WO2006126082A2 - Pyridine [3,4-b] pyrazinones - Google Patents

Pyridine [3,4-b] pyrazinones Download PDF

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WO2006126082A2
WO2006126082A2 PCT/IB2006/001387 IB2006001387W WO2006126082A2 WO 2006126082 A2 WO2006126082 A2 WO 2006126082A2 IB 2006001387 W IB2006001387 W IB 2006001387W WO 2006126082 A2 WO2006126082 A2 WO 2006126082A2
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group
pyrazin
pyrido
formula
alkyl
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WO2006126082A3 (fr
Inventor
Alan George Benson
Andrew Simon Bell
David Graham Brown
David Louis Brown
Yvette Marlene Fobian
John Nicholas Freskos
Steven Edward Heasley
Robert Owen Hughes
Eric Jon Jacobsen
Brent Virgil Mischke
John Major Molyneaux
Dafydd Rhys Owen
Michael John Palmer
Christopher Phillips
Jr. Donald Joseph Rogier
John Keith Walker
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Pharmacia and Upjohn Co LLC
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Pharmacia and Upjohn Co LLC
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Priority to CA002608672A priority Critical patent/CA2608672A1/fr
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Publication of WO2006126082A3 publication Critical patent/WO2006126082A3/fr
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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
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention comprises a class Pyridine [3,4-b] Pyrazinone compounds having the structure of Formula I and pharmaceutical compositions comprising a compound of Formula I.
  • the present invention also comprises methods of treating a subject by administering a therapeutically effective amount of a compound of Formula I to the subject.
  • these compounds inhibit, in whole or in part, the enzyme: cyclic guanylate monophosphate-specific phosphodiesterase type 5 (PDE-5).
  • hypertension is associated with an increased risk of stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease and renal impairment.
  • additional agents useful for the treatment of hypertension are stili needed.
  • vascular endothelial cells secrete nitric oxide (NO). This acts on vascular smooth muscle cells and leads to the activation of guanylate cyclase and the accumulation of cyclic guanosine monophosphate (cGMP).
  • cGMP cyclic guanosine monophosphate
  • the accumulation of cGMP causes the muscles to relax and the blood vessels to dilate, leading to a reduction in blood pressure.
  • the cGMP is inactivated by hydrolysis to guanosine 5'-monophosphate (GMP) by a cGMP-specific phosphodiesterase.
  • PDE5 Phosphodiesterase type 5
  • Inhibitors of PDE5 decrease the rate of hydrolysis of cGMP and so potentiate the actions of nitric oxide. Improved drug therapies for the treatment of subjects suffering from or susceptible to a cardiovascular condition are desirable. In particular, there still is a need for a new class of PDE- 5 inhibitors for treating cGMP-mediated conditions and corresponding drug therapies.
  • the invention comprises compounds having the structure of Formula I:
  • R 2 , X 6 , Y 6 , R 6 , and R 8 are as defined in the detailed description of the invention.
  • the invention comprises a pharmaceutical composition comprising a compound having the structure of Formula I.
  • the invention comprises methods of treating a condition in a subject by administering a therapeutically effective amount of a compound having the Formula I to the subject.
  • the conditions that can be treated in accordance with the present invention include cardiovascular diseases, metabolic diseases, central nervous system diseases, pulmonary diseases, sexual dysfunction, and renal dysfunction.
  • the invention comprises a method for inhibiting PDE-5, and particularly methods for treating a condition (typically a pathological condition) mediated by PDE- 5 activity by administering a compound having a structure of Formula I to the subject.
  • the invention comprises intermediates useful in the synthesis of compounds having the structure of Formula I.
  • the symbol “ ⁇ ” refers to a 1 H NMR chemical shift.
  • the abbreviation “br” refers to a broad 1 H NMR signal.
  • the abbreviation "d” refers to a doublet 1 H NMR peak.
  • dd refers to a doublet of doublets 1 H NMR peak.
  • HRMS High Resolution Mass Spectrocopy (electrospray ionisation positive scan).
  • m refers to a multiplet 1 H NMR peak.
  • q refers to a quartet 1 H NMR peak.
  • the abbreviation “s” refers to a singlet 1 H NMR peak.
  • the abbreviation T refers to a triplet 1 H NMR peak.
  • the abbreviation TFA refers to trifluoroacetic acid.
  • alkyl refers to a linear or branched- chain saturated hydrocarbyl substitutent (i.e., a substitutent containing only carbon and hydrogen) typically containing from about one to about twenty carbon atoms or; in another embodiment from about one to about twelve carbon atoms; in another embodiment, from about one to about ten carbon atoms; in another embodiment, from about one to about six carbon atoms; and in another embodiment, from about one to about four carbon atoms.
  • hydrocarbyl substitutent i.e., a substitutent containing only carbon and hydrogen
  • substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, iso-amyl, hexyl and the like.
  • alkenyl refers to a linear or branched- chain hydrocarbyl substituent containing one or more double bonds and from about two to about twenty carbon atoms; in another embodiment, from about two to about twelve carbon atoms;in another embodiment, from about two to about six carbon atoms; and in another embodiment, from about two to about four carbon atoms.
  • alkenyl radicals include ethenyl, allyl, propenyl, butenyl and 3-methyIbutenyl.
  • alkenyl and “lower alkenyl”, embrace radicals having “cis” and “trans” orientations;- or alternativelyr-Z ⁇ -and-E" orientations ⁇
  • alkynyl refers to linear or branched- chain heterocarbyl substituents containing one or more triple bonds and from about two to about twenty carbon atoms; in another embodiment, from about two to about twelve carbon atoms; in another embodiment, from about two to about six carbon atoms; and in another embodiment, from about two to about four carbon atoms.
  • alkynyl radicals include 1-propynyl, 2- propynyl, 1-butyne, 2-butynyl and 1-pentynyl.
  • amino alone or in combination with another term(s), refers to -NH 2 when it is at a terminal position or to -NH — when it is used in combination with another term(s) and is not at a terminal position.
  • aryl alone or in combination with another term(s), refers to a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
  • aryl moieties include phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl.
  • carboxy alone or in combination with another term(s), refers to a radical of the formula -C(O)OH.
  • cyano alone or in combination with another term(s), means -CN, which also may
  • cycloalkyl refers to saturated carbocyclic radicals having three to about twelve carbon atoms.
  • cycloalkyl radicals are "lower cycloalkyl” radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • cycloalkylalkyl refers to alkyl substituted with cycloalkyl.
  • substituents include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.
  • cycloalkenyl alone or in combination with another term(s), refers to a partially unsaturated carbocyclyl substituent. Examples of such substituents include cyclobutenyl, cyclopentenyl, and cyclohexenyl.
  • halogen or "halo", alone or in combination with another term(s), refers to means a fluorine radical (which may be depicted as -F), chlorine radical (which may be depicted as -Cl), bromine radical (which may be depicted as -Br), or iodine radical (which may be depicted as -I).
  • the halogen is a fluorine or chlorine radical.
  • the halogen is a fluorine radical.
  • halo indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen radicals.
  • haloalkyl refers to an alkyl substituent wherein at least one hydrogen radical is replaced with a halogen radical.
  • halogens- may be-the same-or-different.
  • -haloalkyls include chloromethyl, dichloromethyl, difluorochloromethyl, dichlorofluoromethyl, trichloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trif luoroethyl , difluoroethyl, pentafluoroethyl, difluoropropyl, dichloropropyl, and heptafluoropropyl.
  • haloalkoxy means an alkoxy substituent wherein at least one hydrogen radical is replaced by a halogen radical.
  • haloalkoxy substituents include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as "perfluoromethyloxy"), and 2,2,2, -trifluoroethoxy. If a substituent is substituted by more than one halogen radical, those halogen radicals may be identical or different (unless otherwise stated).
  • heterocyclyl refers to a saturated, partially saturated, or completely unsaturated ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
  • a heterocyclyl may be a single ring, which typically contains from 3 to 10 ring atoms, more typically from 3 to 7 ring atoms, and even more typically 5 to 6 ring atoms.
