy and 1 - or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen.
  • Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
  • suitable alkylthio groups include metnylthio and ethylthio.
  • the bond to the parent moiety is through the sulfur.
  • Arylthio means an aryl-S- group in which the aryl group is as previously described.
  • suitable arylthio groups include phenylthio and naphthylthio.
  • the bond to the parent moiety is through the sulfur.
  • Aralkylthio means an aralkyl-S- group in which the aralkyl group is as previously described.
  • Non-limiting example of a suitable aralkylthio group is benzyithio.
  • the bond to the parent moiety is through the sulfur.
  • Alkoxycarbonyl 11 means an a!kyl-O-CO- group.
  • suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyJ.
  • Aryloxycarbonyl means an aryl-O-C(O)- group.
  • suitable aryloxycarbonyl groups include phenoxycarbony! and naphthoxycarbonyl.
  • the bond to the parent moiety is through the carbonyl.
  • Alkoxycarbonyl means an aralkyl-O-C(O)- group.
  • a suitable aralkoxycarbonyl group is benzyloxycarbonyl.
  • the bond to the parent moiety is through the carbonyl.
  • Alkylsutfonyl means an alkyl-S(O 2 )- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
  • Arylsulfonyl means an aryl-S(O 2 )- group. The bond to the parent moiety is through the sulfonyl.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound' or “stable structure” is meant 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.
  • the term “optionally substituted” means optional substitution with the specified groups, radicals or moieties.
  • the term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof.
  • the term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like) , in sufficient purity to be characterizabie by standard analytical techniques described herein or well known to the skilled artisan.
  • any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
  • protecting groups When a functional group in a compound is termed "protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et a/, Protective Groups in organic Synthesis (1991), Wiley, New York.
  • any variable e.g., aryl, heterocycle, R 2 , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) .14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.
  • the term "prodrug” means a compound (e.g., a drug precursor) that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C 1 -C ⁇ )alkyl, (C 2 - Ci 2 )aikanoyioxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyioxym ethyl having from 3 to 6 carbon atoms, 1 -(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1 -(alkoxycarbo ⁇ yloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyi)aminomethyl having
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C 1 -Ce)alkanoyloxymethyl, 1-((Cr Cejalkanoyloxy ⁇ thyl, 1-methyl-1-((CrC 6 )alkanoyloxy)ethyl, (Cr Cejalkoxycarbonyloxymethyl, N-(Ci-C 6 )alkoxycarbonylaminomethyl, succinoyl, (Ci- C ⁇ Jalkanoyl, ⁇ -amino(Ci-C 4 )alkanyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ - aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 , -P(O)(O(Cr)(Cr)(Cr)(Cr)(Cr)(
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (C r Ci 0 )alkyl, (C 3 -C7) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ -aminoacyl, — C(OH)C(O)OY 1 wherein Y 1 is H, (Cr C 6 )alkyl or benzyl, -C(OY 2 ) Y 3 wherein Y 2 is (C 1 -C 4 ) alkyl and Y 3 is (CrC 6 )alkyl, carboxy (CrC 6 )alkyl, amino(C r C 4 )alkyl or mono-N — or di-N
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covending bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solvate encompasses both solution-phase and isolatable solvates.
  • suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • M. Caira etal, J. Pharmaceutical Set., 93(3), 601 -611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
  • Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et a/, AAPS PharmSciTech., 501 article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001 ).
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
  • the compounds of Formula (I) can form salts which are also within the scope of this invention.
  • Reference to a compound of Formula (I) herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term "SaIt(S)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic saits formed with inorganic and/or organic bases.
  • a compound of Formula (I) contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)" as used herein.
  • Salts of the compounds of the Formula (!) may be formed, for example, by reacting a compound of Formula (i) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenes ⁇ lfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates.) and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quartemized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
  • dimethyl, diethyl, and dibutyl sulfates dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides
  • aralkyl halides e.g. benzyl and phenethyl bromides
  • esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n- propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, mettioxymethyl), aralkyl (for exampl ⁇ , benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, d ⁇ alkyl, or C 1-4 alkoxy or amino); (2) sulfonate esters, such as a
  • the compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • the compounds of Formula (I) may be atropisomers (e.g., substituted biaryis) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column. It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
  • AII stereoisomers for example, geometric isomers, optical isomers and the like
  • the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs, such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4- pyridyl and 3-pyridyl).
  • the use of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 O, 31 P, 32 P, 35 S 1 18 F, and 36 CL respectively.
  • Certain isotopicaliy-labeHed compounds of Formula (I) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • tsotopically labelled compounds of Formula (I) can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
  • the compounds according to the invention can have pharmacological properties; in particular, the compounds of Formula (I) can be modulators of gamma secretase (including inhibitors, antagonists and the like).
  • the compounds of Formula (I) can be useful in the treatment of a variety of disorders of the central nervous system including, for example, including, but not limited to, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration and the like.
  • Another aspect of this invention is a method of treating a mammal (e.g., human) having a disease or condition of the central nervous system by administering a therapeutically effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound to the mammal.
  • a mammal e.g., human
  • a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound to the mammal.
  • a preferred dosage is about 0.001 to 500 mg/kg of body weight/day of the compound of Formula (I).
  • An especially preferred dosage is about 0.01 to 25 mg/kg of body weight/day of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate of said compound.
  • the compounds of this invention may also be useful in combination (administered together or sequentially) with one or more additional agents listed above.
  • the compounds of this invention may also be useful in combination (administered together or sequentially) with one or more compounds selected from the group consisting of A ⁇ antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range.
  • this invention includes combinations comprising an amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an amount of one or more additional agents listed above wherein the amounts of the compounds/ treatments result in desired therapeutic effect.
  • the pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays. Certain assays are exemplified later in this document.
  • compositions which comprise at least one compound of Formula (I), or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and at least one pharmaceutically acceptable carrier.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
  • Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18 th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
  • the compounds of the invention may also be deliverable transdermally.
  • the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the compounds of this invention may also be delivered subcutaneously.
  • the compound is administered orally.
  • the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
  • a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.
  • Another aspect of this invention is a kit comprising a therapeutically effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
  • kits comprising an amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and an amount of at least one additional agent listed above, wherein the amounts of the two or more ingredients result in desired therapeutic effect.
  • the invention disclosed herein is exemplified by the following illustrative processes which should not be construed to limit the scope of the invention. Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art.
  • CARDILLO G.; FABBRONI, S.; GENTILUCCI, L; PERCIACCANTE, R.; PICCINELLI, F.; TOLOMELLI, A.; Tetrahedron 2004, 60 (23), 5031-5040.
  • HEK293 cells overexpressing APP with Swedish and London mutations is treated with the specified compounds for 5 hour at 37 °C in 100 ml of DMEM medium containing 10% fetal bovine serum.
  • total A ⁇ , A ⁇ 40 and A ⁇ 42 is measured using electrochemiluminescence (ECL) based sandwich immunoassays.
  • ECL electrochemiluminescence
  • Total A ⁇ is determined using a pair of antibodies TAG-W02 and biotin-4G8, A ⁇ 40 is identified with antibody pairs TAG-G2-10 and biotin- 4G8, while A ⁇ 42 is identified with TAG-G2- 11 and biotin-4G8.
  • the ECL signal is measured using Sector Imager 2400 (Meso Scale Discovery).
  • a ⁇ profile in conditioned media is determined using surface enhanced laser desorption/ionization (SELDI) mass spectrometry.
  • Conditioned media is incubated with antibody W02 coated PS20 ProteinChip array.
  • Mass spectra of A ⁇ captured on the array is read on SELDI ProteinChip Reader (Bio- Rad) according to manufacturer's instructions.
  • a ⁇ in rat CSF is determined using MSD technology as described above.
  • a ⁇ 40 is measured using antibody pair Tag-G2-10 and biotin-4G8, while A ⁇ 42 is measured using Tag-anti A ⁇ 42 (Meso Scale Discovery) and biotin-4G8.
  • the ECL signal is measured using Sector Imager 2400 (Meso Scale Discovery).
  • Matrix-assisted laser desorption/ionization mass spectrometric (MALDi MS) analysis of A/? is performed on a Voyager-DE STR mass spectrometer (ABI, Framingham, MA). The instrument is equipped with a pulsed nitrogen laser (337 nm). Mass spectra is acquired in the linear mode with an acceleration voltage of 20 kV.
  • Each spectrum presented in this work represents an average of 256 laser shots.
  • 1 /A. of immunoprecipitated A ⁇ sample is mixed with 3 /vL of saturated ⁇ -cyano-4-hydroxycinnamic acid solution in 0.1% TFA/acetonitrile.
  • the sample-matrix solution is then applied to the sample plate and dried at ambient temperature prior to mass spectrometry analysis. All the spectra are externally calibrated with a mixture of bovine insulin and ACTH (18-39 clip).

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Abstract

This invention provides novel compounds that are modulators of gamma secretase. The compounds have the formula (I) wherein R2 is a fused bicyclic ring of the formula (II). Also disclosed are methods of modulating gamma secretase activity and methods of treating Alzheimer's disease using the compounds of formula (I).

Description

GAMMA SECRETASE MODULATORS
REFERENCE TO RELATED APPLICATION
This application claims the benefit of U.S. Provisional Application Serial No. 60/992846 filed December 6, 2007.
FIELD OF THE INVENTION
The present invention relates to certain heterocyclic compounds useful as gamma secretase modulators, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat various diseases including central nervous system disorders such as, for example, neurodegenerative diseases such as Alzheimer's disease and other diseases relating to the deposition of amyloid protein. They are especially useful for reducing Amyloid beta (hereinafter referred to as Aβ) production which is effective in the treatment of diseases caused by Aβ such as, for example, Alzheimers and Down Syndrome.
Background of the Invention
Alzheimer's disease is a disease characterized by degeneration and loss of neurons and also by the formation of senile plaques and neurofibrillary change. Presently, treatment of Alzheimer's disease is limited to symptomatic therapies with a symptom-improving agent represented by an acetylcholinesterase inhibitor, and the basic remedy which prevents progress of the disease has not been developed. A method of controlling the cause of onset of pathologic conditions needs to be developed for creation of the basic remedy of Alzheimer's disease. Aβ protein, which is a metabolite of amyloid precursor protein (hereinafter referred to as APP), is considered to be greatly involved in degeneration and loss of neurons as well as onset of demential conditions (for example, see Klein W L, et al Proceeding National Academy of Science USA, Sep. 2, 2003, 100(18), p. 10417-22, suggest a molecular basis for reversible memory loss.
Nitsch R M, and 16 others, Antibodies against β-amyloid slow cognitive decline in Alzheimer's disease, Neuron, May 22, 2003, 38(4), p. 547-554) suggest that the main components of Aβ protein are Aβ40 consisting of 40 amino acids and Aβ42 having two additional amino acids at the C-terminal. The Aβ40 and Aβ42 tend to aggregate (for example, see Jarrell J T et al, The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease, Biochemistry, May 11 ,1993, 32(18), p. 4693- 4697) and constitute the main components of senile plaques (for example, (Glenner GG, et al, Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochemical and Biophysical Research Communications, May 16, 1984, 120(3), p. 885-90. See also Masters C L, et al, Amyloid plaque core protein in Alzheimer disease and Down syndrome, Proceeding National Academy of Science USA, June 1985, 82(12), p. 4245-4249.).
Furthermore, it is known that mutations of APP and presenelin genes, which are observed in familial Alzheimer's disease, increase production of Aβ40 and Aβ42 (for example, see Gouras G K, et al, lntraneuronal Aβ 142 accumulation in human brain, American Journal of Pathology, January 2000, 156(1), p. 15-20. Also, see Scheuner D, et al, Nature Medicine, August 1996, 2(8), p. 864-870; and Forman M S, et al, Differential effects of the Swedish mutant amyloid precursor protein on β- amyloid accumulation and secretion in neurons and nonneuronal cells, Journal of Biological Chemistry, Dec. 19, 1997, 272(51), p. 32247-32253.). Therefore, compounds which reduce production of Aβ40 and Aβ42 are expected to be agents for controlling progress of Alzheimer's disease or for preventing the disease. These Aβs are produced when APP is cleaved by beta secretase and subsequently cleaved by gamma secretase. In consideration of this, creation of inhibitors of γ-secretase and β-secretase has been attempted for the purpose of reducing production of Aβs. Many of these known secretase inhibitors are peptides or peptidomimetics such as L-685,458. L-685,458, an asparty! protease transition state mimic, is a potent inhibitor of γ-secretase activity, (Biochemistry, Aug. 1 , 2000, 39(30), p. 8698-8704).
Also of interest in connection with the present invention are: US 2007/0117798 (Eisai, published May 24, 2007); US 2007/0117839 (Eisai, published May 24, 2007); US 2006/0004013 (Eisai, published January 5, 2006); WO 2005/110422 (Boehringer Ingetheim, published November 24, 2005); WO 2006/045554 (CeHzone AG, published may 4, 2006); WO 2004/110350 (Neurogenetics , published December 23, 2004); WO 2004/071431 (Myriad Genetics, published August 26, 2004); US 2005/0042284 (Myriad Genetics, published February 23, 2005) and WO 2006/001877 (Myriad Genetics, published January 5, 2006).
There is a need for new compounds, formulations, treatments and therapies to treat diseases and disorders associated with Aβ. It is, therefore, an object of this invention to provide compounds useful in the treatment or prevention or amelioration of such diseases and disorders.
Summary of the Invention
In its many embodiments, the present invention provides a novel class of heterocyclic compounds as gamma secretase modulators (including inhibitors, antagonists and the like), methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more diseases associated with the Aβ using such compounds or pharmaceutical compositions.
One embodiment, of the present invention is directed to compounds of formula (I):
Figure imgf000004_0001
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R1, R2, R3, R4, and L are as defined below.
This invention also provides compounds of formula (I).
This invention also provides compounds of formula (I) in pure and isolated form. This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas fA to IE, 1A to 4A, A1.1 to A28.1, A1.2 to A22.2, A24.2 to A28.2, 5.1, 8.1, 11.1, and A1 to A28.
This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas IA to IE.
This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas 1 A to 4A.
This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas A1.1 to A28.1. This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas A1.2 to A22.2, and A24.2 to A28.2.
This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas 5.1 , 8.1 , and 11.1.
This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas A1 to A28.
This invention also provides pharmaceutical compositions comprising an effective amount of one or more (e.g., one) compounds of formula (I), or a pharmaceutically acceptable salt, ester or solvate thereof, and a pharmaceutically acceptable carrier. This invention also provides pharmaceutical compositions comprising an effective amount of one or more (e.g., one) compounds of formula (I), or a pharmaceutically acceptable salt, ester or solvate thereof, and an effective amount of one or more (e.g., one) other pharmaceutically active ingredients (e.g., drugs), and a pharmaceutically acceptable carrier. The compounds of formula (I) can be useful as gamma secretase modulators and can be useful in the treatment and prevention of diseases such as, for example, central nervous system disorders such as Alzheimers disease and Downs Syndrome.
Thus, this invention also provides methods for: (1) method for modulating (including inhibiting, antagonizing and the like) gamma-secretase; (2) treating one or more neurodegenerative diseases; (3) inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain); (4) Alzheimer's disease; and (5) treating Downs syndrome; wherein each method comprises administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of such treatment. This invention also provides combination therapies for (1) modulating gamma- secretase, or (2) treating one or more neurodegenerative diseases, or (3) inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), or (4) treating Alzheimer's disease. The combination therapies are directed to methods comprising the administration of an effective amount of one or more (e.g. one) compounds of formula (I) and the administration of an effective amount of one or more (e.g., one) other pharmaceutical active ingredients (e.g., drugs).
This invention also provides methods for: (1) treating mild cognitive impairment; (2) treating glaucoma; (3) treating cerebral amyloid angiopathy; (4) treating stroke; (5) treating dementia; (6) treating microgliosis; (7) treating brain inflammation; and (8) treating olfactory function toss; wherein wherein each method comprises administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of such treatment. This invention also provides a kit comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of a compound of formula (I) in a pharmaceutically acceptable carrier, and another container (i.e., a second container) comprises an effective amount of another pharmaceutically active ingredient (as described below), the combined quantities of the compound of formula (I) and the other pharmaceutically active ingredient being effective to treat the diseases or conditions mentioned in any of the above methods.
This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds of formulas IA to IE, 1 A to 4A, A1.1 to A28.1 , A1.2 to A22.2, A24.2 to A28.2, 5.1 , 8.1 , 11.1 , and A1 to A28.
This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds IA to IE. This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from tf\e group consisting of: compounds 1 A to 4A. This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds A1.1 to A28.1.
This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds A1.2 to A22.2, and A24.2 to A28.2.
This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds 5.1 , 8.1 , and 11.1. This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds A1 to A28.
Detailed Description Of The Invention This invention provides compounds, useful as gamma secretase modulators, of formula (I):
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein: R1, R2, R3, R4 and L are each independently selected; R1 is selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl (e.g., heterocycloalkyl), cycloalkenyl, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl), heterocyclenyl (i.e., heterocycloalkenyl), fused cycloalkylaryl (i.e., cycloalkyfusedlaryl-), fused heterocycloalkylaryl- (i.e., heterocycloalkylfusedaryl-), fused cycloalkylheteroaryl- (i.e., cycloalkylfusedheteroaryl-), fused heterocycloalkylheteroaryl- (i.e., heterocycloalkylfusedheteroaryl-), fused benzocycloalkylalkyl- (i.e., benzofusedcycloalkylalkyl-), fused benzoheterocycloalkylalkyl- (i.e., benzofusedheterocycloalkyialkyl-), fused heteroarytcycloalkylalkyl- (i.e., heteroarylfusedcycloalkylalkyl-), fused heteroarylheterocycloalkylalkyl- (i.e., heteroarylfusedheterocycloalkylalkyl-), fused cycloalkylarylalkyl- (i.e., cycloalkyfusedlarylalkyl-), fused heterocycloalkylaryialkyl- (Le., heterocycloalkyifusedarylalkyl-), fused cycloalkylheteroaryialkyl- (i.e.. cycfoalkylfusedheteroarylalkyl-), and fused heterocycloalkylheteroarylalkyl- (i.e., heterocycloalkylfusedheteroarylalkyl-), wherein each of said: alkyl, alkenyf, alkyny!, cycloalkyl, heterocyclyl, cycloatkenyl, aryl, heteroaryl, heterocyclenyl fused cycloalkylaryl, fused heterocycloalkylaryl-, fused cycloalkylheteroaryl-, fused heterocyctoalkylheteroaryl-, fused benzocycloalkyialkyl-, fused benzoheterocycloalkylalkyl- fused heteroarylcyctoalkylalkyl-, fused heteroarylheterocycloalkylalkyl-, fused cycloalkylarylaikyf-, fused heterocycloafkylarylalkyl-, fused cyctoalkylheteroarylalkyl-, and fused heterocycloalkylheteroarylalkyl- R1 groups is optionally substituted with 1-5 independently selected R21 groups;
L is selected from the group consisting of: L is a direct bond, -O-, -N(R5)-, -C(R6XR7)-, -(C=O)-, -(C=NR21 A)-, -S-, -S(O)-, and -S(O)2-;
R2 is the fused bicyctic ring:
Figure imgf000008_0001
wherein:
(1) Ring (A) is a six membered heteroaryl ring comprising atoms A1 to A6, wherein:
(a) A1 is C,
(b) A5 and Aβ are C,
(b) A2, A3 and A4 are each independently selected from the group consisting of: N and C, and wherein each substitutable C is optionally substituted with one R21B group and each R2tB for each C is independently selected, and
(c) provided that at least one (e.g., 1 to 3, or 1 to 2, or 1) of A2 to A4 is nitrogen, and provided that the total number of nitrogens in Ring (A) is 1 to 3,
(2) Ring (B) (which comprises atoms A5, A6, and B1 to B4) is a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl or phenyl ring, and (a) A5 and A6 are as defined for Ring (A) above,
(b) in said phenyl Ring (B): (i) Bτ to B4 are C, and
(ii) B2, B3, and B4 are each optionally substituted with one R21B group (and the substitution on each carbon is independent of the substitutions on the remaining carbons), (C) in said cycloalkyl Ring (B): (i) B1 is C,
(ii) B2, B3, and B4 are each independently selected from the group consisting of: C, -(C=O)- and -(C=NR21A)- (e.g., -(C=N-OR15)-, and -(C=N-N(R15XR16))-), provided that there are only 0 to 2 moieties selected from the group consisting of -(C=O)- and -(C=NR21A)- (i.e. in said cycloalkyi Ring (B) either B2, B3, and B4 are ail C, or one of B2, B3, and B4 is C and the remaining two are selected from the group consisting of -(C=O)- and -(C=NR21A)-, or two of B2, B3, and B4 are C and the remaining one is selected from the group consisting of: -(C=O)- and -(C=NR21A)-), and
(iii) each substitutable B1 to B4 C is optionally substituted with 1 or 2 independently selected R groups (and the substitution on each carbon is independent of the substitutions on the remaining carbons, and those skilled in the art will appreciate that the total number of optional substitutents on a carbon is determined by the number bonds in the ring to the ring atom),
(d) in said cycloalkenyl Ring (B): (i) B1 is C,
(it) B2, B3, and B4 are each independently selected from the group consisting of: C, -(C=O)- and -(C=NR21 A)- (e.g., -(C=N-OR15)-, and -(C=N-N(R15XR16))-), provided that there are only O to 2 moieties selected from the group consisting of -(C=O)- and -(C=NR21A)- (i.e. in said cycloalkenyl Ring (B) either B2, B3, and B4 are all C, or one of B2, B3, and B4 is C and the remaining two are selected from the group consisting of -(C=O)- and -(C=N R21 A)-, or two of B2, B3, and B4 are C and the remaining one is selected from the group consisting of: -(C=O)- and -(C=NR21A)-),
(iii) each substitutable B1 to B4 C is optionally substituted with 1 or 2 independently selected R groups (and the substitution on each carbon is independent of the substitutions on the remaining carbons, and those skilled in the art will appreciate that the total number of optional substitutents on a carbon is determined by the number bonds in the ring to the ring atom), and
(iv) said cycloalkenyl Ring (B) comprises one or two double bonds (and in one example one double bond, and in another example two double bonds),
(e) in said heterocycloalkyl Ring (B):
(i) B1 is selected from the group consisting of N and C, (ii) B2, B3 and B4 are each independently selected from the group consisting of: N, C1 -(C=O)-, -(C=NR21A)- (e.g., -(C=N-OR15)-, and -(C=N-N(R15XR16))-), O, S, S(O), and S(O)2, and provided that there are no -O-O- bonds, no -O-S- bonds, no O-S(O) bonds, no -O- S(O)2 bonds, and no -N-S- bonds in the ring, and provided that the ring does not comprise three adjacent nitrogen atoms,
(iii) at least one (e.g., 1 to 3, or 1 to 2, or 1) of B1 to B4 is a heteroatom, and provided that when B1 is a heteroatom said heteroatom is N, and the heteroatoms for B2 to B4 (when one or more of B2 to B4 are heteroatoms) are selected from the group consisting of: N1 O, S, S(O), and S(O)2,
(iv) the total number of heteroatoms in said heterocycloalkyl Ring (B) is 1 to 4, and
(v) each substitutable B1 to B4 C is optionally substituted with 1 or 2 independently selected R21B groups (and the substitution on each carbon is independent of the substitutions on the remaining carbons, and those skilled in the art will appreciate that the total number of optional substitutents on a carbon is determined by the number bonds in the ring to the ring atom), and
(vi) each substitutable B2 to B4 N is optionally substituted with one R21A group and each R21A for each N is independently selected, (f) in said heterocycloalkenyl Ring (B):
(i) B1 is selected from the group consisting of N and C,
(ii) B2, B3 and B4 are each independently selected from the group consisting of: N, C, -(C=O)-, -(C=NR21A)- (e.g., -(C=N-OR15)-, and -(C=N-N(R15)(R16))-), O1 S, S(O), and S(O)2, and that there are no -O-O- bonds, no - O-S- bonds, no O-S(O) bonds, no -O- S(O)2 bonds, and no -N-S- bonds in the ring, and provided that the ring does not comprise three adjacent nitrogen atoms,
(iii) at least one (e.g., 1 to 4, or 1 to 3, or 1 to 2, or 1) of B1 to B4 is a heteroatom, provided that when B1 is a heteroatom said heteroatom is N, and the heteroatoms for B2 to B4 (when one or more of B2 to B4 are heteroatoms) are selected from the group consisting of: N, O, S, S(O), and S(O)2,
(iv) the total number of heteroatoms in said heterocycloaikenyl Ring (B) is 1 to 4, and
(v) each substitutabie B1 to B4 C is optionally substituted with 1 or 2 independently selected R groups (and the substitution on each carbon is independent of the substitutions on the remaining carbons, and those skilled in the art will appreciate that the total number of optional substitutents on a carbon is determined by the number bonds in the ring to the ring atom),
(vi) each substitutable B2 to B4 N is optionally substituted with one R21Λ group and each R21A for each N is independently selected, and
(vii) said heterocycloalkenyl Ring (B) comprises one or two double bonds (and in one example one double bond, and in another example two double bonds); and
(g) in said heteroaryl Ring (B): (I) B1 is C,
(ii) B2 to B4 are each independently selected from the group consisting of C and N,
(iii) at least one (e.g., 1 to 4, or 1 to 3, or 1 to 2, or 1) of B2 to B4 is a heteroatom (e.g., at least one of B2 to B4 is N), and (iv) the total number of heteroatoms in said heteroaryl Ring (B) is 1 to 3 and wherein each substitutable B2 to B4 C is optionally substituted with one R21B group (and the substitution on each carbon is independent of the substitutions on the remaining carbons);
R3 is selected from the group consisting of: aryl- (e.g., phenyl), heteroaryl- (e.g., pyridyl), cycloalkyl-, cycloalkenyl, cycloalkylalkyl-, heterocyclyl-, heterocyclenyl-, heterocyclylalkyl-, heterocyclyalkenyl-, fused benzocycloalkyl- (i.e., benzofusedcycloalkyl-), fused benzoheterocycloalkyl- (i.e., benzofusedheterocycloalkyl-), fused heteroarylcycloalkyl- (i.e., heteroarylfusedcycloalkyl-), fused heteroarylheterocycloalkyl- (i.e., heteroarylfusedheterocycloalkyi-), fused cycloalkylaryl (i.e., cycloalkyfusedlaryl-), fused heterocycloalkylaryl- (i.e., heterocycloalkylfusedaryl-), fused cycloalkylheteroaryf- (i.e., cycloalkylfusedheteroaryl-), fused heterocycloalkyfheteroaryl- (i.e., heterocycloalkylfusedheteroaryl-),
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
wherein X is selected from the group consisting of: 0, -N(R14)- and -S-; and wherein each of said R3 moieties is optionally substituted with 1 -5 independently selected R21 groups;
R4 is selected from the group consisting of: arylalkoxy-, heteroarylalkoxy-, arylalkylamino-, heteroarylalkylamino-, aryl, heteroaryl, cycloalkyl-, cycloalkenyl, heterocyclyl, heterocyclenyl, and heterocyclyalkyl-, wherein each of said R4 arylalkoxy-, heteroarylalkoxy-, arylalkylamino-, heteroarylalkylamino-, aryl, heteroaryl, heterocyclyl, heterocyclenyl, and heterocyclyalkyl- is optionally substituted with 1 -5 independently selected R21 groups; or R3 and R4 are linked together to form a fused tricyclic ring system wherein R3 and R4 are as defined above and the ring linking R3 and R4 is an alkyl ring, or a heteroalkyl ring, or an aryl ring, or a heteroaryl ring, or an alkenyl ring, or a heteroalkenyl ring (for example, the tricyclic ring system is formed by linking the atoms adjacent to the atoms by which R3 and R4 are bound together); R5 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyi, cycloalkenyl, heterocyclyl, heterocyclylalkyl, aryl, arylaikyl, heteroary!. heteroarylalkyl, -CN, -C(O)R15, -C(O)OR15, -C(O)N(R15)(R16), -S(O)N(R15)(R16), -S(O)2N(R15)(R16), -C(=NOR15)R16, and -P(O)(OR15)(OR16); or R5 taken together with R1 and the nitrogen to which they are bound form a heterocycloalkyl or heterocyctoalkenyl ring fused to said R1 ring, said fused ring is optionaily substituted with 1 to 5 independently selected R21 groups;
R6 and R7 are each independently selected from the group consisting of: H, alky!, alkenyl, alkynyl, aryl, arylalkyl-. alkylaryl-, cycloalkyl, cycloalkylalkyl-, heteroaryl, heteroarylalkyl-, heterocyclyl (i.e., heterocycloaikyl) and heterocyclylalkyl- (i.e., heterocycloalkenyl), wherein independently each of said alkyl, alkenyl and alkynyl, aryl, arylalkyl-, alkylaryl-, cycloalkyl, cycloalkylalkyl-, heteroaryl, heteroarylalkyl-, heterocyclyl and heterocyclylalkyl- is optionally substituted with 1 to 5 independently selected R21 groups; or
R6 taken together with R1 and the carbon to which they are bound form a cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl ring fused to said R1 ring, said fused ring is optionally substituted with 1 to 5 independently selected R21 groups; or R6 and R7 taken together with the carbon to which they are bound form a spirocycloalkyl ring, a spirocycloalkenyl ring, a spiroheterocycloalkyl ring, or a spiroheterocyclalkenyl ring, and wherein the spiro ring is optionally substituted with 1 - 5 independently selected R21 groups;
R15A and R16A are independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocyclyl, (R18)q -alkyl, (R18)q -cycloalkyl, (R18)q -cycloalkylalkyl, (R18)q -heterocyclyl, (R18)q -heterocyclylalkyl, (R18)q -aryl, (R18)q -arylalkyl, (R18)q -heteroaryl and (R18)q -heteroarylalkyl, wherein q is 1 to 5 and each R18 is independently selected (and those skilled in the art will appreciate that the R18 moieties can be bound to any available substitutable atom); R15, R18 and R17 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyi, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocyclyl, (R18)q -alkyl, (R18)q -cycloalkyl, (R18)q -cycloalkylalkyl, (R18)q -heterocyclyl, (R18)q -heterocyclyialkyl, (R18)q -aryl, (R18)q -arylalkyl, (R18)q -heteroary! and (R18)q -heteroarylalkyl, wherein q is 1 to 5 and each R18 is independently selected (and those skilled in the art will appreciate that the R16 moieties can be bound to any available substitutabie atom); or each R18 is independently selected from the group consisting of alkyl, alkenyl, alkynyi, aryi, arylalkyl, arylalkenyl, arylalkynyl, -NO2, halo, heteroaryl, HO-alkyoxyalkyl, -CF3, -CN, alkyl-CN, -C(O)R19, -C(O)OH, -C(O)OR19, -C(O)NHR20, -C(O)NH2, -C(O)NH2-C(O)N(alkyl)2, -C(O)N(alkyl)(aryl), -C(O)N(alkyl)(heteroaryl), -SR19, -S(O)2R20, -S(O)NH2, -S(O)NH(alkyl). -S(O)N(alkyl)(alkyl), -S(O)NH(aryl), -S(O)2NH2, -S(O)2NHR19, -S(O)2NH(heterocyclyl), -S(O)2N(alkyl)2) -S(O)2N(alky!)(ary}), -OCF3, -OH, -OR20, -O-heterocyclyl, -O-cycloalkylalkyl, -O-heterocyclylalkyl, -NH2, -NHR20, -N(alkyl)2) -N(arylalkyl)2, -N(arylalkyl)-(heteroarylalkyl), -NHC(O)R20, -NHC(O)NH2, -NHC(O)NH(alkyl). -NHC(O)N(alkyl)(alkyl)) -N(alkyl)C(O)NH(alkyl), -N(alkyl)C(O)N(alkyl)(alkyl), -NHS(O)2R20, -NHS(O)2NH(alkyl).
-NHS(O)2N(alkyl)(alkyl). -N(alkyl)S(O)2NH(alkyl) and -N(alkyl)S(O)2N(alkyl)(alkyl); or alternately, two R18 moieties on adjacent carbons can be linked together to form:
Figure imgf000015_0001
R19 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;
R20 is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl; each R21 group is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl (i.e., heterocycloalkyl), heterocyclylalkyl (i.e., heterocycloalkylalkyl), aryl, arylafkyl, heteroaryl, heteroarylalkyl, halo, -CN, -OR15, -C(O)R15, -C(O)OR15, -C(O)N(R15)(R16), -P(O)(CH3)2, -SO(=NR15)R16-, -SF5, -OSF5, -Si(R15A)3 wherein each R15A is independently selected, -SR15, -S(O)N(R15)(R16), -CH(R15KR16), -S(O)2N(R15)(R16), -C(=NOR15)R16, -P(O)(OR15)(OR1Θ), -N(R15)(R16), -alkyi-N<R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, -CH2-N(R15)C(O)N(R16)(R17), -CH2-R15, -CH2N(R15)(R16),
-N(R15)S(O)R16A -N(R15)S(O)2R16A, -CH2-N(R15)S(O)2R16A, -N(R15)S(O)2N(R16)(R17), -N(R15)S(O)N(R16)(R17), -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15JC(O)OR16, -CH2-N(R15JC(O)OR16, -S(O)R15A, =NOR15, -N3, -NO2, -S(O)2R15A, -O-N=C(R15)2 (wherein each R15 is independently selected), and -O-N=C(R15)2 wherein said R15 groups are taken together with the carbon atom to which they are bound to form a 5 to 10 membered ring and wherein said ring optionally contains 1 to 3 heteroatoms independently selected from the group consisting of -O-, -S-, -S(O)-, -S(O)2-, and -NR21A; each R21A is independently selected from the group consisting of H, alky!, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl (i.e., heterocycloalkyl), heterocyclylalkyl (i.e., heterocycloalkylalkyl), aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -OR15, -CN, -alkyl-(R15)(R16), -CH(R15)(R16), -CH2-N(R^)C(O)R16, -CH2-N(R15)C(O)N(R16)(R17), -CH2-R15; -CH2N(R15)(R16), -C(O)R15, -C(O)OR15, -C(O)N(R15)(R16), -C(=NOR15)R16, -CH2-N(R15)S(O)2R16A, -CH2-N(R15)C(O)N(R16)(R17), -CH2-N(R15JC(O)OR16, -C(R15)=NOR16, -S(O)R15A; -S(O)(OR15), -S(O)2(OR15), -S(O)2R15A, -S(O)N(R15)(R16), -S(O)2N(R15KR16),
-P(O)(OR15KOR16), -N(R15XR16), -N(R15)C(O)R16, -N(R15)S(O)R16A, -N(R15)S(O)2R16A, -N(R15)S(O)2N(R16)(R17), -N(R15)S(O)N(R16)(R17), -N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -N3, -NO2, -P(O)(CH3)2> -SO(=NR15)R16-, -SF5, and -OSF5; each R21B group is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl (i.e., heterocycloalkyl), heterocyclylalkyl (i.e., heterocycloalkylalkyl), aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -OR15, -CN, -alkyl-(R15)(R1β), -CH(R15)(R16), -CH2-N(R15)C(O)R16, -CH2-N(R15)C(O)N(R16)(R17), -CH2-R15, -CH2N(R15)(R1β), -C(O)R15, -C(O)OR15, -C(O)N(R15)(R1β), -C(=NOR15)R16, -CH2-N(R15)S(O)2R16A, -CH2-N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)OR16, -C(R15)=NOR16, -SR15; -S(O)R15A; -S(O)(OR15), -S(O)2(OR15), -S(O)2R15A, -S(O)N(R15)(R16), -S(O)2N(R15)(R16), -P(O)(OR15)(OR16), -N(R15XR16), -N(R15)C(O)R16, -N(R15)S(O)R16A, -N(R15)S(O)2R16A, -N(R15JS(O)2N(R16XR17), -N(R15)S(O)N(R16)(R17), -N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -N3, -NO2, -P(O)(CH3)2, -SO(=NR15)R16-, -SF5, -OSF5, and -Si(R15A)3 wherein each R15A is independently selected; independently, each alkyl, cycloalkenyl, cycloalkyl, cycloalkyialkyl, heterocyclyl, heterocyclylalkyl , aryl, arylalkyl, heteroaryi, heteroarylalkyl, alkenyl and alkynyl R21, R21A, and R21B group is optionally substituted by 1 to 5 independently selected R22 groups wherein each R22 group is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, halo, -CF3, -CN, -OR15, - C(O)R15, -C(O)OR15, -alkyl-C(O)OR15, C(O)N(R15XR16), -SR15, -S(O)N(R15XR16), -S(O)2N(R15XR16), -C(=NOR15)R16 .. -P(O)(OR 15)(O R16), -N(R15)(R16), -alkyl-N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15JS(O)2R16, -CH2-N(R15)S(O)2R16, -N(R15)S(O)2N(R16)(R17), -N(R15)S(O)N(R16){R17), -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -CH2-N(R15)C(O)OR16, -N3, =NOR15, -NO2, -S(O)R15A and -S(O)2R15A; and
With the proviso that when R3 is aryl and R1 comprises a 5 or 6-membered aryl or heteroaryl ring, then said 5 or 6-membered aryl or hetβroaryl ring is not substituted with an R21 group that is selected from the group consisting of the moieties: -O-(5 or 6 membered aryl), -S-(5 or 6 membered aryl), -S(O)2-(5 or 6 membered aryl), -N(R15)-(5 or 6 membered aryl), -C(O)-(5 or 6 membered aryl), -alkyl-(5 or 6 membered aryl), -O-(5 or 6 membered heteroaryl), -S-(5 or 6 membered heteroaryl), -S(O)2-(5 or 6 membered heteroaryl),
-N(R15)-(5 or 6 membered heteroaryl), -C(O)-(5 or 6 membered heteroaryl), and -alkyl-(5 or 6 membered heteroaryl).
Those skilled in the art will appreciate that the above proviso means that when R3 is aryl and R1 comprises a 5 or 6-membered aryl or heteroaryl ring, then said 5 or 6-membered aryl or heteroaryl ring is not substituted with -O-(5 or 6 membered aryl), -S-(5 or 6 membered aryl), -S(O)2-(5 or 6 membered aryl), -N(R15)-(5 or 6 membered aryi), -C(O)-(5 or 6 membered aryl), -alkyl-(5 or 6 membered aryl), -O-(5 or 6 membered heteroaryl), -S-(5 or 6 membered heteroaryl), -S(O)2-(5 or 6 membered heteroaryl), -N(R15)-(5 or 6 membered heteroaryl), -C(O)-(5 or 6 membered heteroaryl), or -alkyl-(5 or 6 membered heteroaryl).
In one embodiment R3 is selected from the group consisting of: phenyl and pyridyl, wherein said R3 group is optionally substituted with 1 to 4 independently selected R21 groups.
In another embodiment R3 is selected from the group consisting of:
Figure imgf000017_0001
wherein X is selected from the group consisting of: O, -N(R14)- and -S-; and wherein each of said R3 moieties is optionally substituted with 1-5 independently selected R21 groups.
In another embodiment of this invention R3 is selected from the group consisting of: aryi- (e.g., phenyl), heteroaryl- (e.g., pyridyl), cycloalkyl-, cycloalkenyl, cycloalkylalkyl-, heterocyclyl-, heterocyclenyl-, heterocyclylalkyl-, heterocyclyalkenyl-, fused benzocyctoalkyl- (i.e., benzofusedcycloa(kyl-), fused benzoheterocycloalkyl- (i.e., benzofusedheterocycloalkyl-), fused heteroarylcycloalkyl- (i.e., heteroarylfusedcycloalkyl-), fused heteroarylheterocycloalkyl- (i.e., heteroarylfusedheterocycloalkyl-), fused cycloalkylaryl (i.e., cycloalkyfusedlaryl-), fused heterocycloalkylaryl- (i.e., heterocycloalkylfusedaryl-), fused cycloalkylheteroaryl- (i.e., cycloalkylfusedheteroaryl-), fused heterocycloalkylheteroaryl- (i.e., heterocycloalkylfusedheteroaryl-), and wherein each of said R3 moieties is optionally substituted with 1 -5 independently selected R21 groups.
In another embodiment of this invention R3 is selected from the group consisting of:
Figure imgf000018_0001
Figure imgf000019_0001
wherein each of said R3 moieties is optionally substituted with 1 -5 independently selected R21 groups.
In another embodiment R4 is a five membered heteroaryl ring optionally substituted with 1 to 4 independently selected R21 groups.
Examples of moieties formed when R3 and R4 are linked together to form a fused tricyclic ring system include, but are not limited to:
Figure imgf000020_0001
wherein R3 and R4 are as defined for formula (I), and Ring C is the ring linking R3 and R4, that is Ring C is an alkyl ring, or a heteroalkyl ring, or an aryl ring, or a heteroaryl ring, or an alkenyl ring, or a heteroalkenyl ring.
Examples of moieties formed when R3 and R4 are linked together to form a fused tricyclic ring system include, but are not limited to:
Figure imgf000020_0002
wherein R3 and R4 are as defined for formula (I)1 and Ring C is the ring linking R3 and R4, that is Ring C is a heteroalkyl ring, or a heteroaryl ring, or a heteroalkenyl ring. In one example, the fused tricyclic ring system formed when R3 and R4 are linked together is
Figure imgf000020_0003
wherein Ring C is a heteroalkyl ring, or a heteroaryl ring, or a heteroalkenyl ring, thus, for example, the tricyclic ring system is formed by linking the atoms adjacent to the atoms by which R3 and R4 are bound together), and wherein said fused tricyclic ring system is optionally substituted with 1 to 5 independently selected R21 groups.
Other examples of moieties formed when R3 and R4 are linked together to form a fused tricyclic ring system include, but are not limited to:
Figure imgf000021_0001
In one embodiment of this invention R3 is bound to A1 and L is bound to B1.
Thus, in this embodiment the compound of formula (I) is a compound of the formula:
Figure imgf000021_0002
In another embodiment of this invention R3 is bound to B1 and L is bound to A1. Thus, in this embodiment the compound of formula (I) is a compound of the formula:
Figure imgf000022_0004
In another embodiment of this invention the R4-R3- moiety is:
Figure imgf000022_0001
Thus, in another embodiment of this invention the compound of formula (I) is a compound of the formula:
Figure imgf000022_0002
In another embodiment of this invention the compound of formula (I) is a compound of the formula:
Figure imgf000022_0003
In another embodiment of this invention the compound of formula (I) is a compound the formula:
Figure imgf000023_0001
Another embodiment of this is directed to compounds of formula (I) wherein at feast one (e.g., 1 to 3, or 1-2, or 1) group selected from the group consisting of: -SF5, - OSF5, and -Si(R15A)3 is present, and wherein each R15A is independently selected, and wherein when there is more than one group, each group is independently selected.
Another embodiment of this is directed to compounds of formula (I) wherein at least one (e.g., 1 to 3, or 1-2, or 1) group selected from the group consisting of: -SF5 and -OSF5 is present, and wherein when there is more than one group, each group is independently selected. In one embodiment of this invention one group selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected) is present in the compounds of formula (I)-
In another embodiment of this invention two groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected) are present in the compounds of formula (I).
In another embodiment of this invention three groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected) are present in the compounds of formula (I).