  • single-ring heterocyclyls include furanyl, dihydrofurnayl, tetradydrofurnayl, thiophenyl (also known as "thiofuranyl"), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazo
  • oxazinyl including 1 ,2,3-oxazinyl, 1 ,3,2-oxazinyl, 1 ,3,6-oxazinyl (also known as "pentoxazolyl"), 1 ,2,6-oxazinyl, or 1 ,4-oxazinyl), isoxazinyl (including o-isoxazinyl or p-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including 1 ,2,5-oxathiazinyl or 1 ,2,6-oxathiazinyl), oxadiazinyl (including 1 ,4,2-oxadiazinyl or 1 ,3,5,2-oxadiazinyI), morpholinyl, azepinyl, oxepinyl, thiepinyl, and diaze
  • a heterocyclyl alternatively may comprise 2 or 3 rings fused together, wherein at least one such ring contains a heteroatom as a ring atom (e.g., nitrogen, oxygen, or sulfur).
  • 2-fused-ring heterocyclyls include, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyr
  • fused-ring heterocyclyls include benzo-fused heterocyclyls, such as indolyl, isoindolyl (also known as “isobenzazolyl” or “pseudoisoindolyl”), indoleninyl (also known as “pseudoindolyl”), isoindazolyl (also known as “benzpyrazolyl”), benzazinyl (including quinolinyl (also known as “1 -benzazinyl”) or isoquinolinyl (also known as "2-benzazinyl”)), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (also known as “1 ,2-benzodiazinyl”) or quinazolinyl (also known as “1 ,3-benzodiazinyP')), benzopyranyl (including “chromanyi” or “isochromanyl)
  • heteroaryl refers to a completely unsaturated (i.e., aromatic) heterocyclyl containing from 5 to 14 ring atoms.
  • a heteroaryl may comprise a single ring or 2 or 3 fused rings.
  • heteroaryl radicals are 5- or 6- membered heteroaryl, containing one or two heteroatoms selected from sulphur, nitrogen and oxygen, selected from thienyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl and pyrazinyl.
  • heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as 1 ,3,5-, 1 ,2,4- or 1 ,2,3-triazinyI, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, and thiazolyl; 1 ,2,3-, 1 ,2,4-, 1 ,2,5-, or 1 ,3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused rings such as 1 ,2-, 1 ,4-
  • heteroaryls include unsaturated 5 to 6 membered heteromonocyciyl groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1 ,2,4-triazolyl, 1 H-1 ,2,3-triazolyl, 21-1-1 ,2,3- triazolyl]; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1 ,
  • benzoxazolyl, benzoxadiazoly ⁇ unsaturated- ⁇ -to- ⁇ -membered-heteromonocyclic groups containing 1-to 2 sulfur atoms and 1 to 3 nitrogen atoms for example, thiazolyl, thiadiazolyl [e.g., 1 ,2,4- thiadiazolyl, 1 ,3,4-thiadiazolyl, 1 ,2,5-thiadiazolyl]; unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl] and the like.
  • the term also embraces radicals where heterocyclic radicals are fused with aryl radicals.
  • fused bicyclic radicals examples include benzofuran, benzothiophene, and the like.
  • heterocyclylalkyl alone or in combination with another term(s), refers to alkyl substituted with a heterocyclyl.
  • hydroxy alone or in combination with another term(s), refers to -OH.
  • mercapto or “thiol” refers to a sulfhydryl substituent, which also may depicted as - SH.
  • nitro alone or in combination with another term(s) refers to -NO 2 .
  • sulfonyl alone or in combination with another term(s), refers to -S(O) 2 -, which also may be depicted as:
  • alkyl-s u If onyl-al kyl refers to alkyl-S(O) 2 -alkyl.
  • alkyl-S(O) 2 -alkyl examples include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.
  • sulfoxyl alone or in combination with another term(s), refers to -S(O) -, which also may be depicted as:
  • thio or "thia”, alone or in combination with another term(s), refers to a thiaether substituent, i.e., an ether substituent wherein a divalent sulfur atom is in the place of the ether oxygen atom. Such a substituent may be depicted as -S-. This, for example, "alkyl-thio-alkyl” means alkyl-S-alkyl.
  • substituent may be either (1) not substituted, or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the carbon (to the extent there are any) may separately and/or together be replaced with an independently selected optional substituent.
  • substituent and “radical” interchangeably.
  • cGMP-mediated condition refers to any condition mediated by cGMP, whether through direct regulation by cGMP, or through indirect regulation by cGMP as a component of a signaling pathway.
  • composition refers to an article of manufacture which results from the mixing or combining of more than one element or ingredient.
  • hypertensive subject refers to a subject having hypertension, suffering from the effects of hypertension or susceptible to a hypertensive condition if not treated to prevent or control such hypertension.
  • pharmaceutically acceptable carrier refers to a carrier that is compatible with the other ingredients of the composition and is not deleterious to the subject. Such carriers may be pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a chemical agent. The preferred composition depends on the method of administration.
  • prevention refers to either preventing the onset of a preclinically evident condition altogether or preventing the onset of a preclinical evident stage of a condition in a subject. Prevention includes, but is not limited to, prophylactic treatment of a subject at risk of developing a condition.
  • terapéuticaally effective amount refers to that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician.
  • treatment includes palliative, restorative, and preventative treatment of a subject.
  • palliative treatment refers to treatment that eases or reduces the effect or intensity of a condition in a subject without curing the condition.
  • preventative treatment refers to treatment that prevents the occurrence of a condition in a subject.
  • restorative treatment refers to treatment that halts the progression of, reduces the pathologic manifestations of, or entirely eliminates a condition in a subject.
  • the present invention comprises, in part, a novel class of pyridine [3,4-b] pyrazinone compounds. These compounds are useful as inhibitors of PDE5.
  • compounds of the present invention include tautomers of the compounds and pharmaceutically acceptable salts of the compounds and tautomers.
  • the present invention is directed, in part, to a class of compounds having the structure of Formula I:
  • R 2 is selected from the group consisting of aryl and 3 to 10 membered ring heterocycyl wherein R 2 may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, oxo, alky], alkenyl, alkynyl, cycloalkyl, -OR 100 , -C(O)R 100 , -OC(O)R 100 , -C(O)OR 100 , -NR 100 R 101 , -N(R 100 )C(O)R 101 , -C(O)NR 100 R 101 , - C(O)NR 100 C(O)R 101 , -SR 100 -S(O)R 100 and -S(O) 2 R 100 , aziridinyl, azetidinyl, pyrrolidinyl, piperidi ⁇ yl, morpholinyl, thiomorpholinyl, and piperazinyl wherein
  • R 100 , R 101 and R 102 are independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl, wherein the alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, alkoxy, -C(O)OH and - C(O)NH 2 ;
  • X 6 is selected from the group consisting of hydrogen and alkyl wherein the X 6 alkyl substituent may be optionally substituted with one or more substituents selected from the group consisting of chloro, fluoro, hydroxy and alkoxy;
  • Y 6 represents a bond or is selected from the group consisting of alkyl, alkenyl and alkynyl, wherein Y 6 may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, cycloalkyl, -OR 103 , -C(O)R 103 , -C(O)OR 103 , - OC(O)R 103 , -NR 103 R 104 , -N(R 103 )C(O)R 104 , and -C(O)NR 103 R 104 ;
  • R 103 and R 104 are independently selected from the group consisting of hydrogen and alkyl, wherein the alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy;
  • R 6 is selected from the group consisting of aryl, aryl-C(O)-, heterocyclyl, aryl-C(O)-NR 105 -, heterocyclyl-C(O)-, and heterocyclyl-C(O)-NR 105 - wherein R 6 may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, alkenyl, aikynyl, cycloalkyl, aryi, heterocyclyl, -OR 106 , -C(O)R 106 , -C(O)OR 106 , - OC(O)R 106 , -NR 106 R 107 , -N(R 106 )C(O)R 107 , -C(O)NR 106 R 107 , -C(O)NR 106 C(O)R 107 , -SR 106 , - S(
  • R 105 is independently selected from the group consisting of hydrogen and alkyl
  • R 106 and R 107 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl, wherein (a) the R 106 and R 107 alkyl and alkenyl substituents may be optionally substituted with one or more substituents independently selecied from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy, and (b) the R 106 and R 107 alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy;
  • R 8 is alkyl; wherein R 6 may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, alkynyl, - OR 108 , -C(O)R 108 , -C(O)OR 108 , -OC(O)R 108 , -NR 108 R 109 , -N(R 108 )C(O)R 109 , -C(O)NR 108 R 109 , - SR 108 , -S(O)R 108 , -S(O) 2 R 108 , and -C(O)NR 108 C(O)R 109 , wherein the alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkyl, and alkoxy; and R 108 and R 109 are independently
  • R 2 is selected from the group consisting of aryl and 3 to 10 membered ring heterocycyl wherein R 2 may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, -OR 100 , -C(O)R 100 , -OC(O)R 100 , -C(O)OR 100 , -NR 100 R 101 , - N(R 100 )C(O)R 101 , -C(O)NR 100 R 101 , -C(O)NR 100 C(O)R 101 , and -S(O) m R 100 wherein the alkyl, alkenyl, alkynyl and cycloalkyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo,
  • R 2 is selected from the group consisting of phenyl and a 3 to 10 membered ring heteroaryl, optionally substituted as described in Formula I. In another embodiment of Formula I, R 2 is selected from the group consisting of phenyl and a 5 to 7 membered ring heterocyclyl, optionally substituted as described in Formula I. In another embodiment of Formula I, R 2 is selected from the group consisting of phenyl and a 5 to 7 membered ring heteroaryl, optionally substituted as described in Formula I. In another embodiment of Formula I, R 2 is selected from the group consisting of phenyl and a 5-6 membered ring heteroaryl, optionally substituted as described in Formula I. In another embodiment of Formula I, R 2 is a 5 to 6 membered ring heteroaryl that comprises 1 , 2, or 3 ring heteroatoms selected from the group consisting of oxygen and nitrogen.
  • R 2 is selected from the group consisting of phenyl, thienyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrazinyl pyridinyl, triazinyl, imidazyl, thiophenyl, pyrazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrazyl, pyrimidinyl, pyridazinyl, benzofuran, and benzodioxolyl.
  • R 2 is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, isoxazolyl, pyrazolyl, benzofuran, and benzodioxolyl, optionally substituted as described in Formula I.
  • R 2 is selected from the group consisting of phenyl,
  • R 2 is selected from the group consisting of phenyl and pyridinyl, optionally substituted as described in Formula I.
  • R 2 is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, alkyl, -OR 100 , -C(O)R 100 , -OC(O)R 100 , - C(O)OR 100 , -NR 100 R 101 and -C(O)NR 100 R 101 , wherein the alkyl substitutent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OR 102 , and -C(O)OR 102 ; wherein R 100 , R 101 , and R 102 are independently selected from the group consisting of hydrogen and C 1 to C 4 alkyl.
  • R 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, C 1 to C 4 alkyl, -OR 100 , -C(O)OR 100 , and -C(O)NR 100 R 101 , wherein (a) when the alkyl is methyl, the methyl may be optionally substituted with 1 , 2, or 3 halogen substituents, (b) when the alkyl comprises at least two carbon atoms, the alkyl may be optionally substituted with one or more substituents selected from the group consisting of halogen, C-i to C 4 alkoxy and hydroxy; and wherein R 100 and R 101 are independently selected from the group consisting of hydrogen and C 1 to C 2 alkyl.
  • substituents independently selected from the group consisting of halogen, cyano, oxo, C 1 to C 4 alkyl, -OR 100 , -C(O)OR 100 , and -C(O)
  • R 2 is optionally substituted with one or more substituents selected from the group consisting of halogen, C 1 to C 4 alkyl, -OR 100 , and - NR 100 R 101 ; wherein (a) when the alkyl is methyl, the methyl may be optionally substituted with 1 , 2, or 3 halogen substituents, (b) when the alkyl comprises at least two carbon atoms, the alkyl may be optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, C-i to C 2 alkoxy and hydroxy; and wherein R 100 and R 101 are independently selected from the group consisting of hydrogen and C 1 to C 2 alkyl.
  • R 2 is optionally substituted with one or more substituents selected from the group consisting of chloro, fluoro, methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluoromethyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, amino, methylamino, dimethylamino, ethylamino, and diethylamino.
  • R 2 is optionally substituted with one or more substituents selected from the group consisting of fluoro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, amino, methylamino, and dimethylamino.
  • R 2 is substituted with one or more fluoro substituents. In another embodiment of Formula I, R 2 is substituted with one fluoro substituent. In another embodiment of Formula I, R 2 is substituted with two fluoro substituents. In one embodiment of Formula I, R 2 is substituted with methoxy. In one embodiment of Formula I, R 2 is substituted at the para position with a substituent selected from the group consisting of fluoro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, amino, methylamino, and dimethylamino. In another embodiment of Formula I, R 2 is substituted at the para position with a substituent selected from the group consisting of fluoro, methyl, trifluoromethyl, methoxy, and trifluoromethoxy.
  • R 2 is selected from the group in Table A consisting of Formula I-A, Formula I-C, Formula I-G, Formula I-H, Formula l-l, Formula I-J, Formula I-K, Formula I-L, Formula I-M, Formula I-N, Formula 1-0, Formula I-P, Formula I-Q and Formula I-R, wherein R 9 , R 10 , R 11 , R 12 and R 13 are independently selected from the group consisting of hydrogen, halogen, oxo, alkyl, -OR 100 , -C(O)R 100 , -OC(O)R 100 , -C(O)OR 100 , -NR 100 R 101 and - C(O)NR 100 R 101 , wherein the alkyl substitutent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OR 102 , and - C(O)OR 102 ; wherein R 100 , R 101 , R 101
  • R 2 is selected from the group in Table A consisting of Formula I-H, Formula I-A and Formula I-L, wherein R 9 , R 10 , R 11 , R 12 and R 13 are independently selected from the group consisting of hydrogen, halogen, oxo, alkyl, - OR 100 , -C(O)R 100 , -OC(O)R 100 , -C(O)OR 100 , -NR 100 R 101 and -C(O)NR 100 R 101 , wherein the alkyl substitutent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OR 102 , and -C(O)OR 102 ; wherein R 100 , R 101 , and R 102 are independently selected from the group consisting of hydrogen and C 1 to C 4 alkyl.
  • R 2 is selected from the group in Table A consisting of Formula I-A, Formula I-D, Formula I-H and Formula I-L, wherein R 9 , R 10 , R 11 , R 12 and R 13 are independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, oxy, alkoxy, hydroxy, and carboxy.
  • R 2 is selected from the group in Table A _consisting.of Formula I-A, .
  • Formula I-C, Formula I-D and Formula I-H wherein R 9 , R 10 , R 11 , R 12 and R 13 are independently selected from the group consisting of hydrogen, fluoro, methyl, trifluoromethyl, and methoxy.
  • R 2 is selected from the group in Table A consisting of Formula I-D and Formula I-H, wherein R 9 , R 10 . R 11 , R 12 and R 13 are independently selected from the group consisting of hydrogen, fluoro, methyl, trifluoromethyl, and methoxy.
  • R 2 is as described by the structures in Table A consisting of Formula I-D and Formula I-H wherein R 9 , R 10 , R 11 , R 12 and R 13 are independently selected from the group consisting of hydrogen, fluoro, methyl, trifluoromethyl, and methoxy.
  • R 2 is as described in Formula I-D in Table A, wherein R 11 is selected from the group consisting of hydrogen, fluoro, methyl, trifluoromethyl, and methoxy.
  • the R 2 substituent is as described in Formula I-E in Table A.
  • X 6 is selected from the group consisting of hydrogen and Ci to C 4 alkyl wherein the X 6 C 1 to C 4 alkyl substituent may be optionally substituted with one or more substituents selected from the group consisting of chloro, fluoro, hydroxy and alkoxy.
  • X 6 is alkyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluoro and chloro.
  • X 6 alkyl is optionally substituted with 1 to 3 fluoro substituents.