In another embodiment of this invention two groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected) are present in the compounds of formula (!), wherein at least one group is other than -Si(R15A)3.
In another embodiment of this invention three groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected) are present in the compounds of formula (I), wherein at least one group is other than -Si(R15A)3.
In another embodiment of this invention one group selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of alkyi (e.g., methyl and ethyl) and aryl (e.g., phenyl)) is present in the compounds of formula (I).
In another embodiment of this invention two groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) are present in the compounds of formula (I).
In another embodiment of this invention three groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) are present in the compounds of formula (I). In another embodiment of this invention two groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) are present in the compounds of formula (I), wherein at least one group is other than -Si(R15A)3. In another embodiment of this invention three groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) are present in the compounds of formula (I), wherein at least one group is other than -Si(R15A)3. In another embodiment of this invention one group selected from the group consisting of: -SF5, -OSF5, and -St(R15A)3 (wherein each R15A is independently selected from the group consisting of methyl, ethyl and phenyl) is present in the compounds of formula (I).
In another embodiment of this invention two groups selected from the group consisting of: -SF5, -OSF51 and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of methyl, ethyl and phenyl) are present in the compounds of formula (i).
In another embodiment of this invention three groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of methyl, ethyl and phenyl) are present in the compounds of formula (I).
In another embodiment of this invention two groups selected from the group consisting of: -SF5> -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of methyl, ethyl and phenyl) are present in the compounds of formula (I), wherein at least one group is other than -Si(R15A)3.
In another embodiment of this invention three groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of methyl, ethyl and phenyl) are present in the compounds of formula (I)1 wherein at least one group is other than -Si(R15A)3.
In another embodiment of this invention one group selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of methyl and ethyl) is present in the compounds of formula (I). In another embodiment of this invention two groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of methyl and ethyl) are present in the compounds of formula (I).
In another embodiment of this invention three groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of methyl and ethyl) are present in the compounds of formula (I).
In another embodiment of this invention two groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of methyl and ethyl) are present in the compounds of formula (I), wherein at least one group is other than -Si(R15A)3.
In another embodiment of this invention three groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of methyl and ethyl) are present in the compounds of formula (I), wherein at least one group is other than -Si(R15A)3.
In another embodiment of this invention one group selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 is present in the compounds of formula (I), and said -Si(R15A)3 group is selected from the group consisting of: -Si(CH3)3, -Si(CH3)2phenyl, and -Si(CH2CH3)2CH3 In another embodiment of this invention two groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 are present in the compounds of formula (I), and said -Si(R15A)3 group is selected from the group consisting of: -Si(CH3)3, -Si(CH3)2phenyl, and -Si(CH2CH3)2CH3. In another embodiment of this invention three groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 are present in the compounds of formula (I), and said -Si(R15A)3 group is selected from the group consisting of: -Si(CH3)3, - Si(CH3)2phenyl, and -Si(CH2CH3)2CH3.
In another embodiment of this invention two groups sefected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 are present in the compounds of formula (I), wherein at least one group is other than -Si(R15Λ)3, and said -Si(R15A)3 group is selected from the group consisting of: -Si(CH3)3, -Si(CH3)2phenyl, and -Si(CH2CH3)2CH3.
In another embodiment of this invention three groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 are present in the compounds of formula (I), wherein at least one group is other than -Si(R15A)3) and said -Si(R15A)3 group is selected from the group consisting of: -Si(CH3)3, -Si(CH3)2phenyl, and -Si(CH2CH3)2CH3.
In another embodiment of this invention one group selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 is present in the compounds of formula (I), and said -Si(R15A)3 group is selected from the group consisting of: -Si(CH3)3 and -Si(CH2CH3)2CH3,
In another embodiment of this invention two groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 are present in the compounds of formula (I), and said -Si(R15A)3 group is selected from the group consisting of: -Si(CH3)3 and -Si(CH2CH3J2CH3,
In another embodiment of this invention three groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 are present in the compounds of formula (J), and said -Si(R15A)3 group is selected from the group consisting of: -Si(CH3)3 and -Si(CH2CH3)2CH3,
In another embodiment of this invention two groups selected from the group consisting of: -SF5, -OSF5, and -Sf(R15A)3 are present in the compounds of formula (IJ, wherein at least one group is other than -Si(R15A)3, and said -Si(R15A)3 group is selected from the group consisting of: -Si(CH3)3 and -Si(CH2CH3)2CH3, In another embodiment of this invention three groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 are present in the compounds of formula (I), wherein at least one group is other than -Si(R15A)3, and said -Si(R15A)3 group is selected from the group consisting of: -Si(CH3)3, -Si(CH3)2phenyl, and -Si(CH2CH3)2CH3.
In another embodiment of this invention one group selected from the group consisting of: -SF5, -OSF5, and -Si(CH3)3 is present.
In another embodiment of this invention two groups selected from the group consisting of: -SF5, -OSF5, and -Si(CH3)3 are present in the compounds of formula (I).. In another embodiment of this invention three groups selected from the group consisting of: -SF5, -OSF5, and -Si(CH3)3 are present in the compounds of formula (I).
In another embodiment of this invention two groups selected from the group consisting of: -SF5, -OSF5, and -St(CH3)3 are present in the compounds of formula (I), wherein at least one group is other than -Si(CH3)3.. In another embodiment of this invention three groups selected from the group consisting of: -SF5, -OSF5, and -Si(R24)3 are present in the compounds of formula (I), wherein at least one group is other than -Si(CH3)3.
In another embodiment of this invention one group selected from the group consisting of: -SF5 and -OSF5 is present in the compounds of formula (I). In another embodiment of this invention two groups selected from the group consisting of: -SF5 and -OSF5 are present in the compounds of formula (I).
In another embodiment of this invention three groups selected from the group consisting of: -SF5 and -OSF5 are present in the compounds of formula (I)
In another embodiment of this invention one -SF5 group is present in the compounds of formula (I).
In another embodiment of this invention two -SF5 groups are present in the compounds of formula (I).
In another embodiment of this invention three -SF5 groups are present in the compounds of formula (I). In another embodiment of this invention one -OSF5 group is present in the compounds of formula (I).
In another embodiment of this invention two -OSF5 groups are present in the compounds of formula (I). In another embodiment of this invention three -OSF5 groups are present in the compounds of formula (I).
In another embodiment of this invention one -Si(R15a)3 (wherein each R15A is independently selected) group is present in the compounds of formula (I). In another embodiment of this invention two -Si(R15A)3 (wherein each R15A is independently selected) groups are present in the compounds of formula (I).
In another embodiment of this invention three -Si(R15A)3 (wherein each R15A is independently selected) groups are present in the compounds of formula (I).
In another embodiment of this invention one -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of alky! (e.g., methyl and ethyl) and aryl (e.g., phenyl)) is present in the compounds of formula (I).
In another embodiment of this invention two -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) is present in the compounds of formula (I). In another embodiment of this invention three -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) is present in the compounds of formula (I).
In another embodiment of this invention one -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of methyl, ethyl and phenyl) is present in the compounds of formula (I).
In another embodiment of this invention two -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of methyl, ethyl and phenyl) is present in the compounds of formula (I).
In another embodiment of this invention three -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of methyl, ethyl and phenyl) is present in the compounds of formula (I).
In another embodiment of this invention one -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of methyl and ethyl) is present in the compounds of formula (I). In another embodiment of this invention two -Si(R15A)s (wherein each R15A is independently selected from the group consisting of methyl and ethyl) is present in the compounds of formula (I). In another embodiment of this invention three -Si(R15A)3 (wherein each R*5A is independently selected from the group consisting of methyl and ethyl) is present in the compounds of formula (I).
In another embodiment of this invention one -Si(R15A)3 group is present in the compounds of formula (I), and said -Si(R15A)3 group is selected from the group consisting of: -Si(CH3)3l -Si(CH3)2phenyl, and -Si(CH2CH3)2CH3.
In another embodiment of this invention two -Si(R15A)3 groups are present in the compounds of formula (I), and said -Si(R15A)3 groups are independently selected from the group consisting of: -Si(CH3)3, -Si(CH3)2phenyl, and -Si(CH2CH3)2CH3. In another embodiment of this invention three -Si(R15A)3 groups are present in the compounds of formula (I), and said -Si(R15A)3 groups are independently selected from the group consisting of: -Si(CH3)3, -Si(CH3)2phenyl, and -Si(CH2CH3)2CH3..
In another embodiment of this invention one -Si(R15A)3 group is present in the compounds of formula (I), and said -Si(R15A)3 group is selected from the group consisting of: -Si(CH3)3 and -Si(CH2CH3)2CH3.
In another embodiment of this invention two -Si(R15A)3 groups are present in the compounds of formula (I), and said -Si(R15A)3 groups are independently selected from the group consisting of: -Si(CH3)3 and -Si(CH2CH3)2CH3..
In another embodiment of this invention three -Si(R15A)3 groups are present in the compounds of formula (I), and said -Si(R15A)3 groups are independently selected from the group consisting of: -Si(CH3)3 and -Si(CH2CH3)2CH3..
In another embodiment of this invention one -Si(R15A)3 group is present in the compounds of formula (I), and said -Si(R15A)3 group is -Si(CH3)3.
In another embodiment of this invention two -Si(R15A)3 groups are present in the compounds of formula (I), and said -Si(R15A)3 groups are -Si(CH3)3..
In another embodiment of this invention three -Si(R15A)3 groups are present in the compounds of formula (I), and said -Si(R15A)3 groups are -Si(CH3)3.
In another embodiment of this invention one group selected from the group consisting of: -SF5, -OSF5, -Si(CH3)3l -Si(CH3)2phenyl, and -Si(CH2CH3)2CH3) is present in the compounds of formula (I).
In another embodiment of this invention one group selected from the group consisting of: -SF5, -OSF5, -Si(CH3)3, and -Si(CH2CH3)2CH3) is present in the compounds of formula (I). In another embodiment of this invention one group selected from the group consisting of: -SF5, -OSF5, and -Si(CH3)3f is present in the compounds of formula (I).
In another embodiment of this invention one -SF5 group is present in the compounds of formula (I), and one or two additional groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected) are also present in the compounds of formula (I).
In another embodiment of this invention one -SF5 group is present in the compounds of formula (I), and one or two additional groups selected from the group consisting of: -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected) are also present in the compounds of formula (I).
In another embodiment of this invention one -OSF5 group is present in the compounds of formula (I), and one or two additional groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected) are also present in the compounds of formula (I). In another embodiment of this invention one -OSF5 group is present in the compounds of formula (I), and one or two additional groups selected from the group consisting of: -SF5 and -Si(R15A)3 (wherein each R15A is independently selected) are also present in the compounds of formula (I).
In another embodiment of this invention one -SF5 group is present in the compounds of formula (I), and one or two additional groups selected from the group consisting of: -SF5 and -OSF5 are also present in the compounds of formula (I).
In another embodiment of this invention one -OSF5 group is present in the compounds of formula (I), and one or two additional groups selected from the group consisting of: -SF5 and -OSF5 are also present in the compounds of formula (I). In another embodiment of this invention one -Si(R15A)3 (wherein each R15A is independently selected) group is present in the compounds of formula (I), and one or two groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected) are also present in the compounds of formula (I). In another embodiment of this invention one -Si(R15A)3 (wherein each R15A is independently selected) group is present in the compounds of formula (I), and one or two groups selected from the group consisting of: -SF5 and -OSF5 are also present in the compounds of formula (I). In another embodiment of this invention at least one group selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) is present in the compounds of formula (I). In another embodiment of this invention at least one group selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and phenyl) is present in the compounds of formula (I).
In another embodiment of this invention at least one group selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of methyl, ethyl and phenyl) is present in the compounds of formula (I).
In another embodiment of this invention at least one group selected from the group consisting of: -SF5, -OSF5, -Si(CH3)3, -Si(CH3)2phenyl, and -Si(CH2CH3)2CH3) is present in the compounds of formula (I).
In another embodiment of this invention at least one group selected from the group consisting of: -SF5, -OSF5, and -Si(CH3)3 is present in the compounds of formula (I).
In another embodiment of this invention one group selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected) is present in the compounds of formula (I).
In another embodiment of this invention one group selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) is present in the compounds of formula (I).
In another embodiment of this invention one group selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and phenyl) is present in the compounds of formula (I). In another embodiment of this invention one group selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of methyl, ethyl and phenyl) is present in the compounds of formula (I). In another embodiment of this invention one group selected from the group consisting of: -SF5, -OSF5, -Si(CH3)3, -Si(CH3)2phenylf and -Si(CH2CH3)2CH3) is present in the compounds of formula (I).
In another embodiment of this invention one group selected from the group consisting of: -SF5, -OSF5, -Si(CH3)3, and -Si(CH2CH3)2CH3) is present in the compounds of formula (I).
In another embodiment of this invention one group selected from the group consisting of: -SF5, -OSF5, and -St(CH3)3, is present in the compounds of formula (I).
In another embodiment of this invention two groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected) are present in the compounds of formula (I).
In another embodiment of this invention two groups independently selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) are present in the compounds of formula (I).
In another embodiment of this invention two groups independently selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and phenyl) are present in the compounds of formula (I). In another embodiment of this invention two groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of methyl, ethyl and phenyl) are present in the compounds of formula (I).
In another embodiment of this invention two groups independently selected from the group consisting of: -SF5, -OSF5, -Si(CH3)3, -Si(CH3)2phenyl, and -Si(CH2CH3)2CH3) is present in the compounds of formula (I).
In another embodiment of this invention two groups independently selected from the group consisting of: -SF5, -OSF5, -Si(CH3)3) and -Si(CH2CH3)2CH3) are present in the compounds of formula (I). In another embodiment of this invention two groups independently selected from the group consisting of: -SF5, -OSF5, and -Si(CH3)3 are present in the compounds of formula (I). In another embodiment of this invention three groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected) are present in the compounds of formula (I)I.
In another embodiment of this invention three groups independently selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15Λ is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) are present in the compounds of formula (I).
In another embodiment of this invention three groups independently selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15Λ is independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and phenyl) are present in the compounds of formula (I).
In another embodiment of this invention three groups selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of methyl, ethyl and phenyl) are present in the compounds of formula (I).
In another embodiment of this invention three groups independently selected from the group consisting of: -SF5, -OSF5, -Si(CH3)3, -Si(CH3)2phenyl, and -Si(CH2CH3)2CH3) is present in the compounds of formula (I).
In another embodiment of this invention three groups independently selected from the group consisting of: -SF5, -OSF5, -Si(CH3)3l and -Si(CH2CH3)2CH3) are present in the compounds of formula (I).
In another embodiment of this invention three groups independently selected from the group consisting of: -SF5, -OSF5, and -Si(CH3)3 are present in the compounds of formula (I). In another embodiment of this invention at least one group selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is the same or different alkyl group) is present in the compounds of formula (I).
In another embodiment of this invention at least one group selected from the group consisting of: -SF5, -OSF5, and -Si(R15A)3 (wherein each R15A is independently selected from the group consisting of methyl and ethyl) is present in the compounds of formula (I).
In another embodiment of this invention one -SF5 group is present in the compounds of formula (I), and one or two groups selected from the group consisting of: -SF5 and -OSF5 are also present in the compounds of formula (I). In another embodiment of this invention one -OSF5 group is present in the compounds of formula (I), and one or two groups selected from the group consisting of: -SF5 and -OSF5 are also present in the compounds of formula (I).
In another embodiment of this invention L is -C(R6)(R7)-. In another embodiment of this invention L is -C(R6)(R7)- wherein R6 and R7 are taken together with the carbon atom to which they are bound to form a spirocycloalkyf ring (e.g., cyclopropyl).
In another embodiment of this invention L is -C(R6)(R7)- wherein R6 and R7 are taken together with the carbon atom to which they are bound to form a spirocycloalkenyl ring.
In another embodiment of this invention L is -C(R6)(R7)- wherein R6 and R7 are taken together with the carbon atom to which they are bound to form a spiroheterocycloalkyl ring.
In another embodiment of this invention L is -C(R6)(R7)- wherein R6 and R7 are taken together with the carbon atom to which they are bound to form a spiroheterocycloalkenyl ring.
In another embodiment of this invention L is -C(R6)(R7)- wherein R6 and R7 are independently selected from the group consisting of: H, alkyl, and alkyl substituted with one R21 group. In another embodiment of this invention L is -C(R6)(R7)- wherein R6 and R7 are independently selected from the group consisting of: H, methyl, and methyl substituted with one R21 group.
In another embodiment of this invention L is -C(R6)(R7)- wherein R6 and R7 are independently selected from the group consisting of: H, alkyl, and alkyl substituted with one R21 group wherein said R21 group is -OR15.
In another embodiment of this invention L is -C(R6){R7)- wherein R6 and R7 are independently selected from the group consisting of: H, alkyl, and alkyl substituted with one R21 group wherein said R21 group is -OR15, and said R15 is H (i.e., said R21 group is -OH). In another embodiment of this invention L is selected from the group consisting of:
Figure imgf000035_0001
In another embodiment of this invention L is -CH2-. In another embodiment of this invention L is -CH(CH3)-. In another embodiment of this invention L is -CH(CH2OH)-. In another embodiment of this invention, R1 is selected from the group consisting of: alkyl, alkenyi, alkynyl, cycloalkyl, heterocyclyl (e.g., heterocycloalkyl), cycloalkenyl, aryJ (e.g., phenyl), heteroaryi (e.g., pyridyl), heterocyclenyl (i.e., heterocycloalkenyl), wherein each of said: aikyl, alkenyi, alkynyl, cycloalkyl, heterocyciyl, cycloalkenyl, aryl, heteroaryi, and heterocyclenyl R1 groups is optionally substituted with 1-5 independently selected R21 groups.
In another embodiment of this invention R1 is selected from the group consisting of: fused cycloalkylaryl (i.e., cycloalkyfusedlaryl-), fused heterocycloalkylaryl- (i.e., heterocycloalkylfusedaryl-), fused cycloalkylheteroaryl- (i.e., cycloalkylfusedheteroaryl-), fused heterocycloalkylheteroaryl- (i.e., heterocycloalkylfusedheteroaryl-), fused benzocycloalkylalkyl- (i.e., benzofusedcycloalkyialkyl-), fused benzoheterocycloalkylalkyl- (i.e., benzofusedheterocycloalkylalkyl-), fused heteroarylcycloalkylalkyl" (<•©-. heteroaryifusedcycloalkylalkyl-). fused heteroarylheterocycloalkylalkyl- (i.e., heteroarylfusedheterocycloalkylalkyl-), fused cycloalkylarylalkyl- (i.e., cycloalkyfusedlarylalkyl-), fused heterocycloalkylarylalkyl- (i.e., heterocycloalkylfusedarylalkyl-), fused cycloalkylheteroarylalkyl- (i.e., cycloalkylfusedheteroarylalkyl-), and fused heterocycloalkylheteroarylalkyl- (i.e., heterocycloalkylfusedheteroarytalkyl-), wherein each of said R1 groups is optionally substituted with 1 -5 independently selected R21 groups In another embodiment of this invention Rτ is phenyl.
In another embodiment of this invention R1 is phenyl substituted with 1 to 3 halo atoms.
In another embodiment of this invention R1 is phenyl substituted with 1 to 3 F atoms. In another embodiment of this invention R1 is selected from the group consisting of:
Figure imgf000036_0001
and
Figure imgf000037_0001
In another embodiment of this invention R1 is. selected from the group consisting of:
Figure imgf000037_0002
Figure imgf000037_0003
and
Figure imgf000037_0006
Figure imgf000037_0007
In another embodiment of this invention R1 is selected from the group consisting of:
Figure imgf000037_0004
In another embodiment of this invention R1 is, selected from the group consisting of:
Figure imgf000037_0005
In another embodiment of this invention R1 is phenyl. In another embodiment of this invention R1 is
Figure imgf000038_0001
In another embodiment of this invention R1 is
Figure imgf000038_0002
In another embodiment of this invention R1 is:
Figure imgf000038_0003
In another embodiment of this invention R1 is:
Figure imgf000038_0004
In another embodiment of this invention R1 is:
Figure imgf000038_0006
In another embodiment of this invention R1 is:
Figure imgf000038_0005
In another embodiment of this invention R1 is. :
Figure imgf000038_0007
!n another embodiment of this invention R1 is:
Figure imgf000039_0001
In another embodiment of this invention R1 is:
Figure imgf000039_0002
In another embodiment of this invention R1 is:
Figure imgf000039_0003
In another embodiment of this invention R1 is.
Figure imgf000039_0004
In another embodiment of this invention R1 is:
Figure imgf000039_0007
In another embodiment of this invention R1 is:
Figure imgf000039_0008
In another embodiment of this invention R1 is
Figure imgf000039_0009
In another embodiment of this invention R1 is:
Figure imgf000039_0005
In another embodiment of this invention R1 is:
Figure imgf000039_0006
In another embodiment of this invention R1 is:
Figure imgf000040_0001
In another embodiment of this invention R1 is:
Figure imgf000040_0002
In another embodiment of this invention R1 is.
Figure imgf000040_0003
In another embodiment of this invention R1 is:
Figure imgf000040_0004
In another embodiment of this invention R1 is:
Figure imgf000040_0005
In another embodiment of this invention R1 is:
Figure imgf000040_0006
In another embodiment of this invention R1 is
Figure imgf000040_0007
In another embodiment of this invention R1 is
Figure imgf000041_0001
In another embodiment, R1 is phenyl substituted with 1-3 halos independently selected from the group consisting of F and Cl. In one example said phenyl is substituted with one F and one Cl. In another embodiment R1 is aryl (e.g., phenyl) substituted with 1 to 3 independently selected R21 moieties wherein at least one R21 moiety is selected from the group consisting of -SF5, -OSF5 and -Si(R15A)3 (and in one example each R1SA is the same or different alkyl, and in another example the -Si(R24)3 group is -Si(CH3)3 or -Si(CH2CH3)2CH3, and in another example the -Si(R24)3 group is -Si(CH3)3). In another embodiment R1 is aryl (e.g., phenyl) substituted with 1 to 3 independently selected R21 moieties wherein at least one R21 moiety is selected from the group consisting of -SF5 and -OSF5.