  • X 6 is selected from the group consisting of hydrogen and C 1 to C 6 alkyl. In another embodiment of Formula I, X 6 is selected from the group consisting of hydrogen, methyl, and ethyl. In another embodiment, X 6 is hydrogen.
  • Y 6 represents a bond or is selected from the group consisting of alkyl, alkenyl and alkynyl, wherein the Y 6 alkyl, alkenyl and alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, cycloalkyl, -OR 103 , -C(O)R 103 , -C(O)OR 103 , -OC(O)R 103 , - NR 103 R 104 , -N(R 103 )C(O)R 104 , and -C(O)NR 103 R 104 ; and wherein R 103 and R 104 are independently selected from the group consisting of hydrogen and alkyl, wherein the alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, ox
  • Y 6 represents a bond or is alkyl, optionally substituted as described in Formula I. In another embodiment of Formula I, Y 6 represents a bond or is C 1 to C 6 alkyl, optionally substituted as described in Formula I. In another embodiment of Formula I, Y 6 represents a bond or is selected from the group consisting of C 1 to C 4 alkyl and hydroxy ⁇ to C 6 . alkyl. In another embodiment of Formula I, Y 6 represents a bond or is selected from the group consisting of methyl, ethyl, propyl, butyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, djJnydroxyethyLand dihydrpxybutyl.
  • Y 6 represents a bond or is selected from the group consisting of methyl, ethyl, propyl, butyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, dihydroxyethyl,
  • Y 6 represents a bond or is selected from the group consisting of methyl, ethyl, propyl and butyl. In another embodiment of Formula I, Y 6 represents a bond. In one embodiment of Formula I, Y 6 is alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, cycloalkyl, -OR 103 , -C(O)R 103 , -C(O)OR 103 , -OC(O)R 103 , -NR 103 R 104 , -N(R 103 )C(O)R 104 , and -C(O)NR 103 R 104 ; wherein R 103 and R 104 are independently selected from the group consisting of hydrogen and C-i to C 4 alkyl.
  • Y 6 is alkyl substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, oxo, cycloalkyl, hydroxy, and carboxy. In another embodiment of Formula I, Y 6 is alkyl substituted with one to three substituents independently selected from the group consisting of hydroxy and cyclohexyl. In another embodiment of Formula I, Y 6 is unsubstituted alkyl. In another embodiment of Formula I, Y 6 is selected from the group consisting of methyl, ethyl and propyl. In another embodiment, Y 6 is selected from the group consisting of -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -
  • R 6 is selected from the group consisting of phenyl, phenyl- C(O)-, 3 to 10 membered ring heterocyclyl, phenyl-C(O)-NR 105 -, 3 to 10 membered ring heterocyclyl-C(O)-, and 3 to 10 membered ring heterocyclyl-C(O)-NR 105 -, wherein R 6 is optionally substituted as described in Formula I, wherein R 105 is selected from the group consisting of hydrogen and C 1 to C 6 alkyl.
  • R 6 is selected from the group consisting of phenyl, phenyl-C(O)-, 5 to 7 membered ring heterocyclyl, phenyl-C(O)-NR 105 -, 5 to 7 membered ring heterocyclyl-C(O)-, and 5 to 7 membered ring heterocyclyl-C(O)-NR 105 -, wherein R 6 is optionally substituted as described in Formula I, wherein R 105 is selected from the group consisting of hydrogen and Ci to C 4 alkyl.
  • R 6 is selected from the group consisting of phenyl, phenyl-C(O)-, 5 to 6 membered ring heterocyclyl, phenyl-C(O)-NR 105 -, 5 to 6 membered ring heterocyclyl-C(O)-, and 5 to 6 membered ring heterocyclyl-C(O)-NR 105 -, wherein R 6 is optionally substituted as described in Formula I wherein R 105 is hydrogen.
  • R 6 is selected from the group consisting of phenyl, pyridinyl, piperidinyl, piperizinyl, morpholino, pyrazinyl, tetrahydropyran, tetrahydrofuran, isoxazole, imidazole, pyrrolidine, wherein R 6 is optionally substituted as described in Formula I.
  • R 6 is selected from the group consisting of morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, and pyrrolidinyl, wherein R 6 is optionally substituted as provided in Formula I.
  • R 6 is selected from the group consisting of phenyl, phenyl C(O)NH-, and phenyl C(O)-.
  • R 6 is selected from the group consisting of 5 to 7 membered ring heteroaryl, 5 to 7 membered ring heteroaryl-C(O)-, and 5 to 7 membered ring heteroaryl-C(O)-NR 105 -, wherein R 6 is optionally substituted as described in Formula I, wherein R 105 is selected from the group consisting of hydrogen and C-i to C 4 alkyl.
  • R 6 is a 3 to 10 membered ring heteroaryl, optionally substituted as described in Formula I.
  • R 6 is a 5 to 7 membered ring heteroaryl, optionally substituted as described in Formula I.
  • R 6 is a 5 to 6 membered ring heteroaryl, optionally substituted as described in Formula I.
  • R 6 is a 5 to 6 membered ring heteroaryl containing one to three heteroatoms selected from the group consisting of O and N, optionally substituted as described in Formula I.
  • R 6 is selected from the group consisting of imidazole, isoxazole, pyridinyl and pyrazynyl, optionally substituted as described in Formula I.
  • R 6 is selected from the group consisting of imidazole, isoxazole, pyridinyl and pyrazynyl, optionally substituted with one or more substituents independently selected from the group consisting of alkyl, -OR 105 , and -C(O)R 105 , wherein R 105 is selected from the group consisting of hydrogen, methyl, and ethyl.
  • R 6 is selected from the group consisting of imidazole, isoxazole, pyridinyl and pyrazynyl, optionally substituted with one or more substituents independently selected from the group consisting of alkyl, -OR 105 , and -C(O)R 105 , wherein R 105 is selected from the group consisting of hydrogen, methyl, and ethyl.
  • R 6 is selected from the group consisting of imidazole, isoxazole, pyridinyl and pyrazynyl, optionally substituted with one or more
  • R 6 is selected from the group consisting of 3 to 10 membered ring fully or partially saturated heterocylyl, 3 to 10 membered ring fully or partially 5 saturated heterocyclyl-C(O)-, 3 to 10 membered ring fully or partially saturated heterocyclyl- C(O)NH-, optionally substituted as described in Formula I.
  • R 6 is a 5 to 7 membered ring fully or partially saturated heterocylyl, 5 to 7 membered ring fully or partially saturated heterocyclyl-C(O)-, 5 to 7 membered ring fully or partially saturated heterocyclyl-C(O)NH-, wherein R 6 is optionally substituted as described in Formula I.
  • R 6 is optionally substituted as described in Formula I.
  • R 6 is a 5 to 6 membered ring fully saturated heterocylyl, 5 to 6 membered ring fully saturated heterocyclyl-C(O)-, 5 to 6 membered ring fully saturated heterocyclyl-C(O)NH-, wherein R 6 is optionally substituted as described in Formula I.
  • R 6 is a 5 to 6 membered ring fully saturated heterocylyl, wherein R 6 is optionally substituted as described in Formula I.
  • R 6 is
  • R 6 is selected from the group consisting of tetrahydrofuran, tetrahydropyran, pyrrolidinyl, piperidinyl, piperazinyl, and morpholino, wherein R 6 is optionally substituted with one or more substituents independently selected from the group consisting of
  • R 105 is selected from the group consisting of hydrogen, methyl, and ethyl.
  • R 6 is selected from the group consisting
  • R 6 is optionally substituted with one or more substituents independently selected from the group consisting of -OR 106 , -C(O)R 106 , -C(O)OR 106 , -NR 106 R 107 , -N(R 106 )C(O)R 107 , -N(R 106 )C(O)OR 107 , -C(O)NR 106 R 107 , -NHC(O)NR 106 R 107 , - N(R 106 )S(O) 2 R 107 , wherein R 106 and R 107 are independently selected from the group consisting of hydrogen, methyl, ethyl, methylethyl, tert-butyl, cyclopentyl, cyclohexyl, optionally substituted with one or more substituent selected from the group consisting of halogen, oxo, hydroxy, and methyl.
  • R 6 is optionally substituted with one or more substituents independently selected from the group consisting of -OH, -OCH 3 , -OCH 2 CH 3 , - OCH 2 (CH 3 )CH 3 , -C(O)CH 2 CH 2 OH, -C(O)OH, -C(O)OCH 2 (CH 3 )(CH 3 )(CH 3 ), -NH 2 , -NH(CH 2 CH 3 ), - N(CH 3 )(CH 3 ), -N(CH 2 CH 3 )CH 2 CH 3 , -N(H)CH 2 (CH 3 )CH 3 , -N(H)CH 2 CH 2 CH 2 OH, - N(H)CH 2 C(O)CH 3 , -NH(CH 2 CH 2 OH), -N(H)C(O)OCH 3 , -N(H)C(O)CH 2 (CH 3 )(CH 3 ), -NH(CH 2 CH 2 OH),
  • R 6 is optionally substituted with one or more substituents independ-ently selected from the group consisting of alkyl, -C(O)R 106 and -C(O)OR 106 , wherein R 106 is selected from the group consisting of hydrogen, methyl, and ethyl.
  • R 6 is optionally substituted with one or more substituents independently selected from the group consisting of -OH, -CH 3 , - CH 2 CH 3 , -C(O)CH 3 , -C(O)CH 2 CH 3 , -C(O)OCH 2 CH 3 .
  • R 8 is alkyl; wherein the R 8 substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, alkynyl, -OR 108 , -SR 108 , -C(O)R 108 , -C(O)OR 108 , -OC(O)R 108 , - NR 108 R 109 , -N(R 108 )C(O)R 109 , -C(O)NR 108 R 109 , and -C(O)NR 108 C(O)R 109 , wherein the alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkyl, and alkoxy; and wherein R 108 and R 109 are independently selected from the group consisting of hydrogen, alkyl
  • R 8 is C 1 to C 10 alkyl, optionally substituted as described in Formula I. In another embodiment of Formula I, R 8 is Ci to C 8 alkyl, optionally substituted as described in Formula I. In another embodiment of Formula I, R 8 is C 1 to C 6 alkyl, optionally substituted as described in Formula I. In another embodiment of Formula I, R 8 is C 1 to C 4 alkyl, optionally substituted as described in Formula I. In another embodiment of Formula I, R 8 is ethyl, optionally substituted as described in Formula I.
  • R 8 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, -OR 108 , - C(O)R 108 , -C(O)OR 108 , -OC(O)R 108 , -NR 108 R 109 , -N(R 108 )C(O)R 109 , -C(O)NR 108 R 109 , and - C(O)NR 108 C(O)R 109 , wherein R 108 and R 109 are independently selected from the group consisting of hydrogen and C 1 to C 6 alkyl, wherein (a) when the C-i to C 6 alkyl is methyl, the methyl may be optionally substituted with 1 , 2, or 3 fluoro substituents, (b) when the C 1 to C 6 alkyl comprises at least two carbon atoms, the alkyl may be optionally substituted with one or more substituents
  • R 8 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, alkoxy, haloalkyl, hydroxyalkyl, carboxyalkyl, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy.
  • R 8 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, haloalkoxy, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • R 8 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, haloalkoxy, hydroxy, oxo, and alkoxy. In another embodiment of Formula I, R 8 is optionally substituted with one or more substituents independently selected from the group consisting of haloalkoxy and alkoxy. In another embodiment of Formula I, R 8 is ethyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, haloalkoxy, hydroxy, carboxy, cyano, oxo, and alkoxy. In another embodiment of Formula I, R 8 is ethyl optionally substituted with one or more substituents independently selected from the group consisting of haioalkoxy and alkoxy.
  • R 8 is alkoxyalkyl, optionally substituted as described in Formula I.
  • R 8 is a (C 1 to C ⁇ aIkOXy(C 1 to C 4 )alkyl, optionally substituted as described in Formula I.
  • R 8 is methoxyethyl, as described in Formula I-Y in Table A.
  • R 8 is ethoxyethyl, as described in Formula I-Z in Table A.
  • R 8 is propoxyethyl, as described in Formulae I-AA and I-BB in Table A.
  • R 8 is trifluoroethoxyethyl.
  • R 8 is selected from the group consisting of propoxyethyl and ethoxyethyl as described in Formulae I-Z, I-AA and I-BB in Table A, respectively.
  • R 2 is selected from the group consisting of phenyl, thienyl, furanyl, thiazolyl, imidazolyl, pyrazoiyl, isoxazolyl, isothiazolyl, pyrazinyl pyridinyl, triazinyl, imidazyl, thiophenyl, pyrazoiyl, oxazolyl, oxadiazolyl, pyridyl, pyrazyl, pyrimidinyl, pyridazinyl, benzofuran, and benzodioxolyl.
  • X 6 is hydrogen and R 2 is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, isoxazolyl, pyrazoiyl, benzofuran, and benzodioxolyl.
  • X 6 is hydrogen and R 2 is selected from the group consisting of phenyl, pyridinyl and pyrimidinyl, as described in Formulae l-l, I-B and I-M of Table A.
  • X 6 is hydrogen and R 2 is selected from the group consisting of phenyl and pyridinyl, as described in Formulae l-l and I-B of Table A.
  • X 6 is hydrogen and R 2 is phenyl, as described in Formulae I-B of Table A, wherein R 9 , R 10 R 11 , R 12 and R 13 are independently selected from the group consisting of hydrogen, hydroxy, and fluoro.
  • X 6 is hydrogen and R 2 is pyridinyl, as described in Formulae I-B of Table A, wherein R 9 , R 10 and R 13 are each hydrogen, and R 11 is methoxy.
  • X 6 is hydrogen and R 8 is alkoxyalkyl, optionally substituted as described in Formula I.
  • R 8 is a (Ci to C 4 JaIkOXy(C 1 to C 4 )alkyl, optionally substituted as described in Formula I.
  • X 6 is hydrogen and R 8 is selected from the group consisting of methoxyethyl, ethoxyethyl, and propoxyethyl, optionally substituted as described in Formula I.
  • X 6 is hydrogen and R 8 is selected from the group consisting of methoxyethyl, ethoxyethyl, propoxyethyl, and trifluoroethylethoxy.
  • R 8 is selected from the group consisting of propoxyethyl and ethoxyethyl, as described in Formulae I-Z, I-AA and I-BB of Table A, respectively.
  • X 6 is hydrogen
  • R 8 is alkoxyalkyl, optionally substituted as --— — described-in-Formula-l-and-Y— represents-a-bond-or-is-alkyl r optionally-substituted as described in
  • X 6 is hydrogen and R 8 is a (C 1 to C 4 )alkoxy(Ci 20 to C 4 )alkyl, optionally substituted as described in Formula I, and Y 6 represents a bond or is C 1 to C 6 alkyl, optionally substituted as described in Formula I.
  • X 6 is hydrogen
  • R 8 is selected from the group consisting of methoxyethyl, ethoxyethyl, and propoxyethyl, wherein R 8 is optionally substituted as described in Formula I
  • Y 6 represents a bond or is selected from the group consisting of methyl, ethyl, propyl, butyl, methylethyl, tert- 25 butyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, dihydroxyethyl,
  • X 6 is hydrogen
  • R 8 is selected from the group consisting of methoxyethyl, ethoxyethyl, propoxyethyl, and trifluoroethoxyethyl
  • Y 6 represents a bond or is selected from the group consisting of methyl, ethyl, propyl and butyl.
  • X 6 is hydrogen, R 8 is selected from the group consisting of propoxyethyl and ethoxyethyl, and Y 6 represents a bond or is selected from the group consisting of methyl and ethyl.
  • X 6 is hydrogen, R 8 is ethoxyethyl, and Y 6 represents a bond or is selected from the group consisting of methyl and ethyl, as described in Formulae I-GG, I-HH and l-ll in Table A, respectively.
  • X 6 is hydrogen, R 8 is ethoxyethyl, and Y 6 represents a bond or is selected from the group consisting of methyl and ethyl, as described in Formulae I-GG, I-HH and l-ll in Table A, respectively.