In another embodiment R1 is aryl (e.g., phenyl) substituted with 1 to 3 R21 moieties independently selected from the group consisting of: halo (e.g., F), -SF5, -OSF5 and -Si(R15A)3 (and in one example each R15A is the same or different alkyl, and in another example the -Si(R15A)3 group is -Si(CH3)3 or -SKCH2CH3)2CH3, and in another example the -Si(R1 ^)3 group is -Si(CH3)3), and wherein at least one R21 moiety is selected from the group consisting of -SF5, -OSF5 and -Si(R15A)3 (and in one example each R15A is the same or different alkyl, and in another example the -Si(R15A)3 group is -Si(CH3)3 or -Si(CH2CH3)2CH3, and in another example the -Si(R24)3 group is -Si(CH3)3)-
In another embodiment R1 is aryl (e.g., phenyl) substituted with 1 to 3 R21 moieties independently selected from the group consisting of: halo (e.g., F), -SF5 and -OSF5, and wherein at least one R21 moiety is selected from the group consisting of -SF5 and -OSF5.
In another embodiment R1 is aryl (e.g., phenyl) substituted with 1 to 3 independently selected R21 moieties wherein at least one R21 moiety is selected from the group consisting of -SF5, -OSF5 and -Si(R15A)3 (and in one example each R15A is the same or different alky!, and in another example the -Si(RlδA)3 group is -Si(CH3)3 or -Si(CH2CH3)2CH3, and in another example the -Si(R15A)3 group is -Si(CH3)3). In another embodiment, R1 is phenyl substituted with 1-3 R21 groups independently selected from the group consisting of halos, -SF5 and -OSF5, wherein at least one R21 group is -SF5 or -OSF5.
In another embodiment, R1 is phenyl substituted with 1-3 R21 groups independently selected from the group consisting of halos, -SF5 and -OSF5, wherein at least one R21 group is -SF5 or -OSF5.
In another embodiment, R1 is phenyl substituted with 1-3 R21 groups independently selected from the group consisting of F, Cl, -SF5 and -OSF5. In another embodiment, R1 is phenyl substituted with 1-3 R21 groups independently selected from the group consisting of -SF5 and -OSF5.
In another embodiment, R1 is phenyl substituted with 1-3 R21 groups independently selected from the group consisting of F, -SF5 and -OSF5, wherein at least one R21 group is -SF5 or -OSF5.
In another embodiment, R1 is phenyl substituted with one -SF5 group. In another embodiment, R1 is phenyl substituted with two -SF5 groups.
In another embodiment, R1 is phenyl substituted with three -SF5 groups. In another embodiment, R1 is phenyl substituted with one -OSF5 group. In another embodiment, R1 is phenyl substituted with two -OSF5 groups. In another embodiment, R1 is phenyl substituted with three -OSF5 groups. In another embodiment, R1 is phenyl substituted with 1 F.
In another embodiment, R1 is phenyl substituted with 1 F, and also substituted with 1 to 2 groups independently selected from the group consisting of -SF5 and -OSF5.
In another embodiment R1 is phenyl substituted with 2 F. In another embodiment R1 is phenyl substituted with 3F.
In another embodiment of this invention L is selected from the group consisting of:
Figure imgf000042_0005
, and
Figure imgf000042_0006
R1 is selected from the group consisting of:
Figure imgf000042_0001
Figure imgf000042_0002
Figure imgf000042_0003
Figure imgf000042_0004
Figure imgf000043_0001
In another embodiment of this invention L is selected from the group consisting of:
Figure imgf000043_0007
, and
R1 is selected from the group consisting of:
and
Figure imgf000043_0003
Figure imgf000043_0002
In another embodiment of this invention, the compound of formula (I) is selected from the group consisting of the compounds of formulas (IA), (IB), (IC), (ID), and (IE), L is selected from the group consisting of:
Figure imgf000043_0004
and R1 is selected from the group consisting of:
and
Figure imgf000043_0006
Figure imgf000043_0005
In another embodiment of this invention, the compound of formula (i) is the compounds of formula (1A), L is selected from the group consisting of;
Figure imgf000044_0001
"*
Figure imgf000044_0002
, and
,1
R is selected from the group consisting of:
Figure imgf000044_0003
In another embodiment of this invention, the compound of formula {() is the compound of formulas (IB), L is selected from the group consisting of:
Figure imgf000044_0004
-
Figure imgf000044_0005
, and
R » i i ■s selected from the group consisting of:
Figure imgf000044_0006
fn another embodiment of this invention, the compound of formula (I) is the compounds of formula (1C), L is selected from the group consisting of:
and
Figure imgf000044_0007
Figure imgf000044_0008
R1 is selected from the group consisting of:
Figure imgf000044_0009
In another embodiment of this invention, the compound of formula (I) is the compounds of formula (!D), L is selected from the group consisting of: and
Figure imgf000045_0006
Figure imgf000045_0001
, and
R1 is selected from the group consisting of:
Figure imgf000045_0003
Figure imgf000045_0002
In another embodiment of this invention, the compound of formula (f) is the compounds of formula (IE), L is selected from the group consisting of:
and
Figure imgf000045_0007
Figure imgf000045_0004
and R1 is selected from the group consisting of:
Figure imgf000045_0005
In another embodiment of this invention, R5 is taken together with R1 and the carbon to which they are bound to form a heterocycloalkyl or heterocyctoalkenyl ring fused to said R1 ring, said fused ring is optionally substituted with 1 to 5 independently selected R21 groups.
In another embodiment of this invention, R5 is taken together with R1 and the carbon to which they are bound to form a 5 to 7 membered heterocycloafkyl or heterocycloalkenyl ring fused to said R1 ring, and wherein said heterocycloaikyl and said heterocylcloalkenyl rings comprise 1 to 4 (including the atoms common to both rings) heteroatoms selected from the group consisting of: -N-, -O-, -S-, -S(O)-, and -
S(O)2-, and wherein said 5 to 7 membered ring is optionally substituted with 1 to 5 independently selected R21 groups. In another embodmentof this invention, R6 is taken together with R1 and the carbon to which they are bound to form a cycloalkyl, cydoafkenyl, heterocycloaikyl or heterocycloalkenyl ring fused to said R1 ring, said fused ring is optionally substituted with 1 to 5 independently selected R21 groups.
In another embodiment of this invention, R6 is taken together with R1 and the carbon to which they are bound to form a 5 to 7 membered cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl ring fused to said R1 ring, and wherein said heterocycloalkyl and said heterocylcloalkenyl rings comprise 1 to 4 (including the atoms common to both rings) heteroatoms selected from the group consisting of: -N-, -O-, -S-, -S(O)-, and -S(O)2-, and wherein said 5 to 7 membered ring is optionally substituted with 1 to 5 independently selected R21 groups. In another embodiment of this invention, Ring (B) is a cycloalkyl ring.
In another embodiment of this invention, Ring (B) is a cycloalkenyl ring.
In another embodiment of this invention, Ring (B) is a heterocycloalkyl ring.
In another embodiment of this invention, Ring (B) is a heterocycloalkenyl ring.
In another embodiment of this invention, Ring (B) is a phenyl ring. In another embodiment of this invention, Ring (B) is a heteroaryl ring.
In another embodiment of this invention Ring (B) is a cycloalkyl ring wherein B1 to B4 are carbon.
In another embodiment of this invention Ring (B) is a cycloalkyl ring wherein B1 is carbon, one of B2, B3, or B4 is C and the remaining two are selected from the group consisting of: -(C=O)-and -(C=NR21A)- (e.g., -(C=N-OR15)-, and -(C=N-N(R15XR16))-).
In another embodiment of this invention Ring (B) is a cycloalkyl ring wherein B1 is carbon, two of B2, B3, or B4 are C and the remaining one is selected from the group consisting of: -(C=O)-and -(C=NR21A)- (e.g., -(C=N-OR15)-, and -(C=N-N(R15)(R16))-). In another embodiment of this invention Ring (B) is a heterocycloalkyl ring wherein one of B2, B3, or B4 is selected from the group consisting of: -(C=O)-and -(C=NR21A)- (e.g., -(C=N-OR15)-, and-(C=N-N(R15)(R16))-).
In another embodiment of this invention Ring (B) is a heterocycloalkenyl ring wherein one of B2, B3, or B4 is selected from the group consisting of: -(C=O)-and - (C=NR21A)- (e.g., -(C=N-OR15)-, and-(C=N-N(R15)(R16))-).
In another embodiment of this invention L is a direct bond.
In another embodiment of this invention L is -O- .
In another embodiment of this invention L is -NR3-.
In another embodiment of this invention L is -S-. In another embodiment of this invention L is -SO-.
In another embodiment of this invention L is -S(O)2-.
In another embodiment of this invention L is -(C=O)-.
In another embodiment of this invention L is -(C=NR21A)- In another embodiment B1 is CH.
In another embodiment B1 is C. fn another embodiment B1 is N.
In another embodiment of this invention R3 is phenyl.
In another embodiment of this invention R3 is phenyl substituted with 1 to 3 independently selected R21 groups.
In another embodiment of this invention R3 is phenyl substituted with 1 R21 group.
In another embodiment of this invention R3 is phenyl substituted with 1 R21 group wherein said R21 group is halo. In another embodiment of this invention R3 is phenyl substituted with 1 R21 group wherein said R21 group is halo, and said halo is F.
In another embodiment of this invention R3 is phenyl substituted with 1 R21 group, wherein said R21 group is -OR15.
In another embodiment of this invention R3 is phenyl substituted with 1 R21 group, wherein said R21 group is -OR15, and wherein said R15 is alkyl (e.g., methyl).
In another embodiment of this invention R3 is pyridyl.
In another embodiment of this invention R3 is pyridyl substituted with 1 to 3 independently selected R21 groups.
In another embodiment of this invention R4 is heteroaryl. In another embodiment of this invention R4 is heteroaryl substituted with 1 to 3 independently selected R21 groups.
In another embodiment of this invention R4 is heteroaryl substituted with 1 R21 group.
In another embodiment of this invention R4 is heteroaryl substituted with 1 to 3 independently selected R21 groups, wherein said R21 groups are the same or different alky! group.
In another embodiment of this invention R4 is heteroaryl substituted with 1 R21 group, wherein said R21 group is alkyl (e.g., methyl). In another embodiment of this invention R4 is selected from the group consisting of:
Figure imgf000048_0001
In another embodiment of this invention R4 is imidazolyl. In another embodiment of this invention R4 is the imidazolyl:
Figure imgf000048_0002
imidazol-1-yl
In another embodiment of this invention R4 is imidazotyl substituted with 1 to 3 independently selected R21 groups.
In another embodiment of this invention R4 is imidazolyl substituted with 1 R21 group. In another embodiment of this invention R4 is imidazolyl substituted with 1 to 3 independently selected R21 groups, wherein said R21 groups are the same or different alkyl group.
In another embodiment of this invention R4 is imidazolyl substituted with 1 R21 group, wherein said R21 group is alkyl (e.g., methyl). In another embodiment of this invention R4 is:
Figure imgf000049_0002
4-methyl-imidazol-1-yl
Examples of the R ,4- rR->3- moiety include, but are not limited to:
Figure imgf000049_0001
Figure imgf000050_0001
F3CO
\
NNJ
Figure imgf000051_0002
33bb
Figure imgf000051_0001
HX
Figure imgf000051_0003
V 34bb H3C
Figure imgf000051_0004
Figure imgf000051_0005
and
Figure imgf000051_0006
In another embodiment the R4-R3- moiety is 1 bb. In another embodiment the R4-R3- moiety is 2bb. In another embodiment the R4-R3- moiety is 3bb. In another embodiment the R4-R3- moiety is 4bb. In another embodiment the R4-R3- moiety is 5bb. in another embodiment the R4-R3- moiety is 6bb, In another embodiment the R4-R3- moiety is 7bb. in another embodiment the R4-R3- moiety is 8bb. In another embodiment the R4-R3- moiety is 9bb. In another embodiment the R4-R3- moiety is 10bb. In another embodiment the R4-R3- moiety is 11bb. In another embodiment the R4-R3- moiety is 12bb. In another embodiment the R4-R3- moiety is 13bb. In another embodiment the R4-R3- moiety is 14bb. In another embodiment the R4-R3- moiety is 15bb. In another embodiment the R4-R3- moiety is 16bb. In another embodiment the R4-R3- moiety is 17bb. In another embodiment the R4-R3- moiety is 18bb. In another embodiment the R4-R3- moiety is 19bb. In another embodiment the R4-R3- moiety is 20bb. In another embodiment the R4-R3- moiety is 21 bb. In another embodiment the R4-R3- moiety is 22bb. In another embodiment the R4-R3- moiety is 23bb. In another embodiment the R4-R3- moiety is 24bb. In another embodiment the R4-R3- moiety is 25bb. In another embodiment the R4-R3- moiety is 26bb. In another embodiment the R4-R3- moiety is 27bb. In another embodiment the R4-R3- moiety is 28bb. In another embodiment the R4-R3- moiety is 29bb. In another embodiment the R4-R3- moiety is 30bb. In another embodiment the R4-R3- moiety is 31 bb. In another embodiment the R4-R3- moiety is 32bb. In another embodiment the R4-R3- moiety is 33bb. In another embodiment the R4-R3- moiety is 34bb. In another embodiment the R4-R3- moiety is 35bb. In another embodiment the R4-R3- moiety is 36bb. In another embodiment the R4-R3- moiety is 37bb. In another embodiment the R4-R3- moiety is 38bb. In another embodiment the R4-R3- moiety is 39bb. In another embodiment the R4-R3- moiety is 40bb.
In another embodiment of the invention: R3 is selected from the group consisting of: (1 ) heteroaryl and (2) hetereoaryl substituted with 1 to 3 independently selected R21 groups; and
R4 is selected from the group consisting of: (1) heteroaryl (e.g., imidazolyl, such as, for example imidazol-1-yl), (2) heteroaryl (e.g., imidazolyl, such as, for example imidazol-1-yl) substituted with 1 to 3 independently selected R21 groups, (3) heteroaryl (e.g., imidazolyl, such as, for example imidazol-1-yl) substituted with 1 R21 group, (4) heteroaryl (e.g., imidazolyl, such as, for example imidazol-1-yl) substituted with 1 to 3 independently selected R21 groups, wherein said R21 groups are the same or different alkyl group, and (5) heteroaryl (e.g., imidazolyl, such as, for example imidazol-1 -yl) substituted with 1 R21 group, wherein said R21 group is alkyl (e.g., methyl).
!n another embodiment of this invention the -R3-R4 moiety is:
Figure imgf000052_0001
In another embodiment of this invention the -R3-R4 moiety is: In another embodiment of this invention the -R %3-R moiety is: alkyl
^>
N=/
Figure imgf000053_0001
In another embodiment of this invention the -R3-R4 moiety is
OR15
N=/v X=/
In another embodiment of this invention the -R3-R4 moiety is:
Oalky! alkyl
N=/
Figure imgf000053_0002
In another embodiment of this invention the -R3-R4 moiety is:
N=/
Figure imgf000053_0003
In another embodiment of this invention the -R3-R4 moiety is:
OCHo alkyl
N==/
Figure imgf000053_0004
In another embodiment of this invention the -R >3- πR* moiety is:
OCH3
N
Figure imgf000053_0005
N=/ in another embodiment of this invention the -R »3- tR->* moiety is: al Ik. yl I halo
N=/
Figure imgf000053_0006
In another embodiment of this invention the -R3-R4 moiety is halo
N
Figure imgf000054_0001
In another embodiment of this invention the -R ■>^3-R p-,*4 moiety is:
Figure imgf000054_0002
In another embodiment of this invention the -R ,3- DR4 moiety is:
R
Figure imgf000054_0003
In another embodiment of this invention the -R i3-R moiety is: alkyl
N=/ Vl=
In another embodiment of this invention the -R 3- oR4 moiety is
In another embodiment of this invention the -R -.3- nR4 moiety is:
Figure imgf000054_0004
in another embodiment of this invention the -R ϊ3- DR4 moiety is:
OR15
Figure imgf000054_0005
In another embodiment of this invention the -R ■»3- nR4 moiety is:
Figure imgf000054_0006
In another embodiment of this invention the -R 3- DR4 moiety is: O-alkyl
V N=V/ f N=V/
In another embodiment of this invention the -R3-R4 moiety is:
Figure imgf000055_0001
in another embodiment of this invention the -R i3- oR4 moiety is:
Figure imgf000055_0002
In another embodiment of this invention the -R i3- πR4 moiety is: halo
Figure imgf000055_0003
In another embodiment of this invention the -R )3- nR4 moiety is: halo
N=/ N=/ S .
In another embodiment of this invention the -R -R moiety is: alkyl F
N ^==// \=/
In another embodiment of this invention the ~R3-R4 moiety is:
R
N
N=/
Figure imgf000055_0004
In another embodiment of this invention R1 is H. In another embodiment of this invention R1 is alkyl. In another embodiment of this invention R1 is aryl. In another embodiment of this invention R1 is aryl substituted with 1 to 3 independently selected R21 groups. In another embodiment of this invention R1 is aryl substituted with 1 to 3 independently selected R21 groups wherein said R21 groups are halo.
In another embodiment of this invention R1 is aryl substituted with 1 to 3 independently selected R21 groups wherein said R21 groups are F. In another embodiment of this invention R1 is aryl substituted with 1 R21 group.
In another embodiment of this invention R1 is aryl substituted with 2 R21 groups.
In another embodiment of this invention R1 is aryl substituted with 3 R21 groups. In another embodiment of this invention R1 is aryl substituted with 1 R21 group wherein said R21 group is halo.
In another embodiment of this invention R1 is aryl substituted with 2 R21 groups wherein said R21 groups are the same or different halo.
In another embodiment of this invention R1 is aryl substituted with 3 R21 groups wherein said R21 groups are the same or different halo.
In another embodiment of this invention R1 is phenyl substituted with 1 to 3 independently selected R21 groups.
In another embodiment of this invention R1 is phenyl substituted with 1 to 3 independently selected R21 groups wherein said R21 groups are halo. In another embodiment of this invention R1 is phenyl substituted with 1 to 3 independently selected R21 groups wherein said R21 groups are F.
In another embodiment of this invention R1 is
Figure imgf000056_0001
F
In another embodiment of this invention R1 is phenyl substituted with 1 R21 group.
In another embodiment of this invention R1 is phenyl substituted with 2 R21 groups.
In another embodiment of this invention R1 is phenyl substituted with 3 R21 groups. In another embodiment of this invention R1 is phenyl substituted with 1 R21 group wherein said R21 group is halo. In another embodiment of this invention R1 is phenyl substituted with 2 R21 groups wherein said R21 groups are the same or different halo.
In another embodiment of this invention R1 is phenyl substituted with 3 R21 groups wherein said R21 groups are the same or different hato.
In another embodiment of this invention R1 is 4-F-phenyl.
In another embodiment of this invention the -L-R1 moiety is:
Figure imgf000057_0001
In another embodiment of this invention the -L-R1 moiety is:
Figure imgf000057_0002
In another embodiment of this invention the -L-R1 moiety is:
Figure imgf000057_0003
In another embodiment of this invention the -L-R1 moiety is:
Figure imgf000057_0004
In another embodiment of this invention the -L-R1 moiety is selected from the group consisting of:
and \
Figure imgf000057_0008
Figure imgf000057_0007
Figure imgf000057_0005
Figure imgf000057_0006
1 ^ ^F .
In another embodiment of this invention the -L-R1 moiety is selected from the group consisting of:
Figure imgf000058_0001
Figure imgf000058_0002
Figure imgf000058_0003
and
Figure imgf000058_0004
Figure imgf000058_0006
Figure imgf000058_0005
in another embodiment of this invention R3 is selected from the group consisting of phenyl and phenyl substituted with one or more R21 groups, and said R4 group is selected from the group consisting of heteroaryl and heteroaryl substituted with one or more R21 groups, and wherein each R21 is independently selected.
In another embodiment of this invention: (a) L is -C(R6)(R7)- wherein R6 and R7 are independently selected from the group consisting of H and alkyl (e.g., methyl), and in one example one of R6 and R7 is H and the other is alkyl (e.g., methyl), and in another example both R6 and R7 are H1 (b) R1 is aryl (e.g. phenyl) substituted with 1 to 3 independently selected R21 groups wherein said R21 groups are halo (e.g., F), and in one example R1 is phenyl substituted with two F1 and in another example R1 is phenyl substituted with 1 F, (c) R3 is selected from the group consisting of phenyl and phenyl substituted with one or more independently selected R21 groups, and (d) R4 is selected from the group consisting of heteroaryl and heteroaryl substituted with one or more independently selected R21 groups.