  • R 35 is hydrogen, R 8 is propoxyethyl, and Y 6 represents a bond or is selected from the group consisting of methyl and ethyl, as described in Formulae I-OO, I-QQ and I-PP in Table A, respectively.
  • R 8 is alkoxyalkyl
  • R 2 is phenyl or 3-10 membered heterocyclyl
  • R 8 is alkoxyalkyl, optionally substituted as described in Formula I and R 2 is selected from the group consisting of phenyl, thienyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrazinyl pyridinyl, triazinyl, imidazyl, thiophenyl, 5 pyrazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrazyl, pyrimidinyl, pyridazinyl, benzofuran, and benzodioxolyl, wherein R 2 is optionally substituted as described in Formula I.
  • R 8 is a (C 1 to C 4 JaIkOXy(C 1 to C 4 )alkyl, optionally substituted as described in Formula I, and R 2 is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, isoxazolyl, pyrazolyl, benzofuran, and benzodioxolyl, wherein R 2 is optionally
  • R 8 is selected from the group consisting of trifluroethoxyethyl, ethoxyethyl, and propoxyethyl
  • R 2 is selected from the group consisting of phenyl, pyridinyl and pyrimidinyl, wherein R 2 is optionally substituted as described in Formula I.
  • R 8 is selected from the group consisting of ethoxyethyl and propoxyethyl
  • R 2 is selected from the group consisting of
  • R 8 is ethoxyethyl, and R 2 is pyridinyl, optionally substituted as described in Formula I.
  • R 8 is ethoxyethyl and R 2 is a — — methox-y-pyr-idinyl-as-described-in-Formula-l-F-of Table A.
  • R 8 is propoxyethyl and R 2 is a methoxy pyridinyl.
  • X 6 is hydrogen
  • R 8 is alkoxyalkyl, optionally substituted as described in Formula I and R 2 is selected from the group consisting of phenyl, thienyl, furanyl,
  • X 6 is hydrogen
  • R 8 is a (C 1 to C 4 JaIkOXy(C 1 to C 4 )alkyl, optionally substituted as described in Formula I
  • R 2 is selected from the group consisting of phenyl
  • X 6 is hydrogen
  • R 8 is selected from the group consisting of trifluoroethoxyethyl, ethoxyethyl, and propoxyethyl, wherein R 8 is optionally substituted as described in Formula I
  • R 2 is selected from the group consisting of phenyl, pyridinyl and pyrimidinyl, wherein R 2 is optionally substituted
  • X 6 is hydrogen, R 8 is selected from the group consisting of ethoxyethyl and propoxyethyl, and R 2 is selected from the group consisting of phenyl and pyridinyl wherein R 2 is optionally substituted as described in Formula I.
  • X 6 is hydrogen, R 8 is ethoxyethyl, and R 2 is pyridinyl, optionally substituted as described in Formula I.
  • X 6 is
  • R 8 is ethoxyethyl and R 2 is a para-substitued pyridinyl, as described in Formula I-FF of Table A.
  • X 6 is hydrogen, R 8 is propoxyethyl and R 2 is a para-substitued pyridinyl, as described in Formula I-NN of Table A.
  • X 6 is hydrogen, R 8 is propoxyethyl and R 2 is a pyridinyl, substituted at the para position with a methoxy as described in Formula I-UU of Table A.
  • X 6 is hydrogen, R 8 is alkoxyalkyl, Y 6 represents a bond or is alkyl and R 2 is phenyl or 3-10 membered heterocyclyl
  • X 6 is hydrogen
  • Y 6 is a bond or is alkyl, optionally substituted as described in Formula I
  • R 8 is alkoxyalkyl, optionally substituted as described in Formula I
  • R 2 is selected from the group consisting of phenyl, thienyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrazinyl pyridinyl, triazinyl, imidazyl, thiophenyl, pyrazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrazyl, pyrimidinyl, pyridazinyl, benzofuran, and benzodioxolyl, wherein R 2 is optionally substituted as described in Formula I.
  • X 6 is hydrogen
  • Y 6 represents a bond or is C 1 to C 6 alkyl, optionally substituted as described in Formula I
  • R 8 is a (Ci to C ⁇ aIkOXy(C 1 to C 4 )alkyl, optionally substituted as described in Formula I
  • R 2 is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, isoxazolyl, pyrazolyl, benzofuran, and benzodioxolyl wherein R 2 is optionally substituted as described in Formula I.
  • X 6 is hydrogen,-R 8 Js selected .from Jhe-group-consisting of-trifluroethoxyethyl 1 -ethoxyethyl,-and propoxyethyl, optionally substituted as described in Formula I and R 2 is selected from the group consisting of phenyl, pyridinyl and pyrimidinyl wherein R 2 is optionally substituted as described in Formula I.
  • X 6 is hydrogen
  • Y 6 represents a bond or is selected from the group consisting of methyl, ethyl, propyl, butyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, dihydroxyethyl, and dihydroxybutyl
  • R 8 is selected from the group consisting of ethoxyethyl and propoxyethyl
  • R 2 is selected from the group consisting of phenyl and pyridinyl wherein R 2 is optionally substituted as described in Formula I.
  • X 6 is hydrogen, Y 6 represents a bond or is selected from the group consisting of methyl, ethyl, methylethyi, propyl and butyl, R 8 is selected from the group consisting of ethoxyethyl and propoxyethyl, and R 2 is pyridinyl, optionally substituted as described in Formula I.
  • X 6 is hydrogen, Y 6 represents a bond, R 8 is ethoxyethyl and R 2 is a para-substitued pyridinyl, as described in Formula I-LL of Table A.
  • X 6 is hydrogen, Y 6 is methyl, R 8 is ethoxyethyl and R 2 is a para- substitued pyridinyl, as described in Formula I-JJ of Table A.
  • X 6 is hydrogen, Y 6 is ethyl, R 8 is ethoxyethyl and R 2 is a para-substitued pyridinyl, as described in Formula I-KK of Table A.
  • X 6 is hydrogen, Y 6 represents a bond, R 8 is propoxyethyl and R 2 is a para-substitued pyridinyl, as described in Formula I-TT of Table A.
  • X 6 is hydrogen, Y 6 is methyl, R 8 is propoxyethyl and R 2 is a para-substitued pyridinyl, as described in Formula I-RR of Table A.
  • X 6 is hydrogen, Y 6 is ethyl, R 8 is propoxyethyl and R 2 is a para- substitued pyridinyl, as described in Formula I-SS of Table A.
  • X 6 is hydrogen, R 8 is alkoxyalkyl, Y 6 represents a bond or is alkyl and R 2 is phenyl or 3-10 membered heterocyclyl, and R 6 is selected from various embodiments
  • X 6 is hydrogen, Y 6 represents a bond, R 8 is selected from the group consisting of propoxyethyl and ethoxyethyl and R 2 is a para-substitued pyridinyl, R 6 is selected from the group consisting of selected from the group consisting of phenyl, phenyl C(O)NH-, phenyl C(O)-, 3 to 10 membered ring heterocyclyl, phenyl-C(O)-NH-, 3 to 10 membered ring heterocyclyl-C(O)-, and 3 to 10 membered ring heterocyclyl-C(O)-NH, optionally substituted with one or more substituents independently selected from the group consisting of - OR 105 , -C(O)R 105 , -C(O)OR 105 , -NR 105 R 106 , -N(R 105 )C(O)R 106 , -N
  • X 6 is hydrogen, Y 6 is methyl, R 8 is selected from the group consisting of propoxyethyl and ethoxyethyl, and R 2 is a para- substitued pyridinyl, optionally substituted as described in Formula I, and R 6 is selected from the group consisting of phenyl, phenyl C(O)NH-, phenyl C(O)-, 5 to 7 membered ring heterocyclyl, phenyl-C(O)-NH-, 5 to 7 membered ring heterocyclyl-C(O)-, and 5 to 7 membered ring heterocyGlyl-G(0)-NH-optionally-substituted-with-one-or-more-substituents-independently selected from the group consisting of of -OR 106 , -C(O)R 106 , -C(O)OR 106 , -NR 106 R 107 , - N(
  • X 6 is hydrogen
  • Y 6 is ethyl
  • R 8 is selected from the group consisting of propoxyethyl and ethoxyethyl
  • R 2 is a para-substitued pyridinyl, optionally substituted as described in Formula I
  • R 6 is selected from the group consisting of 5 to 6 membered ring heteroaryl, 5 to 6 membered ring heteroaryl-C(O)-, and 5 to 6 membered ring heteroaryl-C(O)- NH, optionally substituted with one or more substituents independently selected from the group consisting of alkyl, -OR 106 , and -C(O)R 106 , wherein R 106 is selected from the group consisting of hydrogen, methyl, and ethyl.