In another embodiment of this invention: (a) L is -C(R6)(R7)- wherein R6 and R7 are independently selected from the group consisting of H and alkyl (e.g., methyl), and in one example one of R6 and R7 is H and the other is alkyl (e.g., methyl), and in another example both R6 and R7 are H, (b) R1 is aryl (e.g. phenyl) substituted with 1 to 3 independently selected R21 groups wherein said R21 groups are halo (e.g., F), and in one example R1 is phenyl substituted with two F, and in another example R1 is phenyl substituted with 1 F, (c) R3 is selected from the group consisting of phenyl and phenyl substituted with one or more independently selected R21 groups, and (d) R4 is selected from the group consisting of imϊdazoiyl and tmidazoiyl substituted with one or more independently selected R21 groups. In another embodiment of this invention: (a) L is -C(R6)(R7)- wherein R6 and R7 are independently selected from the group consisting of H and alkyl (e.g., methyl), and in one example one of R6 and R7 is H and the other is alkyl (e.g., methyl), and in another example both R6 and R7 are H, (b) R1 is aryl (e.g. phenyl) substituted with 1 to 3 independently selected R21 groups wherein said R21 groups are halo (e.g., F), and in one example R1 is phenyl substituted with two F, and in another example R1 is phenyl substituted with 1 F1 (c) R3 is selected from the group consisting of phenyl and phenyl substituted with one or more independently selected -OR15 groups, and (d) R4 is selected from the group consisting of imidazolyl and imidazolyl substituted with one or more independently selected alkyl groups groups.
In another embodiment of this invention: (a) L is -C(R6)(R7)- wherein R3 and R4 are independently selected from the group consisting of H and alkyl (e.g., methyl), and in one example one of R6 and R7 is H and the other is alkyl (e.g., methyl), and in another example both R6 and R7 are H, (b) R1 is aryl (e.g. phenyl) substituted with 1 to 3 independently selected R21 groups wherein said R21 groups are halo (e.g., F), and in one example R1 is phenyl substituted with two F, and in another example R1 is phenyl substituted with 1 F, (c) R3 is selected from the group consisting of phenyl and phenyl substituted with one or two independently selected -OR15 groups, wherein R15 is alkyl, and (d) R4 is selected from the group consisting of imidazolyl and imidazolyl substituted with one or two independently selected alkyl groups groups.
In another embodiment of this invention: (a) L is -C(R6)(R7)- wherein R3 and R4 are independently selected from the group consisting of H and alkyl (e.g., methyl), and in one example one of R6 and R7 is H and the other is alkyl (e.g., methyl), and in another example both R6 and R7 are H, (b) R1 is aryl (e.g. phenyl) substituted with 1 to 3 independently selected R21 groups wherein said R21 groups are halo (e.g., F), and in one example R1 is phenyl substituted with two F, and in another example R1 is phenyl substituted with 1 F, (c) R3 is selected from the group consisting of phenyl and phenyl substituted with one or two independently selected -OR15 groups, wherein R15 is methyl , and (d) R4 is selected from the group consisting of imidazolyl and imidazolyl substituted with one or two independently selected methyl groups groups.
In another embodiment of this invention: (a) L is -C(Re)(R7)- wherein R6 and R7 are independently selected from the group consisting of H and alkyi (e.g., methyt), and in one example one of R6 and R7 is H and the other is alkyl (e.g., methyl), and in another example both R6 and R7 are H, (b) R1 is aryl (e.g. phenyl) substituted with 1 to 3 independently selected R21 groups wherein said R21 groups are halo (e.g., F), and in one example R1 is phenyl substituted with two F, and in another example R1 is phenyl substituted with 1 F, (c) R3 is phenyl substituted with one-OR15 group, wherein R15 is methyl, and (d) R4 is selected from the group consisting of imidazolyl and imidazolyl substituted with one methyl group.
In another embodiment of this invention the -L-R1 moiety is selected from the group consisting of:
and
Figure imgf000060_0001
Figure imgf000060_0002
F, and the R4-R3- moiety is:
R15O
Figure imgf000060_0003
alkyl
In another embodiment of this invention the -L-R1 moiety is selected from the group consisting of:
and
Figure imgf000060_0004
Figure imgf000060_0005
F, and the R3-R4- moiety is:
Figure imgf000060_0006
In another embodiment of this invention: (a) L is -C(R6)(R7)- wherein R6 and R7 are independently selected from the group consisting of H and alkyl (e.g., methyl), and in one example one of R6 and R7 is H and the other is alkyl (e.g., methyl), and in another example both R3 and R4 are H, (b) R1 is aryl (e.g. phenyl) substituted with 1 to 3 independently selected R21 groups wherein said R21 groups are halo (e.g., F), and in one example R1 is phenyl substituted with two F, and in another example R1 is phenyl substituted with 1 F, (c) R3 is selected from the group consisting of phenyl and phenyl substituted with one or two independently selected -OR15 groups, wherein R15 is methyl, and (d) R4 is selected from the group consisting of imidazolyl and imidazolyl substituted with one or two independently selected methyf groups groups,.
In another embodiment of this invention: (a) L is -C(R6)(R7)- wherein R6 and R7 are independently selected from the group consisting of H and alkyl (e.g., methyl), and in one example one of R6 and R7 is H and the other is alkyl (e.g., methyl), and in another example both R6 and R7 are H, (b) R1 is aryl (e.g. phenyl) substituted with 1 to 3 independently selected R21 groups wherein said R21 groups are halo (e.g., F), and in one example R1 is phenyl substituted with two F, and in another example R1 is phenyl substituted with 1 F, (c) R3 is phenyl substituted with one-OR15 group, wherein R15 is methyf, and (d) R4 is selected from the group consisting of imidazolyl and imidazolyl substituted with one methyl group.
In another embodiment of this invention the -L-R1 moiety is selected from the group consisting of:
and
Figure imgf000061_0001
Figure imgf000061_0002
F, and the R4-R3- moiety is:
R15O
Figure imgf000061_0003
alkyl in another embodiment of this invention the -L-R1 moiety is selected from the group consisting of:
and
Figure imgf000061_0004
Figure imgf000061_0005
F, and the R4-R3- moiety is:
Figure imgf000061_0006
In another embodiment the -L- R1 moiety is selected from the group consisting of:
Figure imgf000062_0001
and
Figure imgf000062_0002
Other embodiments of this invention are directed to compounds of formula (I) wherein R3 is phenyl or phenyl substituted with one or more (e.g., one or two, or one) R21 groups (e.g., -OR15, wherein, for example, R15 is alkyl, such as, for example, methyl), and R9 is heteroaryl (e.g., imidazolyi) or heteroaryl (e.g., imidazoly!) substituted with one or more (e.g., one or two, or one) R21 groups (e.g., alkyl, such as, for example, methyl).
Thus, examples of the
moiety of the compounds of this invention include, but are not limited to:
<F 3n21 o-2
(R2V2 such as, for example,
(OR15)i or2 i
(alkyl), „ 2 wherein R \15 is alkyl (e.g., methyl), such as, for example, ORl5
alkyl wherein R15 ; is, alkyl (e.g., methyl), such as, for example, J3\
Figure imgf000063_0001
alkyl wherein R ,15 : i,s alkyl (e.g., methyl), such as, for example,
Figure imgf000063_0002
3 H^
Representative (A) and (B) fused rings for formula (I) include but are not limited to:
and
Figure imgf000063_0003
Figure imgf000063_0004
4A
Compounds of formula (I) include but are not limited to:
Figure imgf000063_0005
,
A1.1 A2.1
Figure imgf000063_0006
Figure imgf000064_0001
•R1 SR1
Figure imgf000065_0001
,
Figure imgf000065_0002
,
A19.1 A20.1
Figure imgf000065_0003
Figure imgf000065_0004
Figure imgf000065_0005
, R'
Figure imgf000065_0007
H ,
Figure imgf000065_0008
Figure imgf000065_0006
A26.1 A27.1
and R3 AΛN-uR, Λ NR21A
A28.1 wherein R3, R4, L, R1 and R21Λ are as defined for formula (I) and the embodiments thereof. Representative (A) and (B) fused rings for formula (I) also include but are not limited to:
OMe i* N C-,
Figure imgf000065_0009
Figure imgf000065_0010
A1.2 A2.2 A3.2
Figure imgf000066_0001
Figure imgf000067_0001
wherein R i21A is as defined for formula (I) and the embodiments thereof.
Representative compounds of this invention include, but are not limited to:
Figure imgf000067_0002
Figure imgf000068_0001
Figure imgf000068_0002
Figure imgf000068_0003
Figure imgf000068_0004
Figure imgf000068_0005
Figure imgf000068_0006
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000070_0004
Figure imgf000070_0002
and
Figure imgf000070_0003
Other embodiments of this invention are directed to any of the embodiments above that are directed to L1 R1, R3, and R4 (or any combinations thereof) wherein the fused rings are selected from the group consisting of: 1 A to 4A.
Other embodiments of this invention are directed to any of the embodiments above that are directed to L, R1, R3, and R4 (or any combinations thereof) wherein the fused rings are selected from the group consisting of: A1.2 to A22.2, and A24.2 to A28.2.
Another embodiment of this invention is directed to a compound of formula (I) selected from the group consisting of: compounds IA to IE, 1 A to 4A, A1.1 to A28.1 , A1.2 to A22.2, A24.2 to A28.2, 5.1 , 8.1 , 11.1 , and A1 to A28. Another embodiment of this invention is directed to a compound of formula (I) selected from the group consisting of: compounds iA to IE.
Another embodiment of this invention is directed to a compound of formula (I) selected from the group consisting of: compounds 1A to 4A.
Another embodiment of this invention is directed to a compound of formula (I) selected from the group consisting of: compounds A1.1 to A28.1.
Another embodiment of this invention is directed to a compound of formula (I) selected from the group consisting of: compounds A1.2 to A22.2, and A24.2 to A28.2.
Another embodiment of this invention is directed to a compound of formula (I) selected from the group consisting of: compounds 5.1 , 8.1 , and 11.1. Another embodiment of this invention is directed to a compound of formula (I) selected from the group consisting of: compounds A1 to A28.
Another embodiment of this invention is directed to compound 5.1.
Another embodiment of this invention is directed to compound 8.1. Another embodiment of this invention is directed to compound 11.1.
Another embodiment of this invention is directed to compound A1.
Another embodiment of this invention is directed to compound A2.
Another embodiment of this invention is directed to compound A3.
Another embodiment of this invention is directed to compound A4. Another embodiment of this invention is directed to compound A5.
Another embodiment of this invention is directed to compound A6.
Another embodiment of this invention is directed to compound A7.
Another embodiment of this invention is directed to compound A8.
Another embodiment of this invention is directed to compound A9. Another embodiment of this invention is directed to compound A10.
Another embodiment of this invention is directed to compound A11.
Another embodiment of this invention is directed to compound A12.
Another embodiment of this invention is directed to compound A13.
Another embodiment of this invention is directed to compound A14. Another embodiment of this invention is directed to compound A15.
Another embodiment of this invention is directed to compound A16.
Another embodiment of this invention is directed to compound A17.
Another embodiment of this invention is directed to compound A18.
Another embodiment of this invention is directed to compound A19. Another embodiment of this invention is directed to compound A20.
Another embodiment of this invention is directed to compound A21.
Another embodiment of this invention is directed to compound A22.
Another embodiment of this invention is directed to compound A23.
Another embodiment of this invention is directed to compound A24. Another embodiment of this invention is directed to compound A25.
Another embodiment of this invention is directed to compound A26.
Another embodiment of this invention is directed to compound A27.
Another embodiment of this invention is directed to compound A28.
In the embodiments below Groups A, B, C, D and E are as defined as follows: (1 ) Group A: compounds tA to IE, 1 A to 4A, A1.1 to A28.1 , A1.2 to A22.2, A24.2 to A28.2, 5.1 , 8.1 , 11.1 , and A1 to A28;
(2) Group B: compounds IA to IE;
(3) Group C: compounds 1 A to 4A, A1.1 to A28.1, A1.2 to A22.2, and A24.2 to A28.2;
(4) Group D: compounds 5.1 , 8.1 , and 11.1 ; and
(5) Group E: compounds A1 to A28.
Another embodiment of this invention is directed to a compound of formula (I). Another embodiment of this invention is directed to a pharmaceutically acceptable salt of a compound of formula (I). And in one example the salt is a salt of a compound selected from the group consisting of Group A. And in another example the salt is a salt of a compound selected from the group consisting of Group B. And in another example the salt is a salt of a compound selected from the group consisting of Group C. And in another example the salt is a salt of a compound selected from the group consisting of Group D. And in another example the salt is a salt of a compound selected from the group consisting of Group E.
Another embodiment of this invention is directed to a pharmaceutically acceptable ester of a compound of formula (I). And in one example the ester is an ester of a compound selected from the group consisting of Group A. And in another example the ester is an ester of a compound selected from the group consisting of Group B. And in another example the ester is an ester of a compound selected from the group consisting of Group C. And in another example the ester is an ester of a compound selected from the group consisting of Group D. And in another example the ester is an ester of a compound selected from the group consisting of Group E. Another embodiment of this invention is directed to a solvate of a compound of formula (J). And in one example the solvate is a solvate of a compound selected from the group consisting of Group A. And in another example the solvate is a solvate of a compound selected from the group consisting of Group B. And in another example the solvate is a solvate of a compound selected from the group consisting of Group C. And in another example the solvate is a solvate of a compound selected from the group consisting of Group D. And in another example the solvate is a soivate of a compound selected from the group consisting of Group E.
Another embodiment of this invention is directed to a compound of formula (I) in isolated form. And in one example the compound of formula (I) is selected from the group consisting of Group A. And in one example the compound of formula (I) is selected from the group consisting of Group D. And in one example the compound of formula (I) is selected from the group consisting of Group E.
Another embodment of this invention is directed to a compound of formula (I) in pure form. And in one example the compound of formula (I) is selected from the group consisting of Group A. And in one example the compound of formula (I) is selected from the group consisting of Group D. And in one example the compound of formula (I) is selected from the group consisting of Group E.
Another embodiment of this invention is directed to a compound of formula (I) in pure and isolated form. And in one example the compound of formula (I) is selected from the group consisting of Group A. And in one example the compound of formula (I) is selected from the group consisting of Group D. And in one example the compound of formula (I) is selected from the group consisting of Group E.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, or ester thereof, and one or more (e.g., one) pharmaceutically acceptable carriers.
Another embodiment is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I) and a pharmaceutically acceptable carrier.
Another embodiment is directed to a pharmaceutical composition comprising an effective amount of a pharmaceutically acceptable salt of one or more (e.g., one) compounds of formula (I) and a pharmaceutically acceptable carrier.
Another embodiment is directed to a pharmaceutical composition comprising an effective amount of a pharmaceutically acceptable ester of one or more (e.g., one) compounds of formula (I) and a pharmaceutically acceptable carrier.
Another embodiment is directed to a pharmaceutical composition comprising an effective amount of a solvate of one or more (e.g., one) compounds of formula (I) and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I)1 and an effective amount of one or more (e.g., one) other pharmaceutically active ingredients (e.g., drugs), and a pharmaceutically acceptable carrier. Examples of the other pharmaceutically active ingredients include, but are not limited to drugs selected form the group consisting of: (a) drugs useful for the treatment of Alzheimer's disease, (b) drugs useful for inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), (c) drugs useful for treating neurodegenerative diseases, and (d) drugs useful for inhibiting gamma- secretase.
Another embodiment of this invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of one or more (e.g. one) compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, or ester thereof, and one or more (e.g., one) pharmaceutically acceptable carriers, and an effective amount of one or more compounds selected from the group consisting of cholinesterase inhibitors, Aβ antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more BACE inhibitors, and a pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more cholinesterase inhibitors (e.g., acetyl- and/or butyrylchlolinesterase inhibitors), and a pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I).
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more muscarinic antagonists (e.g., mi agonist or m2 antagonists), and a pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of Exelon (rivastigmine), and a pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of Cogneκ (tacrine), and a pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of a Tau kinase inhibitor, and a pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more Tau kinase inhibitor (e.g., GSK3beta inhibitor, cdk5 inhibitor, ERK inhibitor), and a pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one anti-Abeta vaccine (active immunization), and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more APP ligands, and a pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more agents that upregulate insulin degrading enzyme and/or neprilysin, and a pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more cholesterol lowering agents (for example, statins such as Atorvastatin, Ruvastatin, Lovastatin, Mevastatin, Pravastatin, Pravastatin, Rosuvastatin, Simvastatin, and cholesterol absorption inhibitor such as Ezetimibe), and a pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more fibrates (for example, clofibrate, Clofibricte, Etofibrate, Aluminium Ciofϊbrate), and a pharmaceutically acceptable carrier Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more LXR agonists, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more LRP mimics, and a pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more 5-HT6 receptor antagonists, and a pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more nicotinic receptor agonists, and a pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more H3 receptor antagonists, and a pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more histone deacetylase inhibitors, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more hsp90 inhibitors, and a pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more ml muscarinic receptor agonists, and a pharmaceuticaily acceptable carrier.
Another embodiment of this invention is directed to combinations, i.e., a pharmaceutical composition, comprising a pharmaceuticaily acceptable carrier, an effective (i.e., therapeutically effective) amount of one or more compounds of formula
(I), in combination with an effective (i.e., therapeutically effective) amount of one or more compounds selected from the group consisting of cholinesterase inhibitors
(such as, for example, (±)-2,3-dihydro-5,6-dimethoxy-2-[[1 -(phenylmethyl)-4- piperidinyl]methyl]-i H -inden-1 -one hydrochloride, i.e., donepezil hydrochloride, available as the Aricept® brand of donepezil hydrochloride), Aβ antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more 5-HT6 receptor antagonists mGluRI or mGluRδ positive allosteric modulators or agonists, and a pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more one mGluR2/3 antagonists, and a pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more anti-inflammatory agents that can reduce neυroinflammation, and a pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more Prostaglandin EP2 receptor antagonists, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more PAJ-1 inhibitors, and a pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of formula (I), and effective amount of one or more agents that can induce Abeta efflux such as geisolin, and a pharmaceutically acceptable carrier. Othβr embodiments of this invention are directed to any one of the above embodiments directed to pharmaceutical compositions wherein the compound of formula (J) is selected from the group consisting of Group A.
Other embodiments of this invention are directed to any one of the above embodiments directed to pharmaceutical compositions wherein the compound of formula (I) is selected from the group consisting of Group B.
Other embodiments of this invention are directed to any one of the above embodiments directed to pharmaceutical compositions wherein the compound of formula (I) is selected from the group consisting of Group C. Other embodiments of this invention are directed to any one of the above embodiments directed to pharmaceutical compositions wherein the compound of formula (I) is selected from the group consisting of Group D.
Other embodiments of this invention are directed to any one of the above embodiments directed to pharmaceutical compositions wherein the compound of formula (I) is selected from the group consisting of Group E.
The compounds of formula (I) can be useful as gamma secretase modulators and can be useful in the treatment and prevention of diseases such as, for example, central nervous system disorders (such as Alzheimers disease and Downs Syndrome), mild cognitive impairment, glaucoma, cerebral amyloid angiopathy, stroke, dementia, microgliosis, brain inflammation, and olfactory function loss.
Another embodiment of this invention is directed to a method of treating a central nervous system disorder comprising administering a therapeutically effective amount of at least one compound of formula (I) to a patient in need of such treatment.
Another embodiment of this invention is directed to a method of treating a central nervous system disorder comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt, solvate, or ester thereof, and at least one pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a method of treating a central nervous system disorder comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (ϊ), or a pharmaceutically acceptable salt, solvate, or ester thereof, and at least one pharmaceutically acceptable carrier, and a therapeutically effective amount of one or more compounds selected from the group consisting of cholinesterase inhibitors, Aβ antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors.
Thus, another embodiment of this invention is directed to a method for modulating (including inhibiting, antagonizing and the like) gamma-secretase comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I) to a patient in need of such treatment.
Another embodiment of this invention is directed to a method for modulating (including inhibiting, antagonizing and the like) gamma-secretase, comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula (I) to a patient in need of treatment.
Another embodiment of this invention is directed to a method of treating one or more neurodegenerative diseases, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating one or more neurodegenerative diseases, comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula (I) to a patient in need of treatment.
Another embodiment of this invention is directed to a method of inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
Another embodiment of this invention is directed to a method of inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula (I) to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula (I) to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula (I) to a patient in need of treatment.
Another embodiment of this invention is directed to a method of treating mild cognitive impairment, glaucoma, cerebral amyloid angiopathy, stroke, dementia, microgliosis, brain inflammation, or olfactory function loss, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
Another embodiment of this invention is directed to a method of treating mild cognitive impairment, glaucoma, cerebral amyloid angiopathy, stroke, dementia, microgliosis, brain inflammation, or olfactory function loss, comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula (I) to a patient in need of treatment.
Another embodiment of this invention is directed to a method of treating mild cognitive impairment, comprising administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
Another embodiment of this invention is directed to a method of treating glaucoma, comprising administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating cerebral amyloid angiopathy, comprising administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
Another embodiment of this invention is directed to a method of treating stroke, comprising administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
Another embodiment of this invention is directed to a method of treating dementia, comprising administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
Another embodiment of this invention is directed to a method of treating microgliosis, comprising administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
Another embodiment of this invention is directed to a method of treating brain inflammation, comprising administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating olfactory function toss, comprising administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
Another embodiment of this invention is directed to a method of treating Downs syndrome, comprising administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
Another embodiment of this invention is directed to a method of treating Downs syndrome, comprising administering an effective amount of a compound of formula (I) to a patient in need of treatment. Other embodiments of this invention are directed to any one of the above embodiments directed to methods of treating wherein the compound of formula (I) is selected from the group consisting of Group A.
Other embodiments of this invention are directed to any one of the above embodiments directed to methods of treating wherein the compound of formula (I) is selected from the group consisting of Group B.
Other embodiments of this invention are directed to any one of the above embodiments directed to methods of treating wherein the compound of formula (I) is selected from the group consisting of Group C.
Other embodiments of this invention are directed to any one of the above embodiments directed to methods of treating wherein the compound of formula (I) is selected from the group consisting of Group D.
Other embodiments of this invention are directed to any one of the above embodiments directed to methods of treating wherein the compound of formula (I) is selected from the group consisting of Group E. This invention also provides combination therapies for (1 ) modulating gamma- secretase, or (2) treating one or more neurodegenerative diseases, or (3) inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), or (4) treating Alzheimer's disease. The combination therapies are directed to methods comprising the administration of one or more (e.g. one) compounds of formula (I) and the administration of one or more (e.g., one) other pharmaceutical active ingredients (e.g., drugs). The compounds of formula (I) and the other drugs can be administered separately (i.e., each is in its own separate dosage form), or the compounds of formula (I) can be combined with the other drugs in the same dosage form. Thus, other embodiments of this invention are directed to any one of the methods of treatment, or methods of inhibiting, described herein, wherein an effective amount of the compound of formula (I) is used in combination with an effective amount of one or more other pharmaceutically active ingredients (e.g., drugs). The other pharmaceutically active ingredients (i.e., drugs) are selected from the group consisting of: BACE inhibitors (beta secretase inhibitors), muscarinic antagonists (e.g., mi agonists or m2 antagonists), cholinesterase inhibitors (e.g., acetyl- and/or butyrylchloltnesterase inhibitors); gamma secretase inhibitors; gamma secretase modulators; HMG-CoA reductase inhibitors; non-steroidal anti-inflammatory agents; N-methyl-D-aspartatθ receptor antagonists; anti-amyloid antibodies; vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists or CB1 receptor antagonists; an antibiotic; growth hormone secretogogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABAA inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-10 inhibitors; Exelon (rivastigmine); Cognex (tacrine); Tau kinase inhibitors (e.g., GSK3beta inhibitors, cdk5 inhibitors, or ERK inhibitors); anti- Abeta vaccine; APP ligands; agents that upregulate insulin cholesterol lowering agents (for example, statins such as Atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pravastatin, Pravastatin, Rosuvastatin, Simvastatin); cholesterol absorption inhibitors (such as Ezetimibe); fibrates (such as, for example, for example, clofibrate, Clofibride, Etofibrate, and Aluminium Clofibrate); LXR agonists; LRP mimics; nicotinic receptor agonists; H3 receptor antagonists; histone deacetylase inhibitors; hsp90 inhibitors; ml muscarinic receptor agonists; 5-HT6 receptor antagonists; mGluRI ; mGluR5; positive allosteric modulators or agonists; mGluR2/3 antagonists; anti-inflammatory agents that can reduce neuroinflammation; Prostaglandin EP2 receptor antagonists; PAI-1 inhibitors; and agents that can induce Abeta efflux such as gelsolin.
Other embodiments of this invention are directed to any one of the methods of treatment, or methods of inhibiting, described herein, wherein the compound of formula (I) is used in combination with an effective amount of one or more other pharmaceutically active ingredients selected from the group consisting of: BACE inhibitors (beta secretase inhibitors), muscarinic antagonists (e.g., m, agonist or rτi2 antagonists), cholinesterase inhibitors (e.g., acetyl- and/or butyrylchlolinesterase inhibitors); gamma secretase inhibitors; gamma secretase modulators; HMG-CoA reductase inhibitors; non-steroidal anti-inflammatory agents; N-methy!-D-aspartate receptor antagonists; anti-amyloid antibodies; vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists or CB1 receptor antagonists; an antibiotic; growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABAA inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-10 inhibitors and cholesterol absorption inhibitors (e.g., ezetimibe).
Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I), in combination with an effective (i.e., therapeutically effective) amount of one or more cholinesterase inhibitors (such as, for example, (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4- piperidinyl]methyl]-1 H-inden-1-one hydrochloride, i.e., donepezil hydrochloride, available as the Aricept® brand of donepezil hydrochloride), to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating
Alzheimer's disease, comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula (I), in combination with an effective (i.e., therapeutically effective) amount of one or more (e.g., one) cholinesterase inhibitors (such as, for example, (±)-2,3-dihydro-5,6-dimethoxy-2-[[1 *(phenylmethyl)-4- piperidinyl]methyl]-1 H -inden-1-one hydrochloride, i.e., donepezil hydrochloride, available as the Aricept® brand of donepezil hydrochloride), to a patient in need of treatment.
Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I), in combination with an effective (i.e., therapeutically effective) amount of one or more compounds selected from the group consisting of Aβ antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors.
Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I), in combination with an effective (i.e., therapeutically effective) amount of one or more BACE inhibitors. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of Exeion (rivastigmine). Another embodiment of this invention is directed to a method of treating
Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of Cognex (tacrine).
Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of a Tau kinase inhibitor.
Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more Tau kinase inhibitor (e.g., GSK3beta inhibitor, cdkδ inhibitor, ERK inhibitor).
This invention also provides a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one anti-Abeta vaccination (active immunization).
Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more APP ligands. Another embodiment of this invention is directed to a method of treating
Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more agents that upregulate insulin degrading enzyme and/or neprilysin.
Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more cholesterol lowering agents (for example, statins such as Atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, and cholesterol absorption inhibitor such as Ezetimibe). This invention also provides a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I)1 in combination with an effective amount of one or more fibrates (for example, clofibrate, Clofibride, Etofibrate, Aluminium Clofibrate). Another embodiment of this invention is directed to a method of treating
Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more LXR agonists.
Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more LRP mimics.
Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more 5- HT6 receptor antagonists.
Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more nicotinic receptor agonists.
Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more H3 receptor antagonists. This invention also provides a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more histone deacetylase inhibitors.
Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more hsp90 inhibitors.
Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (i), in combination with an effective amount of one or more ml muscarinic receptor agonists.
Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more 5- HT6 receptor antagonists mGiuRI or mGluRδ positive allosteric modulators or agonists.
Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I)1 in combination with an effective amount of one or more mGluR2/3 antagonists.
Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more anti-inflammatory agents that can reduce neuroinflammation.
Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more Prostaglandin EP2 receptor antagonists. Another embodiment of this invention is directed to a method of treating
Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more PAI-1 inhibitors.
Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of formula (I), in combination with an effective amount of one or more agents that can induce Abeta efflux such as gelsolin.
Another embodiment of this invention is directed to a method of treating Downs syndrome, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I) to a patient in need of treatment.
Another embodiment of this invention is directed to a method of treating Downs syndrome, comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula (I) to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating Downs syndrome, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I), in combination with an effective (i.e., therapeutically effective) amount of one or more cholinesterase inhibitors (such as, for example, (±)-2,3-dihydro-5,6-dimethoxy-2-([Hphenylmethyr)-4- piperidinyl}methyl]-1 H -inden-1 -one hydrochloride, i.e., donepezil hydrochloride, available as the Aricept® brand of donepezϋ hydrochloride), to a patient in need of treatment.
Another embodiment of this invention is directed to a method of treating Downs syndrome, comprising administering an effective (i.e., therapeutically effective) amount of a compound of formula (I)1 in combination with an effective (i.e., therapeutically effective) amount of one or more (e.g., one) cholinesterase inhibitors (such as, for example, (±)-2,3-dihydro-5,6-dimethoxy-2-[[1 -{phenylmethyl)-4- piperidinyf]methyl]-1 H -inden-1 -one hydrochloride, i.e., donepezil hydrochloride, available as the Aricept® brand of donepezil hydrochloride), to a patient in need of treatment.
Another embodiment of this invention is directed to combinations (i.e., pharmaceutical compositions) comprising an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of formula (I), in combination with an effective (i.e., therapeutically effective) amount of one or more compounds selected from the group consisting of cholinesterase inhibitors (such as, for example, (±)-2,3- dihydro-5,6-dϊrnetboxy-2-[[1 -(phenylmethyl)-4-piperidinyl]methyl]-1 H -inden-1 -one hydrochloride, i.e., donepezil hydrochloride, available as the Aricept® brand of donepezif hydrochloride), Aβ antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors. The pharmaceutical compositions also comprise a pharmaceutically acceptable carrier.
Other embodiments of this invention are directed to any one of the above embodiments directed to combination therapies (i.e., the above methods of treating wherein compounds of formula (I) are used in combination with other pharmaceutically active ingredients, i.e., drugs) wherein the compound of formula (I) is selected from the group consisting of Group A.
Other embodiments of this invention are directed to any one of the above embodiments directed to combination therapies (i.e., the above methods of treating wherein compounds of formula (I) are used in combination with other pharmaceutically active ingredients, i.e., drugs) wherein the compound of formula (I) is selected from the group consisting of Group B.
Other embodiments of this invention are directed to any one of the above embodiments directed to combination therapies (i.e., the above methods of treating wherein compounds of formula (I) are used in combination with other pharmaceutically active ingredients, i.e., drugs) wherein the compound of formula (I) is selected from the group consisting of Group C.
Other embodiments of this invention are directed to any one of the above embodiments directed to combination therapies (i.e., the above methods of treating wherein compounds of formula (I) are used in combination with other pharmaceutically active ingredients, i.e., drugs) wherein the compound of formula (I) is selected from the group consisting of Group D.
Other embodiments of this invention are directed to any one of the above embodiments directed to combination therapies (i.e., the above methods of treating wherein compounds of formula (I) are used in combination with other pharmaceutically active ingredients, i.e., drugs) wherein the compound of formula (I) is selected from the group consisting of Group E.
Another embodiment of this invention is directed to a kit comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of a compound of formula (I) in a pharmaceutically acceptable carrier, and another container (i.e., a second container) comprises an effective amount of another pharmaceutically active ingredient (as described above), the combined quantities of the compound of formula (I) and the other pharmaceutically active ingredient being effective to: (a) treat Alzheimer's disease, or (b) inhibit the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), or (c) treat neurodegenerative diseases, or (d) modulate the activity of gamma-secretase, or (e) mild cognitive impairment, or (f) glaucoma, or (g) cerebral amyloid angiopathy, or (h) stroke, or (i) dementia, or (j) microgliosis, or (k) brain inflammation, or (I) olfactory function loss.
Another embodiment of this invention is directed to a kit comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of one or more (e.g., one) compounds of formula (I) in a pharmaceutically acceptable carrier, and another container (i.e., a second container) comprises an effective amount of another pharmaceutically active ingredient (as described above), the combined quantities of the compounds of formula (I) and the other pharmaceutically active ingredient being effective to: (a) treat Alzheimer's disease, or (b) inhibit the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), or (c) treat neurodegenerative diseases, or (d) modulate the activity of gamma- secretase.
Another embodiment of this invention is directed to a kit comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of a compound of formula (I) in a pharmaceutically acceptable carrier, and another container (i.e., a second container) comprises an effective amount of another pharmaceutically active ingredient (as described above), the combined quantities of the compound of formula (I) and the other pharmaceutically active ingredient being effective to: (a) treat Alzheimer's disease, or (b) inhibit the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), or (c) treat neurodegenerative diseases, or (d) modulate the activity of gamma-secretase.
Other embodiments of this invention are directed to any one of the above embodiments directed to kits wherein the compound of formula (I) is selected from the group consisting of Group A.
Other embodiments of this invention are directed to any one of the above embodiments directed to kits wherein the compound of formula (I) is selected from the group consisting of Group B.
Other embodiments of this invention are directed to any one of the above embodiments directed to kits wherein the compound of formula (I) is selected from the group consisting of Group C.
Other embodiments of this invention are directed to any one of the above embodiments directed to kits wherein the compound of formula (I) is selected from the group consisting of Group D. Other embodiments of this invention are directed to any one of the above embodiments directed to kits wherein the compound of formula (I) is selected from the group consisting of Group E. Examples of cholinesterase inhibitors are tacrine, donepezil, rivastigmine, galantamine, pyridostigmine and neostigmine, with tacrine, donepezil, rivastigmine and galantamine being preferred.
Examples of agonist are known in the art. Examples of m2 antagonists are also known in the art; in particular, m2 antagonists are disclosed in US patents
5,883,096; 6,037,352; 5,889,006; 6,043,255; 5,952,349; 5,935,958; 6,066,636; 5,977,138; 6,294,554; 6,043,255; and 6,458,812; and in WO 03/031412, all ot which are incorporated herein by reference.
Examples of BACE inhibitors include those described in: US2005/0119227 published 06/02/2005 (see also WO2005/016876 published 02/24/2005),
US2005/0043290 published 02/24/2005 (see also WO2005/014540 published 02/17/2005 ), WO2005/058311 published 06/30/2005 (see also US2007/0072852 published 03/29/2007), US2006/0111370 published 05/25/2006 (see also WO2006/065277 published 06/22/2006), US Application Serial No. 11/710582 filed 02/23/2007, US2006/0040994 published 02/23/2006 (see also WO2006/014762 published 02/09/2006), WO2006/014944 published 02/09/2006 (see also US2006/0040948 published 02/23/2006), WO2006/138266 published 12/28/2006 (see also US2007/0010667 published 01/11/2007), WO2006/138265 published 12/28/2006, WO2006/138230 published 12/28/2006, WO2006/138195 published 12/28/2006 (see also US2006/0281729 published 12/14/2006), WO2006/138264 published 12/28/2006 (see also US2007/0060575 published 03/15/2007), WO2006/138192 published 12/28/2006 (see also US2006/0281730 published 12/14/2006), WO2006/138217 published 12/28/2006 (see also US2006/0287294 published 12/21/2006), US2007/0099898 published 05/03/200 (see also WO2007/050721 published 05/03/2007), WO2007/053506 published 05/10/2007 (see also US2007/099875 published 05/03/2007), U.S. Application Serial No. 11/759336 filed 06/07/2007, U.S. Application Serial No. 60/874362 filed 12/12/2006, and U.S. Application Serial No. 60/874419 filed 12/12/2006, the disclosures of each being incorporated incorporated herein by reference thereto.
As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the foltowing meanings: "Patient" includes both human and animals. "Mammal" means humans and other mammalian animals. One or more" means that there is at least one and there can be more than one, and examples include 1 , 2 or 3, or 1 and 2, or 1.
"At least one" means there is at least one and there can be more than one, and examples include 1 , 2 or 3, or 1 and 2, or 1. It is noted that the carbons of formula (I) and other formulas herein may be replaced with 1 to 3 silicon atoms so long as all valency requirements are satisfied.
"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. "Alkyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, oxime (e.g., =N- OH), -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2> -O-C(O)-alkyl, -O-C(O)-aryl, -0-C(O)- cyctoalkyl, carboxy and -C(O)O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl. "Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. "Alkenyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and -S(alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
"Aikylene" means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of aikylene include methylene, ethylene and propylene. "Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred aikynyf groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. "Alkynyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
"Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.
"Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. "Heteroaryl" may also include a heteroaryl as defined above fused to an aryl as defined above. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyi, furanyl, thienyl, pyrimidinyl, pyrkϊone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4- thiadiazolyl, pyrazinyi, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2- a]pyridinyl, imidazo^i -bjthiazolyl, benzofurazanyl, indolyl, azaindolyi, benzimidazolyl, benzothrenyl, quinolinyi, imidazoryl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyf, isoquinolinyl, benzoazaindolyl, 1 ,2,4-triazinyl, benzothiazotyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
"Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyf and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
"Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.
"Cycloalkylalkyl" means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl and the like.
"Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyciopentenyl, cyciohexenyl, cyclohepta-1 ,3-dienyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl. "Cycloalkenylalkyl" means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloaikenylalkyls include cycfopentenylmethyl, cyclohexenylmethy! and the like.
"Halogen" means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine. "Halo" refers to fluoro, chloro, bromo or iodo. ting system substituent" means a substituent attached to an aromatic or non- aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alky!, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkyJheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkyisulfonyl, arylsuffonyi, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyctyl, -O-C(O)-alkyl, -OC(0)-aryl, -0-C(O)- cycloalkyl, -C(^N-CN)-NH2, -C(=NH)-NH2, -C(=NH)-NH(alkyl), oxime (e.g., =N-OH), YiYaN-, Y1Y2N-^yI-, Y1Y2NC(O)-, Y1Y2NSO2- and -SO2NY1Y2, wherein Y1 and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyi. "Ring system substituenf may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH3)2- and the like which form moieties such as, for example:
Figure imgf000094_0001
Figure imgf000094_0002
and
Figure imgf000094_0003
"Heteroarylalkyr means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like.
Ηeterocyclyl" (or heterocycloalkyl) means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), - N(Tos) group and the like; such protections are also considered part of this invention. The heterocycfyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S.S-dioxide. Non-(imiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyi, thiazolidinyl, 1 ,4-dioxanyf, tetrahydrofuranyl, tetrahydrothiopheπyl, lactam, lactone, and the like. "Heterocyclyl" may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidone:
Figure imgf000095_0001
O . "HβterocyclylalkyF (or heterocycloalkylalkyl) means a heterocyclyl moiety as defined above linked via an alky! moiety (defined above) to a parent core. Non-limiting examples of suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like.
"HeterocyclenyP (or heterocycloalkenyl) means a non-aromatic monocyclic or multicycltc ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon- nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyt rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituenf is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable heterocyclenyl groups include 1,2,3,4- tetrahydropyridinyl, 1 ,2-dihydropyridinyl, 1 ,4-dihydropyridinyf, 1 ,2,3,6- tetrahydropyridinyl, 1 ,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2- imidazoliπyl, 2-pyrazoKnyl, dihydroimidazoiyK dihydrooxazofyl, dihydrooxadiazolyl, dihydrothiazolyf, 3,4-dihydro-2H-pyranyl, dihydrofuranyi, fluorodihydrofuranyt, 7- oxabicyclo[2.2.ijheptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like. "Heterocyclenyl" may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidinone:
Figure imgf000096_0001
O .
Ηeterocyclenylalkyl" (or heterocycloalkenylalkyl) means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:
Figure imgf000096_0002
there is no -OH attached directly to carbons marked 2 and 5.
It should also be noted that tautomeric forms such as, for example, the moieties:
Figure imgf000096_0003
Figure imgf000096_0004
H and are considered equivalent in certain embodiments of this invention.
"Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.
"Heteroaralkyl" means a heteroaryl-alkyi- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-fimiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3- ylmethyl. The bond to the parent moiety is through the alkyl.
"Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
"Acyl" means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl. "Aroyl" means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1 - naphthoyl.
"Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.
"Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen. "Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1 - or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen.
"Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include metnylthio and ethylthio. The bond to the parent moiety is through the sulfur.
"Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur. "Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzyithio. The bond to the parent moiety is through the sulfur. "Alkoxycarbonyl11 means an a!kyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyJ.
"Aryloxycarbonyl" means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbony! and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Aralkoxycarbonyl" means an aralkyl-O-C(O)- group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl. "Alkylsutfonyl" means an alkyl-S(O2)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
"Arylsulfonyl" means an aryl-S(O2)- group. The bond to the parent moiety is through the sulfonyl. The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant 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.
The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties. The term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof. Thus, the term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like) , in sufficient purity to be characterizabie by standard analytical techniques described herein or well known to the skilled artisan. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et a/, Protective Groups in organic Synthesis (1991), Wiley, New York. When any variable (e.g., aryl, heterocycle, R2, etc.) occurs more than one time in any constituent or in Formula (I), its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) .14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g., a drug precursor) that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. For example, if a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxyiic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C1-Cβ)alkyl, (C2- Ci2)aikanoyioxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyioxym ethyl having from 3 to 6 carbon atoms, 1 -(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1 -(alkoxycarboπyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyi)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyI, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(CrC2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbamoyKCrC2)alkyl, N,N-di (CrC2)alkyJcarbamoyl-(C1 - C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl, and the like.
Similarly, if a compound of Formula (I) contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C1-Ce)alkanoyloxymethyl, 1-((Cr Cejalkanoyloxy^thyl, 1-methyl-1-((CrC6)alkanoyloxy)ethyl, (Cr Cejalkoxycarbonyloxymethyl, N-(Ci-C6)alkoxycarbonylaminomethyl, succinoyl, (Ci- CβJalkanoyl, α-amino(Ci-C4)alkanyl, arylacyl and α-aminoacyl, or α-aminoacyl-α- aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(CrCe)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.
If a compound of Formula (I) incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (CrCi0)alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl, — C(OH)C(O)OY1 wherein Y1 is H, (Cr C6)alkyl or benzyl, -C(OY2) Y3 wherein Y2 is (C1-C4) alkyl and Y3 is (CrC6)alkyl, carboxy (CrC6)alkyl, amino(CrC4)alkyl or mono-N — or di-N,N-(CrC6)alkylaminoalkyl, — C(Y4)Y5 wherein Y4 is H or methyl and Y5 is mono-N — or di-N,N-(CrC6)alkylamino morpholino, piperidin-1 -yl or pyrrolidin-1-yl, and the like.
One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covaient bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H2O.
One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira etal, J. Pharmaceutical Set., 93(3), 601 -611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et a/, AAPS PharmSciTech., 501 article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001 ). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
"Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
The compounds of Formula (I) can form salts which are also within the scope of this invention. Reference to a compound of Formula (I) herein is understood to include reference to salts thereof, unless otherwise indicated. The term "SaIt(S)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic saits formed with inorganic and/or organic bases. In addition, when a compound of Formula (I) contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the Formula (!) may be formed, for example, by reacting a compound of Formula (i) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesυlfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates.) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl etal, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley- VCH; S. Berge etal, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, international J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D. C. on their website). These disclosures are incorporated herein by reference thereto.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quartemized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and afl acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention. Pharmaceutically acceptable esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n- propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, mettioxymethyl), aralkyl (for examplθ, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, d^alkyl, or C1-4alkoxy or amino); (2) sulfonate esters, such as afkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C1-2o alcohol or reactive derivative thereof, or by a 2,3-di (Ce-24)acyl glycerol.
Compounds of Formula (I), and salts, solvates, esters and prodrugs thereof, may exist in their tautomeric form (for example, as an amide, enol, keto or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
The compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryis) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column. It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention. AII stereoisomers {for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4- pyridyl and 3-pyridyl). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.) Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds. The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 17O, 31P, 32P, 35S1 18F, and 36CL respectively.