  • X 6 is hydrogen
  • Y 6 is ethyl
  • R 8 is selected from the group consisting of propoxyethyl and ethoxyethyl
  • R 2 is a para-substitued pyridinyl optionally substituted as described in Formula I
  • R 6 is selected from the group consisting of 5 to 6 membered ring fully saturated heterocyclyl, 5 to 6 membered ring fully saturated heterocyclyl-C(O)-, and 5 to 6 membered ring fully saturated heterocyclyl-C(O)-NH, optionally substituted with one or more substituents independently selected from the group consisting of alkyl, -OR 106 , and -C(O)R 106 , wherein R 106 is selected from the group consisting of hydrogen, methyl, and ethyl.
  • R 9 , R 10 , R 11 and R 13 are independently selected from the group consisting of hydrogen, halogen, oxo, alkyl, -OR 100 , -C(O)R 100 , -OC(O)R 100 , -C(O)OR 100 , -NR 100 R 101 and -C(O)NR 100 R 101 , wherein the alkyl substitutent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OR 102 , and -C(O)OR 102 ; wherein R 100 , R 101 , and R 102 are independently selected from the group consisting of hydrogen and C 1 to C 4 alkyl;
  • Y 6 represents a bond or is selected from the group consisting of alkyl, alkenyl and alkynyl, wher r eeiinn ((aa)) tthhee YY 66 aallkkyyll,, aallkkeennyyll aanndd aallkkyynnyyll ssuubbssttiittuueennttss mmaayy bbee ooppttiioonnaallllyy ssuubbssttiittuutteedd wwiitthh oonnee or more substittuuueennttss iinnddeeppeennddeennttllyy sseelleecctteedd ffrroomm tthhee ggrroouupp ccoonnssiissttiinngg ooff hhaallooggeen
  • R 103 and R 104 are independently selected from the group consisting of hydrogen and alkyl, wherein the alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy;
  • R 6 is selected from the group consisting of aryl, aryl-C(O)-, heterocyclyl, aryl-C(O)-NR 105 -, heterocyclyl-C(O)-, and heterocyclyl-C(0)-NR 105 - wherein R 6 may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -OR 106 , -C(O)R 106 , -C(O)OR 106 , - OC(O)R 106 , -NR 106 R 107 , -N(R 106 )C(O)R 107 , -C(O)NR 106 R 107 , -C(O)NR 106 C(O)R 107 , -SR 106 , - S(O)R
  • R 105 is independently selected from the group consisting of hydrogen and alkyl
  • R 106 and R 107 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl
  • substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy
  • the R 106 and R 107 alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy
  • the R 106 and R 107 alkynyl substituents may be optionally substituted with one or more substituents independently selected from the
  • R 8 is alkoxyalkyl, optionally substituted with halogen.
  • R 9 , R 10 , R 11 and R 13 are selected from the group consisting of hydrogen, chloro, fluoro, methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluoromethyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, amino, methylamino, dimethylamino, ethylamino, and diethylamino.
  • R 9 , R 10 , R 11 and R 13 are selected-from-the group-eonsisting-of-hydrOgen r fluoro r methylptrifluoromethyl T -methoxy, trifluoromethoxy, amino, methylamino, and dimethylamino.
  • R 11 and R 13 are hydrogen, and R 9 and R 10 are selected from the group consisting of hydrogen, chloro, fluoro, methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluoromethyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, amino, methylamino, dimethylamino, ethylamino, and diethylamino.
  • R 9 and R 10 are hydrogen, and R 11 and R 13 are selected from the group consisting of hydrogen, methoxy, and fluoro.
  • R 9 R 10 and R 13 are hydrogen, and R 11 is methoxy.
  • Y 6 represents a bond or is selected from the group consisting of alkyl, alkenyl and alkynyl, wherein the Y 6 alkyl, alkenyl and alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, cycloalkyl, -OR 103 , -C(O)R 103 , -C(O)OR 103 , - OC(O)R 103 , -NR 103 R 104 , -N(R 103 )C(O)R 104 , and -C(O)NR 103 R 104 ; and wherein R 103 and R 104 are independently selected from the group consisting of hydrogen and alkyl, wherein the alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyan
  • Y 6 represents a bond or is alkyl, optionally substituted as described in Formula I-B. In another embodiment of Formula I-B, Y 6 represents a bond or is C 1 to C 6 alkyl, optionally substituted as described in Formula I-B. In another embodiment of Formula I-B, Y 6 represents a bond or is selected from the group consisting of C 1 to C 4 alkyl and hydroxy ⁇ to C 4 .alkyl.
  • Y 6 represents a bond or is selected from the group consisting of methyl, ethyl, propyl, butyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, dihydroxyethyl, and dihydroxybutyl. In one embodiment of Formula I-B, Y 6 represents a bond or is selected from the group consisting of methyl, ethyl, propyl and butyl.
  • Y 6 is alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, cycloalkyl, -OR 103 , -C(O)R 103 , -C(O)OR 103 , -OC(O)R 103 , -NR 103 R 104 , -N(R 103 )C(O)R 104 , and -C(O)NR 103 R 104 ; wherein R 103 and R 104 are independently selected from the group consisting of hydrogen and Ci to C 4 alkyl.
  • Y 6 is alkyl substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, oxo, cycloalkyl, hydroxy, and carboxy. In another embodiment of Formula I-B, Y 6 is alkyl substituted with one to three substituents independently selected from the group consisting of hydroxy and cyclohexyl. In another embodiment of Formula I-B, Y 6 is unsubstituted alkyl.
  • Ff Substituent Embodiments of Ff Substituent
  • R 6 is selected from the group consisting of phenyl, phenyl-C(O)-, 3 to 10 membered ring heterocyclyl, phenyl-C(O)-NR 105 -, 3 to 10 membered ring heterocyclyl-C(O)-, and 3 to 10 membered ring heterocyclyl-C(O)-NR 105 -, wherein R 6 is optionally substituted as described in Formula I-B, wherein R 105 is selected from the group consisting of .hydro ⁇ eii.aniLC ⁇ JSe ⁇ alk ⁇ consisting of phenyl, phenyl-C(O)-, 5 to 7 membered ring heterocyclyl, phenyl-C(O)-NR 105 -, 5 to 7 membered ring heterocyclyl-C(O)-, and 5 to 7 membered ring heterocyclyl-C(O)-NR 105 -, wherein R 6 is optionally
  • R 6 is selected from the group consisting of phenyl, phenyl-C(O)-, 5 to 6 membered ring heterocyclyl, phenyl-C(O)-NR 105 -, 5 to 6 membered ring heterocyclyl-C(O)-, and 5 to 6 membered ring heterocyclyl-C(O)-NR 105 -, wherein R 6 is optionally substituted as described in Formula I-B wherein R 105 is hydrogen.
  • R 6 is selected from the group consisting of phenyl, pyridinyl, piperidinyl, piperizinyl, morpholino, pyrazinyl, tetrahydropyran, tetrahydrofuran, isoxazole, imidazole, pyrrolidine, wherein R 6 is optionally substituted as described in Formula I.
  • R 6 is selected from the group consisting of morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, and pyrrolidinyl, wherein R 6 is optionally substituted as provided in Formula I.