Certain isotopicaliy-labeHed compounds of Formula (I) (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances, tsotopically labelled compounds of Formula (I) can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
Polymorphic forms of the compounds of Formula (I), and of the salts, solvates, esters and prodrugs of the compounds of Formula (I), are intended to be included in the present invention.
The compounds according to the invention can have pharmacological properties; in particular, the compounds of Formula (I) can be modulators of gamma secretase (including inhibitors, antagonists and the like).
More specifically, the compounds of Formula (I) can be useful in the treatment of a variety of disorders of the central nervous system including, for example, including, but not limited to, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration and the like.
Another aspect of this invention is a method of treating a mammal (e.g., human) having a disease or condition of the central nervous system by administering a therapeutically effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound to the mammal.
A preferred dosage is about 0.001 to 500 mg/kg of body weight/day of the compound of Formula (I). An especially preferred dosage is about 0.01 to 25 mg/kg of body weight/day of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate of said compound.
The compounds of this invention may also be useful in combination (administered together or sequentially) with one or more additional agents listed above.
The compounds of this invention may also be useful in combination (administered together or sequentially) with one or more compounds selected from the group consisting of Aβ antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range.
Accordingly, in an aspect, this invention includes combinations comprising an amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an amount of one or more additional agents listed above wherein the amounts of the compounds/ treatments result in desired therapeutic effect.
The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays. Certain assays are exemplified later in this document.
This invention is also directed to pharmaceutical compositions which comprise at least one compound of Formula (I), or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and at least one pharmaceutically acceptable carrier.
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
The compounds of this invention may also be delivered subcutaneously. Preferably the compound is administered orally. Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses. Another aspect of this invention is a kit comprising a therapeutically effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
Yet another aspect of this invention is a kit comprising an amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and an amount of at least one additional agent listed above, wherein the amounts of the two or more ingredients result in desired therapeutic effect. The invention disclosed herein is exemplified by the following illustrative processes which should not be construed to limit the scope of the invention. Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art.
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
I) BCI3;
Z) PhNTf2/NEt3
Figure imgf000111_0001
Zn(N(SiMe3)2)
MeO Pd2(dba)s/P(t-Bu)3 "
H ^N
Figure imgf000111_0002
Org. Lett.; EN; 7; 6; 2 Y005; 1169 - 1172.
CHO OBn
I) MeOCH2PPh3Br, base Me0 Z) HCI
Figure imgf000111_0003
CHO OH ' VD1
Figure imgf000111_0004
1) NH2NH2
2) oxidation •
Figure imgf000111_0005
Chem. Res. Synop.; EN; 11 ; 2004; 717 - 721.
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
O O
MeI, base BrNf ^N
Figure imgf000115_0001
*" O
Figure imgf000115_0002
1)
Br5 2)
NH _
Figure imgf000115_0004
Figure imgf000115_0003
/
Same procedure wilt apply
\
Figure imgf000115_0005
O
N
Figure imgf000115_0007
Br
Figure imgf000115_0006
Figure imgf000115_0008
CARDILLO, G.; FABBRONI, S.; GENTILUCCI, L; PERCIACCANTE, R.; PICCINELLI, F.; TOLOMELLI, A.; Tetrahedron 2004, 60 (23), 5031-5040.
I) MeI, base; 2) BnBr, base.
Figure imgf000115_0009
Figure imgf000115_0010
H H
POBr, Br
N
Figure imgf000115_0012
Figure imgf000115_0011
Figure imgf000115_0013
FLElTZ, F. J.; LYLE, T. A.; ZHENG, N.; ARMSTRONG, J. D. Ill; VOLANTE, R. P.; Synth Commun 2000, 30 (17), 3171-3180. Example 1
Figure imgf000116_0001
/"V-B(OH)2
4.1
O,
3.1
Figure imgf000116_0002
Step 1
If one were to react Compound 1.1 under N2 in THF and 5% Fe(acac)3 with 1 eq of benzylmagnesium bromide in ether at -30C then one would obtain compound 3.1 after workup.
Step 2
If one were to mix Compound 3.1 with compound 4.1 (1eq), K2CO3 (3eq) and 5% Palladium tetrakistriphenylphosphine in DMF/H2O (99.5/0.5 v/v) and heat the solution to 100 °C under microwave one would obtain compound 5.1 after purification.
Example 2
Ct
N
Figure imgf000116_0003
Cl 6.1
Figure imgf000116_0004
Figure imgf000117_0001
7.1
Figure imgf000117_0002
Step i
If one were to react Compound 6.1 under N2 in THF and 5% Fe(acac)3 with 1 eq of benzylmagnesium bromide in ether at -30°C one would obtain compound 7.1 after workup.
Step 2
If one were to mix Compound 4.1 with compound 7.1 (1eq), K2CO3 (3eq) and 5% Palladium tetrakistriphenylphosphine in DMF/H2O (99.5/0.5 v/v) and heat the solution to 100 °C under microwave one would obtain compound 8.1 after purification.
Example 3
MgCl
Figure imgf000117_0004
Fe(acac)3
Figure imgf000117_0005
Figure imgf000117_0003
BrMg
Figure imgf000117_0006
10.1
Pd(PPh3)4
Figure imgf000117_0007
Step i
If one were to react Compound 1.1 under N2 in THF and 5% Fe(acac)3 with 1 eq of 9.1 (obtain from halogen/metal exchange) in ether at -30C one would obtain compound 10.1 after workup. Step 2
If one would mix Compound 10.1 with tetrakistriphenylphosphine in ether before compound 2.1 (1eq) would be added one would obtain compound 11.1 after purification.
Assay:
Secretase Reaction and Aβ Analysis in Whole Cells: HEK293 cells overexpressing APP with Swedish and London mutations is treated with the specified compounds for 5 hour at 37 °C in 100 ml of DMEM medium containing 10% fetal bovine serum. At the end of the incubation, total Aβ, Aβ40 and Aβ42 is measured using electrochemiluminescence (ECL) based sandwich immunoassays. Total Aβ is determined using a pair of antibodies TAG-W02 and biotin-4G8, Aβ40 is identified with antibody pairs TAG-G2-10 and biotin- 4G8, while Aβ42 is identified with TAG-G2- 11 and biotin-4G8. The ECL signal is measured using Sector Imager 2400 (Meso Scale Discovery).
MS Analysis of Aβ Profile: Aβ profile in conditioned media is determined using surface enhanced laser desorption/ionization (SELDI) mass spectrometry. Conditioned media is incubated with antibody W02 coated PS20 ProteinChip array. Mass spectra of Aβ captured on the array is read on SELDI ProteinChip Reader (Bio- Rad) according to manufacturer's instructions.
CSF Aβ Analysis: Aβ in rat CSF is determined using MSD technology as described above. Aβ40 is measured using antibody pair Tag-G2-10 and biotin-4G8, while Aβ42 is measured using Tag-anti Aβ42 (Meso Scale Discovery) and biotin-4G8. The ECL signal is measured using Sector Imager 2400 (Meso Scale Discovery). Matrix-assisted laser desorption/ionization mass spectrometric (MALDi MS) analysis of A/? is performed on a Voyager-DE STR mass spectrometer (ABI, Framingham, MA). The instrument is equipped with a pulsed nitrogen laser (337 nm). Mass spectra is acquired in the linear mode with an acceleration voltage of 20 kV. Each spectrum presented in this work represents an average of 256 laser shots. To prepare the sample-matrix solution, 1 /A. of immunoprecipitated Aβ sample is mixed with 3 /vL of saturated α-cyano-4-hydroxycinnamic acid solution in 0.1% TFA/acetonitrile. The sample-matrix solution is then applied to the sample plate and dried at ambient temperature prior to mass spectrometry analysis. All the spectra are externally calibrated with a mixture of bovine insulin and ACTH (18-39 clip).
While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims

WHAT IS CLAIMED IS:
1. A compound of the formula (I):
B4'R-*'L-κ' <■> or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein: R1, R2, R3, R4 and L are each independently selected; R1 is selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkenyl, aryl, heteroaryl, hetenocyclenyl, fused cycloalkylaryl, fused heterocycloalkylaryl-, fused cycloalkylheteroaryl-, fused heterocycloalkylheteroaryl-, fused benzocycloalkylalkyl-, fused benzoheterocycloalkylalkyl-, fused heteroarylcycloalkylalkyl-, fused heteroarylheterocycloalkylalkyl-, fused cycloalkylarylalkyl-, fused heterocycloalkylarylalkyl-, fused cycloalkylheteroarylalkyl-, and fused heterocydoalkylheteroarylalkyl-, wherein each of said: alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkenyl, aryl, heteroaryl, heterocyclenyl fused cycloalkylaryl, fused heterocycloalkylaryl-, fused cycloalkylheteroaryl-, fused heterocycloalkylheteroaryl-, fused benzocycloalkylalkyl-, fused benzoheterocycloalkylalkyl-, fused heteroarylcycloalkylalkyl-, fused heteroaryiheterocycloalkylalkyl-, fused cycloalkylarylalkyl-, fused heterocycloalkylarylalkyl-, fused cycloalkylheteroarylalkyl-, and fused heterocydoalkylheteroarylalkyl- R1 groups is optionally substituted with 1 -5 independently selected R21 groups;
L is selected from the group consisting of: L is a direct bond, -O-, -N(R5)-, -C(R6KR7)-, -(C=O)-, -(C=NR21A)-, -S-, -S(O)-, and -S(O)2-;
R2 is the fused bicyclic ring: v/WΛΛ
^ A4 ^ B^ I ((A)) I (B) I (l)
\ \
^A1 B4 vΛΛΛΛ wherein:
(1) Ring (A) is a six membered heteroaryl ring comprising atoms A1 to A6. wherein:
(a) A' is C, (b) A5 and A6 are C1
(b) A2 t A3 and A4 are each independently selected from the group consisting of: N and C, and wherein each substitutable C is optionally substituted with one R21B group and each R21B for each C is independently selected, and (c) provided that at least one of A2 to A4 is N, and provided that the total number of nitrogens in Ring (A) is 1 to 3,
(2) Ring (B) (which comprises atoms A5, A6, and B1 to B4) is a cycloalkyl, cycloafkenyl, heterocyctoalkyl, heterocycloalkenyl, heteroaryl or phenyl ring, and
(a) A5 and A6 are as defined for Ring (A) above, (b) in said phenyl Ring (B):
(i) B1 to B4 are C, and
(H) B2, B3, and B4 are each optionally substituted with one R21B group (and the substitution on each carbon is independent of the substitutions on the remaining carbons), (c) in said cycloalkyl Ring (B):
(i) B1 is C,
(ii) B2, B3, and B4 are each independently selected from the group consisting of: C, -(C=O)- and -(C=NR21A)-, provided that there are only 0 to 2 moieties selected from the group consisting of -(C=O)- and -(C=NR21 A)-, and (iii) each substitutable B1 to B4 C is optionally substituted with 1 or 2 independently selected R21B groups (and the substitution on each carbon is independent of the substitutions on the remaining carbons),
(d) in said cycloalkenyl Ring (B): (i) B1 is C, (ii) B2, B3, and B4 are each independently selected from the group consisting of: C, -(C=O)- and -(C=NR21A)-, provided that there are only 0 to 2 moieties selected from the group consisting of -(C=O)- and -(C=NR21 A)-,
(iii) each substitutable B1 to B4 C is optionally substituted with 1 or 2 independently selected R21B groups (and the substitution on each carbon is independent of the substitutions on the remaining carbons), and
(iv) said cycloalkenyl Ring (B) comprises one or two double bonds,
(e) in said heferocycloalkyl Ring (B):
(I) B1 is selected from the group consisting of N and C, (ii) B2, B3 and B4 are each independently selected from the group consisting of: N, C, -(C=O)-, -(C=NR21A)-, O, S, S(O), and S(O)2, and provided that there are no -O-O- bonds, no -O-S- bonds, no O-S(O) bonds, no -O- S(O)2 bonds, and no -N-S- bonds in the ring, and provided that the ring does not comprise three adjacent nitrogen atoms,
(iii) at teast one of B1 to B4 is a heteroatom, and provided that when B1 is a heteroatom said heteroatom is N, and the heteroatoms for B2 to B4 are selected from the group consisting of: N1 O, S, S(O), and S(O)2, and
(iv) the total number of heteroatoms in said heterocycloalkyl Ring (B) is 1 to 4, and
(v) each substitutabie B1 to B4 C is optionally substituted with 1 or 2 independently selected R groups (and the substitution on each carbon is independent of the substitutions on the remaining carbons), and
(vi) each substitutable B2 to B4 N is optionally substituted with one R21A group and each R21A for each N is independently selected, (f) in said heterocycloalkenyl Ring (B):
(i) B1 is selected from the group consisting of N and C, (ii) B2, B3 and B4 are each independently selected from the group consisting of: N, C, -(C=O)-, -(C=NR21A)-, O1 S, S(O)1 and S(O)2, and provided that there are no -O-O- bonds, no -O-S- bonds, no O-S(O) bonds, no -O- S(O)2 bonds, and no -N-S- bonds in the ring, and provided that the ring does not comprise three adjacent nitrogen atoms,
(iii) at least one of B1 to B4 is a heteroatom, provided that when B1 is a heteroatom said heteroatom is N, and the heteroatoms for B2 to B4 are selected from the group consisting of: N, O, S, S(O), and S(O)2, and
(iv) the total number of heteroatoms in said heterocycioalkenyi Ring (B) is 1 to 4, and
(v) each substitutable B1 to B4 C is optionally substituted with 1 or 2 independently selected R21B groups (and the substitution on each carbon is independent of the substitutions on the remaining carbons),
(vi) each substitutabie B2 to B4 N is optionally substituted with one R21A group and each R21A for each N is independently selected, and
(vii) said heterocycloalkenyl Ring (B) comprises one or two double bonds; and (g) in said heteroaryl Ring (B):
(i) B1 is C,
(ii) B2 to B4 are each independently selected from the group consisting of C and N1
(Hi) at least one of B2 to B4 is a heteroatom, and
(iv) the total number of heteroatoms in said heteroaryl Ring (B) is 1 to 3 and wherein each substitutable B2 to B4 C is optionally substituted with one R21B group (and the substitution on each carbon is independent of the substitutions on the remaining carbons);
R3 is selected from the group consisting of: aryl-, heteroaryl-, cycloalkyl-, cycloalkenyl, cycloalkylalkyl-, heterocyclyl-, heterocyclenyl-, heterocyclylalkyl-, heterocyclyalkenyl-, fused benzocycloalkyl-, fused benzoheterocycloalkyl-, fused heteroarylcycloalkyl-, fused heteroarylheterocycloalkyl-, fused cycloalkylaryl, fused heterocycloalkylaryl-, fused cycloalkylheteroaryl-, fused heterocycloalkylheteroaryl-,
> :- / C
Figure imgf000123_0001
Figure imgf000123_0002
A
Figure imgf000123_0005
■
A
Figure imgf000123_0003
Figure imgf000123_0004
Figure imgf000123_0006
■ vΛΛΛΛ ΛΛΛΛ
Figure imgf000123_0007
Figure imgf000123_0008
y/\rv\j\ s/WV\ ΛΛΛΛ
^/vw\
Figure imgf000123_0009
JW\Λ
Figure imgf000123_0010
ΛΛΛΛy
Figure imgf000124_0001
wherein X is selected from the group consisting of: O, -N(R14)- and -S-; and wherein each of said R3 moieties is optionally substituted with 1 -5 independently selected R21 groups;
R4 is selected from the group consisting of: arylalkoxy-, heteroarylalkoxy-, arylalkylamino-, heteroarylaikylamino-, aryl, heteroaryl, cycloalkyl-, cycloalkenyl, heterocyclyl, heterocyclenyl, and heterocyclyalkyl-, wherein each of said R4 arylalkoxy-, heteroarylalkoxy-, arylalkylamino-, heteroarylaikylamino-, aryt, heteroaryl, heterocyclyl, heterocyclenyl, and heterocyclyalkyl- is optionally substituted with 1 -5 independently selected R21 groups; or R3 and R4 are linked together to form a fused tricyclic ring system wherein R3 and R4 are as defined above and the ring linking R3 and R4 is an alky! ring, or a heteroalkyl ring, or an aryl ring, or a heteroaryl ring, or an alkenyl ring, or a heteroalkenyl ring;
R5 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -CN, -C(O)R15, -C(O)OR15, -C(O)N(R15)(R16), -S(O)N(R15)(R16), -S(O)2N(R15)(R16), -C(=NOR15)R16, and -P(O)(OR15)(OR16); or
R5 taken together with R1 and the nitrogen to which they are bound form a heterocycloalkyl or heterocycloalkenyl ring fused to said R1 ring, said fused ring is optionally substituted with 1 to 5 independently selected R21 groups;
R6 and R7 are each independently selected from the group consisting of: H, alkyl, alkenyl, afkynyl, aryl, arylalkyl-, alkylaryl-, cycloalkyl, cycloalkylalkyl-, heteroaryl, heteroarylalkyl-, heterocyclyl and heterocyclylalkyl-, wherein independently each of said alkyl, alkenyl and alkynyl, aryl, arylalkyl-, alkylaryl-, cycloalkyl, cycloalkylalkyl-, heteroaryl, heteroarylalkyl-, heterocyclyl and heterocyclylalkyl- is optionally substituted with 1 to 5 independently selected R21 groups; or
R6 taken together with R1 and the carbon to which they are bound form a cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl ring fused to said R1 ring, said fused ring is optionally substituted with 1 to 5 independently selected R21 groups; or
R6 and R7 taken together with the carbon to which they are bound form a spirocycloaikyl ring, a spirocycloalkenyl ring, a spiroheterocycioaikyf ring, or a spiroheterocyclalkenyl ring, and wherein the spiro ring is optionally substituted with 1- 5 independently selected R21 groups; R15A and R16A are independently selected from the group consisting of aikyi, alkenyl, aJkynyl, cyctoalkyl, cycloafkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloaikyi, arylheterocydyl, (R18)q -alkyl, (R18)q -cycloalkyl. (R18)q -cycloalkylalkyl. (R18)q -heterocyclyl, (R1β)q -heterocyclylalkyl, (R18)q -aryl, (R1β)q -arylalkyl. (R18)q -heteroaryl and (R18)q -heteroarylalkyl, wherein q is 1 to 5 and each R18 is independently selected;
R15, R16 and R17 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyi, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyt, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocyclyl, (R18)q -alkyl, (R18)q -cycloalkyl, <R18)q -cycloalkylalkyl. (R1% -heterocyclyl, (R18)q -heterocyclylalkyl, (R18)q -aryl, (R18)q -arylalkyl, (R18)q -heteroaryl and (R18)q -heteroarylalkyl, wherein q is 1 to 5 and each R18 is independently selected; or each R18 is independently selected from the group consisting of alkyl, atkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, -NO2, halo, heteroaryl, HO-alkyoxyalkyl, -CF3, -CN, alkyl-CN, -C(O)R19, -C(O)OH, -C(O)OR19, -C(O)NHR20, -C(O)NH2, -C(O)NH2-C(O)N(aikyl)2, -C(O)N(afkyl)(aryl), -C(O)N(alkyl)(heteroaryl), -SR19, -S(O)2R20, -S(O)NH2, -S(O)NH(alkyl), -S(O)N(alkyl)(alkyl), -S(O)NH(aryl), -S(O)2NH2, -S(O)2NHR19, -S(O)2NH(heterocyclyl), -S(O)2N(alkyl)2, -S(O)2N(alkyl)(aryl), -OCF3, -OH, -OR20, -O-heterocyclyl, -O-cydoalkylalkyl, -O-heterocyclylalkyl, -NH2, -NHR20, -N(alkyl)2, -N(arylalkyl)2, -N(arylalkylMheteroarylalkyf), -NHC(O)R20, -NHC(O)NH2, -NHC(O)NH(alkyl), -NHC(O)N(alkyl)(alkyl), -N(alkyl)C(O)NH(alkyl). -N(alkyl)C(O)N(alkyl)(alkyl), -NHS(O)2R20, -NHS(O)2NH(alkyl), -NHS(O)2N(alkylXalkyl), -N(alkyl)S(O)2NH(alkyl) and -N(alky1)S(O)2N(alkyl)(alkyl); or alternately, two R18 moieties on adjacent carbons can be linked together to form:
V\ V - ^ A/ , A > or
Figure imgf000126_0001
R19 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;
R20 is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyi, heteroaryl or heteroarylalkyl; each R21 group is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkytalkyl, cycloalkenyl, heterocyclyl (i.e., heterocycloalkyl), heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CN, -OR15, -C(O)R15, -C(O)OR15, -C(O)N(R15)(R16), -P(O)(CH3)2, -SO(=NR15)R16-, -SF5, -OSF5, -Si(R1SA)3 wherein each R15A is independently selected, -SR15, -S(O)N(R15KR16), -CH(R15KR16), -S(O)2N(R15)(R16), -C(=NOR15)R16, -P(O)(OR15KOR16), -N(R15KR16), -alkyl-N(R15)(R16), -N(R15)C(O)R16,
-CH2-N(R15)C(O)R16, -CH2-N(R15)C(O)N(R16)(R17), -CH2-R15, -CH2N(R15)(R16), -N(R15)S(O)R16A, -N(R15)S(O)2R16A, -CH2-N(R15)S(O)2R16A, -N(R15)S(O)2N(R16)(R17), -N(R15JS(O)N(R16)(R17J, -N(R15JC(OJN(R16)(R17), -CH2-N(R15JC(O)N(R16)(R17J, -N(R15JC(OJOR16, -CH2-N(R15JC(O)OR16, -S(O)R15A, =NOR15, -N3, -NO2, -S(O)2R15A, -O-N=C(R15)2 (wherein each R15 is independently selected), and ~O-N=C(R15)2 wherein said R15 groups are taken together with the carbon atom to which they are bound to form a 5 to 10 membered ring and wherein said ring optionally contains 1 to 3 heteroatoms independently selected from the group consisting of -O-, -S-, -S(O)-, -S(O)2-, and -NR21A; each R21A is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl. cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl. heteroaryl, heteroarylalkyl, halo, -OR15, -CN, -alkyl-(R15)(R16), - CH(R15KR16), -CH2-N(R15)C(O)R16, -CH2-N(R15)C(O)N(R16)(R17), -CH2-R15; -CH2N(R15)(R16), -C(O)R15, -C(O)OR15, -C(O)N(R15)(R16), -C(=NOR15)R16, -CH2-N(R15JS(O)2R16A, -CH2-N(R15JC(O)N(R16)(R17J, -CH2-N(R15JC(OJOR16,
-C(R15J=NOR16, -S(O)R15A; -S(O)(OR15J, -S(O)2(OR15J, -S(O)2R15A, -S(O)N(R15)(R16J, -S(O)2N(R15)(R16J, -P(O)(OR15)(OR16J, -N(R15)(R16J, -N(R15JC(O)R16, -N(R15)S(O)R16A, -N(R15)S(O)2R16A, -N(R15)S(O)2N(R16)(R17), -N(R15)S(O)N(R16)(R17), -N(R15)C(O)N(R16)(R17), -N(R15JC(O)OR16, -N3, -NO2, -P(O)(CH3)2, -SO(=NR15)R16-, -SF5, and -OSF5; each R218 group is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloaikylafkyl, cycloalkenyf, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -OR15, -CN, -alkyl-(R15)(R16), - CH(R15)(R16J, -CH2-N(R15JC(O)R16, -CH2-N(R15)C(O)N(R16)(R17), -CH2-R15, -CH2N(R15KR16), -C(O)R15, -C(O)OR15, -C(O)N(R15)(R16), -C(=NOR15)R16, -CH2-N(R15)S(O)2R16A, -CH2-N(R15)C(O)N(R16)(R17)t -CH2-N(R15JC(O)OR16, -C(R15)=NOR16, -SR15; -S(O)R15A; -S(O)(OR15), -S(O)2(OR15), -S(O)2R15A, -S(O)N(R15)(R16)t -S(O)2N{R15)(R16), -P(O)(OR15)(OR16), -N(R15)(R16), -N(R15JC(O)R16, -N(R15)S(O)R16A, -N(R15)S(O)2R1δA, -N(R15JS(O)2N(R16)(R17J, -N(R1 S)S(O)N(R16)(R17), -N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -N3, -NO2, -P(O)(CH3)2, -SO(=NR15)R16-, -SF5, -OSF5, and -Si(R15A)3 wherein each R15A is independently selected; independently, each afkyl, cycloalkenyl, cyctoalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryf, aryialkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl R21, R21A, and R21B group is optionally substituted by 1 to 5 independently selected R22 groups wherein each R22 group is independently selected from the group consisting of alkyl, cycloalkyl, cycloafkenyl, heterocyclyl, aryl, heteroaryl, halo, -CF3, -CN, -OR15, - C(O)R15, -C(O)OR15, -alkyt-C(O)OR15, C(O)N(R15)(R16), -SR15, -S(O)N(R15)(R16), -S(O)2N(R15XR16), -C(=NOR15)R16, -P(O)(OR15)(OR1β), -N(R15)(R16), -alkyl«N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15JC(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -CH2-N(R15JS(O)2R16, -N(R15)S(O)2N(R16)(R17), -N(R15)S(O)N(R16)(R17), -N(R15)C(O)N(R16)(R17), -CH2-N(R15JC(O)N(R16KR17), -N(R15JC(O)OR16, -CH2-N(R15)C(O)OR16, -N3, ^NOR15, -NO2, -S(O)R15A and -S(O)2R15A; and With the proviso that when R3 is aryl and R1 comprises a 5 or 6-membered aryl or heteroaryl ring, then said 5 or 6-membered aryl or heteroaryl ring is not substituted with an R21 group that is selected from the group consisting of the moieties: -O-(5 or 6 membered aryl), -S-(5 or 6 membered aryl), -S(O)2-(5 or 6 membered aryl), -N(R15H5 or 6 membered aryl), -C(O)-(5 or 6 membered aryl), -alkyl-(5 or 6 membered aryl), -O-(5 or 6 membered heteroaryl),
-S-(5 or 6 membered heteroaryl), -S(O)2-(5 or 6 membered heteroaryl), -N(R15)-(5 or 6 membered heteroaryl), -C(O)-(S or 6 membered heteroaryl), and -alkyl-(5 or 6 membered heteroaryl).
2. The compound of Claim 1 wherein R3 is selected from the group consisting of
JΛΛAΛ VΛΛΛΛ t/WW «/W/\Λ
Figure imgf000128_0001
Figure imgf000128_0002
ΛΛΛA iΛΛΛΛ v/VW\ */WAΛ
Figure imgf000129_0001
O 2009/073779
,ΛΛ/VA/ iΛΛΛΛ J\ΛΛΛ ΛΛΛΛ
\ and
Figure imgf000130_0001
(H3C)3St , F5SO F5S u\ι\ι\/\r
Figure imgf000130_0002
Figure imgf000130_0003
Figure imgf000130_0004
3. The compound of Claim 2 wherein at least one group selected from the group consisting of: -SF5, -OSF5, and -Si(R15A>3 (wherein each R15A is independently selected) is present in the compounds of formula (I).
4. The compound of Claim 1 wherein R4 is selected from the group consisting of: 1gg to 13gg.
5. The compound of Claim 2 wherein R4 is selected from the group consisting of: 1gg to 13gg.
6. The compound of Claim 1 wherein the R4-R3 moiety is selected from the group consisting of: 1 bb to 40bb.
7. The compound of Claim 1 wherein R »1 : is. selected from the group consisting of:
-
Figure imgf000130_0005
Figure imgf000130_0006
F ' F ,
Figure imgf000130_0007
Figure imgf000130_0008
Cl Cl
- Cl
Figure imgf000130_0009
Figure imgf000130_0010
Figure imgf000130_0011
Figure imgf000130_0012
Cl
Figure imgf000130_0013
SF5
Figure imgf000130_0014
Figure imgf000130_0015
SiMθ 3 '
Figure imgf000131_0001
8. The compound of Claim 1 wherein R1 is selected from the group consisting of:
Figure imgf000131_0002
SFB
Figure imgf000132_0001
SFc
Figure imgf000132_0002
Figure imgf000132_0003
SiMe^.
Figure imgf000132_0004
OSF5
OSF,
*
Figure imgf000132_0005
- *
N
9. The compound of Claim 1 wherein R1 is phenyl substituted with 1 to 3 independently selected R i21 moieties wherein at least one R 21 moiety is selected from the group consisting of -SF5, -OSF5 and -Si(R 15Ax )3
10. The compound of Claim 1 wherein R is phenyl substituted with 1 to 3 independently selected R21 moieties wherein at least one R21 moiety is selected from the group consisting of -SF5 and -OSF5.
11. The compound of Claim 1 wherein L is selected from the group consisting of:
H M £H3 and
Figure imgf000132_0006
, and
R1 is selected from the group consisting of: F
Figure imgf000132_0007
Figure imgf000132_0008
F ,
Figure imgf000132_0009
Figure imgf000132_0010
F
Ϋ
Figure imgf000132_0011
τra
Figure imgf000133_0001
12. The compound of Claim 1 wherein the R4-R3- moiety is:
Figure imgf000133_0003
13. The compound of Claim 7 wherein the R4-R3- moiety is:
Figure imgf000133_0002
14. The compound of Claim 8 wherein the R4-R3- moiety is:
Figure imgf000133_0004
15. The compound of Claim 11 wherein the R4-R3- moiety is:
Figure imgf000133_0005
16. The compound of Claim 1 wherein sakl R3 is selected from the group consisting of aryf and aryl substituted with 1 to 3 independently selected R21 groups, and said R9 group is selected from the group consisting of heteroaryl and heteroaryl substituted with 1 to 3 independently selected R21 groups.
17. The compound of Claim 1 wherein: (1 ) said R3 is selected from the group consisting of: phenyl, and phenyl substituted with one R21 group, and (2) said R4 is imidazol-t-yl substituted with one R21 group.
18. The compound of Claim 1 wherein the R •»4-R r->3- moiety is selected from the group consisting of:
OR15 OCH3
Figure imgf000134_0001
alkyl
Figure imgf000134_0003
N=/ N=
Figure imgf000134_0002
NN==: / \i=
Figure imgf000134_0004
19. The compound of Claim 1 wherein the R4-R3- moiety is selected from the group consisting of: aHcyl afkyi
N=/ W=
Figure imgf000135_0001
V=/ 1 N=/ V=/
Figure imgf000135_0002
halo alkyl
N=/ N=/ < N=/
Figure imgf000135_0003
and N=/
20. The compound of Claim 1 wherein the -L-R1 moiety is selected from the group consisting:
and
Figure imgf000135_0006
Figure imgf000135_0004
Figure imgf000135_0005
21. The compound of Claim 1 wherein L is -C(R3){R4)- wherein R3 and R4 are independently selected from the group consisting of: H and alkyl.
22. The compound of Claim 1 wherein L is -C(R6)(R7)- wherein R6 is taken together with R1 and the carbon to which they are bound to form a cycloalkyi. cycloalkenyl, heterocycloalkyl or heterocycloalkenyl ring fused to said R1 ring, said fused ring is optionally substituted with 1 to 5 independently selected R21 groups.
23. The compound of Claim 1 wherein L is is -N(R5)-, and R5 taken together with R1 and the nitrogen to which they are bound form a heterocycloalkyl or heterocycioalkenyi ring fused to said R1 ring, said fused ring is optionally substituted with 1 to 5 independently selected R21 groups.
24. The compound of Claim 1 wherein R3 is pyridyl substituted with 1 to 3 independently selected R21 groups and R4 is heteroaryl substituted with 1 to 3 independently selected R21 groups.
25. The compound of Claim 1 wherein R1 is phenyl substituted with 1 to 3 independently selected R21 groups wherein said R21 groups are halo.
26. The compound of Claim 1 wherein L is selected from the group consisting of:
OH H H ?H3 J
R1 is selecte vd from* thy N e group consisting of: "* ...
F and F
Figure imgf000136_0002
Figure imgf000136_0003
Figure imgf000136_0001
27. The compound of Claim 1 wherein the -L-R1 moiety is:
Figure imgf000136_0004
28. The compound of Claim 1 wherein the fused Rings (A) and (B) are selected from the group consisting of: 1A to 4A1 A1.2 to A22.2, and A24.2 to A28.2
29. The compound of Claim 1 wherein the compound of formula (I) is a compound selected from the group consisting of the compounds of formulas (IA), (IB), (IC), (ID), and (IE).
30. The compound of Claim 28 wherein the compound of formula (I) is a compound selected from the group consisting of the compounds of formulas (IA), (IB), (IC), (ID), and (IE).
31. The compound of Claim 1 wherein the compound of formula (I) is a compound selected from the group consisting of compounds 5.1 , 8.1 , 11.1, and A1 to A28.
32. The compound of Claim 1 in pure and isolated form.
33. The compound of Claim 31 in pure and isolated form.
34. A pharmaceutically acceptable salt of a compound of Claim 31.
35. A solvate of a compound of Claim 31.
36. A pharmaceutically acceptable ester of a compound of Claim 31.
37. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1 , and a pharmaceutically acceptable carrier.
38. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 31 , and a pharmaceutically acceptable carrier.
39. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1 , and a pharmaceutically acceptable carrier, and and an effective amount of one or more other pharmaceutically active drugs selected form the group consisting of: (a) drugs useful for the treatment of Alzheimer's disease, (b) drugs useful for inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue, (c) drugs useful for treating neurodegenerative diseases, and (d) drugs useful for inhibiting gamma-sθcretase.
40, A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 31 , and a pharmaceutically acceptable carrier, and and an effective amount of one or more other pharmaceutically active drugs selected form the group consisting of: (a) drugs useful for the treatment of Alzheimer's disease, (b) drugs useful for inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue, (c) drugs useful for treating neurodegenerative diseases, and (d) drugs useful for inhibiting gamma-secretase.
41. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1 , and a pharmaceutically acceptable carrier, and an effective amount of one or more BACE inhibitors.
42. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 31 , and a pharmaceutically acceptable carrier, and an effective amount of one or more BACE inhibitors.
43. A pharmaceutical composition:
(1) comprising a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or ester thereof, and at least one pharmaceutically acceptable carrier, or
(2) comprising a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or ester thereof, and at least one pharmaceutically acceptable carrier, and an effective amount of one or more other pharmaceutically active drugs selected form the group consisting of: (a) drugs useful for the treatment of Alzheimer's disease, (b) drugs useful for inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue, (c) drugs useful for treating neurodegenerative diseases, and (d) drugs useful for inhibiting gamma-secretase, or
(3) comprising a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or ester thereof, and at least one pharmaceutically acceptable carrier, and an effective amount of one or more BACE inhibitors,
(4) comprising a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or ester thereof, and at least one pharmaceutically acceptable carrier, and effective amount of one or more cholinesterase inhibitors, or (5) comprising a therapeutically effective amount of at least one compound of claim 1 , and at least one pharmaceutically acceptable carrier, and effective amount of one or more cholinesterase inhibitors, or
(6) comprising a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or ester thereof, and at least one pharmaceutically acceptable carrier, and effective amount of one or more BACE inhibitors, muscarinic antagonists, cholinesterase inhibitors; gamma secretase inhibitors; gamma secretase modulators; HMG-CoA reductase inhibitors; non-steroidal anti-inflammatory agents; N-methyl-D-aspartate receptor antagonists; anti-amyloid antibodies; vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists or CB1 receptor antagonists; an antibiotic; growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABAA inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-10 inhibitors and cholesterol absorption inhibitors, or
(7) comprising a therapeutically effective amount of at least one compound of claim 1 , and at least one pharmaceutically acceptable carrier, and effective amount of one or more BACE inhibitors, muscarinic antagonists, cholinesterase inhibitors; gamma secretase inhibitors; gamma secretase modulators; HMG-CoA reductase inhibitors; non-steroidal anti-inflammatory agents; N-methyl-D- aspartate receptor antagonists; anti-amyloid antibodies; vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists or CB1 receptor antagonists; an antibiotic; growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABAA inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-10 inhibitors and cholesterol absorption inhibitors, or
(8) comprising a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or ester thereof, and at least one pharmaceutically acceptable carrier, and an effective amount of donepezil hydrochloride, or
(9) comprising a therapeutically effective amount of at least one compound of claim 1 , and at least one pharmaceutically acceptable carrier, and an effective amount of donepezil hydrochloride.
44. A method of modulating gamma-secretase comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of such treatment.
45. A method of treating one or more neurodegenerative diseases, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment.
46. A method of inhibiting the deposition of amyloid protein in, on or around neurological tissue, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment.
47. A method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment.
48. A method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 31 to a patient in need of treatment.
49. A method of treating Alzheimer's disease, comprising administering an effective amount of a compound of Claim 1 to a patient in need of treatment.
50. A method of treating Alzheimer's disease, comprising administering an effective amount of a compound of Claim 31 to a patient in need of treatment.
51. A method of (a) modulating gamma-secretase, (b) treating one or more neurodegenerative diseases, (c) inhibiting the deposition of amyloid protein in, on or around neurological tissue, or (d) treating Alzheimer's disease, comprising administering administering:
(1 ) an effective amount of a compound of Claim 1 , and
(2) an effective amount of one or more other pharmaceutically active ingredients selected from the group consisting of: BACE inhibitors, muscarinic antagonists, cholinesterase inhibitors; gamma secretase inhibitors; gamma secretase modulators; HMG-CoA reductase inhibitors; non-steroidal anti-inflammatory agents; N-methyl-D-aspartate receptor antagonists; anti-amyloid antibodies; vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists or CB1 receptor antagonists; an antibiotic; growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABAA inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-10 inhibitors and cholesterol absorption inhibitors, to a patient in need of such treatment.
52. A method of treating Alzheimer's disease, comprising administering an effective amount of a compound of Claim 1 , and an effective amount of one or more compounds selected from the group consisting of Aβ antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors, to a patient in need of such treatment.
53. A method of treating Alzheimer's disease, comprising administering an effective amount of a compound of Claim 1 , and an effective amount of one or more BACE inhibitors, to a patient in need of such treatment.
54. A method of:
(1) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more cholinesterase, to a patient in need of treatment, or
(2) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of donepezil hydrochloride, to a patient in need of treatment, or
(3) treating Alzheimer's disease, comprising administering an effective amount of a compound Claim 1 , in combination with an effective amount of one or more cholinesterase, to a patient in need of treatment, or (4) treating Alzheimer's disease, comprising administering an effective amount of a compound of Claim 1 , in combination with an effective amount of donepezil hydrochloride, to a patient in need of treatment, or (5) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of (rivastigmine, to a patient in need of such treatment, or
(6) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of tacrine, to a patient in need of such treatment, or
(7) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of a Tau kinase inhibitor, to a patient in need of such treatment, or (8) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more Tau kinase inhibitors selected from the group consisting of: GSK3beta inhibitors, cdk5 inhibitors, ERK inhibitors, to a patient in need of such treatment, or (9) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one anti-Abeta vaccination, to a patient in need of such treatment, or
(10) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more APP ligands, to a patient in need of such treatment, or
(11) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more agents that upregulate insulin degrading enzyme and/or neprilysin, to a patient in need of such treatment, or (12) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more cholesterol lowering agents, to a patient in need of such treatment or
(13) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more cholesterol lowering agents selected from the group consisting of: Atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, and Ezetimibe, to a patient in need of such treatment, or (14) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more fibrates, to a patient in need of such treatment, or
(15) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more fibrates selected from the group consisting of, clofibrate, Clofibride, Etofibrate, Aluminium Clofibrate, to a patient in need of such treatment, or
(16) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more LXR agonists, to a patient in need of such treatment, or
(17) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more LRP mimics, to a patient in need of such treatment, or
(18) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more 5-HT6 receptor antagonists, to a patient in need of such treatment, or
(19) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more nicotinic receptor agonists, to a patient in need of such treatment, or
(20) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more H3 receptor antagonists, to a patient in need of such treatment, or
(21) treating Alzheimer's disease, comprising administering an effective amount of one cr more compounds of Claim 1 , in combination with an effective amount of one or more histone deacetylase inhibitors, to a patient in need of such treatment, or (22) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more hsp90 inhibitors, to a patient in need of such treatment, or
(23) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more ml muscarinic receptor agonists, to a patient in need of such treatment, or
(24) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more 5-HT6 receptor antagonists mGluRI or mGluRδ positive allosteric modulators or agonists, to a patient in need of such treatment, or
(25) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more mGluR2/3 antagonists, to a patient in need of such treatment, or
(26) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more anti-inflammatory agents that can reduce neuroinflammation, to a patient in need of such treatment, or (27) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more Prostaglandin EP2 receptor antagonists, to a patient in need of such treatment, or
(28) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more PAI-1 inhibitors, to a patient in need of such treatment, or
(29) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more agents that can induce Abeta efflux, to a patient in need of such treatment, or
(30) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of gelsolin, to a patient in need of such treatment.or
(31) treating Downs syndrome, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment, or
(32) treating Downs syndrome, comprising administering an effective amount of a compound of Claim 1 to a patient in need of treatment, or (33) treating Downs syndrome, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of one or more cholinesterase inhibitors, to a patient in need of treatment.
(34) treating Downs syndrome, comprising administering an effective amount of one or more compounds of Claim 1 , in combination with an effective amount of donepezil hydrochloride, to a patient in need of treatment, or
(35) treating Downs syndrome, comprising administering an effective amount of acompound of Claim 1 , in combination with an effective amount of one or more cholinesterase inhibitors, to a patient in need of treatment. (37) treating Downs syndrome, comprising administering an effective amount of a compound of Claim 1 , in combination with an effective amount of donepezil hydrochloride, to a patient in need of treatment, or
(38) treating mild cognitive impairment, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment, or
(39) treating glaucoma, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment, or
(40) treating cerebral amyloid angiopathy, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment, or
(41 ) treating stroke, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment, or
(42) This invention also provides a method of treating dementia, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment, or
(43) treating microgliosis, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment, or
(44) treating brain inflammation, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment, or (45) treating olfactory function loss, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment.
55. A kit comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of a compound of Claim 1 in a pharmaceutically acceptable carrier, and another container comprises an effective amount of another pharmaceutically active ingredient, the combined quantities of the compound of claim 1 and the other pharmaceutically active ingredient being effective to: (a) treat Alzheimer's disease, or (b) inhibit the deposition of amyloid protein in, on or around neurological tissue, or (c) treat neurodegenerative diseases, or (d) modulate the activity of gamma-secretase.
PCT/US2008/085520 2007-12-06 2008-12-04 Gamma secretase modulators WO2009073779A1 (en)

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CA2707722A CA2707722A1 (en) 2007-12-06 2008-12-04 Gamma secretase modulators
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CN2008801263971A CN101939312A (en) 2007-12-06 2008-12-04 Gamma secretase modulators
EP08857874A EP2229375A1 (en) 2007-12-06 2008-12-04 Gamma secretase modulators
US12/746,313 US20100298359A1 (en) 2007-12-06 2008-12-04 Gamma secretase modulators
MX2010006244A MX2010006244A (en) 2007-12-06 2008-12-04 Gamma secretase modulators.

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JP2011506336A (en) 2011-03-03
US20100298359A1 (en) 2010-11-25

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