  • R 6 is selected from the group consisting of phenyl, phenyl C(O)NH-, and phenyl C(O)-
  • R 6 is selected from the group consisting of 5 to 7 membered ring heteroaryl, 5 to 7 membered ring heteroaryl-C(O)-, and 5 to 7 membered ring heteroaryl-C(O)-NR 105 -, wherein R 6 is optionally substituted as described in Formula I, wherein R 105 is selected from the group consisting of hydrogen and C 1 to C 4 alkyl.
  • R 6 is a 3 to 10 membered ring heteroaryl, optionally substituted as described in Formula I.
  • R 6 is a 5 to 7 membered ring heteroaryl, optionally substituted as described in Formula I.
  • R 6 is a 5 to 6 membered ring heteroaryl, optionally substituted as described in Formula I.
  • R 6 is a 5 to 6 membered ring heteroaryl containing one to three heteroatoms selected from the group consisting of O and N, wherein R 6 is optionally substituted as described in Formula I.
  • R 6 is selected from the group consisting of imidazole, isoxazole, pyridinyl and pyrazynyl, wherein R 6 is optionally substituted as described in Formula I.
  • R 6 is selected from the group consisting of imidazole, isoxazole, pyridinyl and pyrazynyl, wherein R 6 is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, -OR 105 , and -C(O)R 105 , wherein R 105 is selected from the group consisting of hydrogen,
  • R 6 is selected from the group consisting of O'
  • R 6 is selected from the group consisting of 3 to 10 membered ring fully or partially saturated heterocylyl, 3 to 10 membered ring fully or partially
  • R 6 is optionally substituted as described in Formula I.
  • R 6 is a 5 to 7 membered ring fully or partially saturated heterocylyl, 5 to 7 membered ring fully or partially saturated heterocyclyl-C(O)-, 5 to 7 membered ring fully or partially saturated heterocyclyl-C(O)NH-, wherein R 6 is optionally substituted as described in Formula I.
  • R 6 is a 5 to 6 membered ring fully saturated
  • R 6 is optionally substituted as described in Formula I.
  • R 6 is a 5 to 6 membered ring fully saturated heterocylyl, optionally substituted as described in Formula I.
  • R 6 is selected from the group consisting of tetrahydrofuran, tetrahydropyran, pyrrolidinyl, piperidinyl,
  • R 6 is optionally substituted as described in Formula I.
  • R 6 is selected from the group consisting of tetrahydrofuran, tetrahydropyran, pyrrolidinyl, piperidinyl, piperazinyl, and morpholino, wherein R 6 is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, -OR 105 , -C(O)R 105 and -C(O)OR 105 wherein R 105 is selected from the group consisting of
  • R 6 is selected from the group consisting of
  • R 6 is optionally substituted with one or more substituents independently selected from the group consisting of -OR 105 , -C(O)R 105 , -C(O)OR 105 , -NR 105 R 106 , -N(R 105 )C(O)R 106 , -N(R 105 )C(O)OR 106 , -C(O)NR 105 R 106 , -NHC(O)NR 105 R 106 , - N(R 105 )S(O) 2 R 106 , wherein R 105 and R 106 are independently selected from the group consisting of hydrogen, methyl, ethyl, methylethyl, tert-butyl, cyclopentyl, cyclohexyl, optionally substituted with one or more substituent selected from the group consisting of halogen, oxo, hydroxy, and methyl.
  • R 6 is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, -C(O)R 105 and - C(O)OR 105 , wherein R 105 is selected from the group consisting of hydrogen, methyl, and ethyl.
  • R 6 is optionally substituted with one or more substituents independently selected from the group consisting of -OH, -CH 3 , -CH 2 CH 3 , -C(O)CH 3 , - C(O)CH 2 CH 3 , -C(O)OCH 2 CH 3 .
  • R 8 is a (C 1 to C 4 )BIkOXy(C 1 to C 4 )alkyl, optionally substituted with one to three substituents selected from fluoro and chloro.
  • R 8 is methoxyethyl.
  • R 8 is ethoxyethyl.
  • R 8 is propoxyethyl.
  • R 8 is trifluoroethoxyethyl.
  • R 8 is selected from the group consisting of propoxyethyl and ethoxyethyl.
  • Y 6 is a bond or is alkyl, optionally substituted as - — desGr-ibed-in-Formula I-B, and-R ⁇ -and-R— are-hydrogen.— In-another-embodiment-of Formula I-B,
  • Y 6 is a bond or is alkyl, optionally substituted as described in Formula I-B, R 9 and R 10 are hydrogen and R 11 and R 13 are selected from the group consisting of hydrogen, methoxy, and fluoro.
  • Y 6 is a bond or is alkyl, optionally substituted as described in Formula I-B, R 9 R 10 and R 13 are hydrogen, and R 11 is methoxy.
  • R 9 , R 10 , R 13 are hydrogen
  • Y 6 represents a bond or is alkyl
  • Y 6 is a bond or is alkyl, optionally substituted as described in Formula I-B, and R 9 , R 10 and R 13 are hydrogen.
  • Y 6 is a bond or is alkyl, optionally substituted as described in Formula I-B, R 9 , R 10 and R 13 are hydrogen and R 11 is selected from the group consisting of hydrogen, methoxy, and fluoro.
  • Y 6 is a bond or is alkyl, optionally substituted as described in Formula I-B, R 9 R 10 and R 13 are hydrogen, and R 11 is methoxy.
  • R 9 , R 10 , R 13 are hydrogen and R 8 is ethoxyethyl or propoxyethyl
  • R 9 , R 10 and R 13 are hydrogen, and R 8 is selected from the group consisting of ethoxyethyl and propoxyethyl.
  • R 9 , R 10 and R 13 are hydrogen and R 11 is selected from the group consisting of hydrogen, methoxy, and fluoro, and R 8 is selected from the group consisting of ethoxyethyl and propoxyethyl.
  • R 9 R 10 and R 13 are hydrogen, R 11 is methoxy, and R 8 is ethoxyethyl, as described in Formula I-FF in Table A.
  • R 9 R 10 and R 13 are hydrogen, R 11 is methoxy, and R 8 is propoxyethyl, as described in Formula I-UU in Table A.
  • Y 6 represents a bond or is alkyl optionally substituted as described in Formula I-B, and R 6 is selected from the group consisting of hydrogen, halogen, oxo, hydroxy, amino, aminoalkyl, alkyl, alkynyl, alkoxy, alkylamino, and cycloalkyl, optionally substituted as described in Formula I-B.
  • Y 6 represents a bond or is selected from the group consisting of unsubstituted Ci to C 4 alkyl and unsubstituted hydroxy ⁇ to C 4 .alkyl
  • R 6 is selected from the group consisting of phenyl, phenyl-C(O)-, 5 to 6 membered ring heterocyclyl, phenyl-C(O)- NR 105 -, 5 to 6 membered ring heterocyclyl-C(O)-, and 5 to 6 membered ring heterocyclyl-C(O)- NR 105 -, wherein R 6 is optionally substituted as described in Formula I-B wherein R 105 is hydrogen.
  • Y 6 represents a bond or is selected from the group consisting of methyl, ethyl, propyl, butyl, hydroxyethyl, hydroxypropyi, hydroxybutyl, dihydroxyethyl, and dihydroxybutyl
  • R 6 is selected from the group consisting of phenyl, phenyl-C(O)-, 5 to 6 membered ring heterocyclyl, phenyl-C(O)-NH-, 5 to 6 membered ring heterocyclyl-C(O)-, and 5 to 6 membered ring heterocyclyl-C(O)-NH-, wherein R 6 is optionally substituted with one or more substituents independently selected from the group consisting of -OH, -CH 3 , -CH 2 CH 3 , -C(O)CH 3 , -C(O)CH 2 CH 3 , -C(O)OCH 2 CH 3 .
  • R 9 , R 10 and R 13 are hydrogen, R 8 is selected from the group consisting of ethoxyethyl and propoxyethyl, and R 6 is selected from the group consisting of phenyl, phenyl C(O)NH-, phenyl C(O)-, 5 to 7 membered ring heterocyclyl, phenyl-C(O)-NH-, 5 to 7 membered ring heterocyclyl-C(O)-, and 5 to 7 membered ring heterocyclyl-C(O)-NH, optionally substituted with one or more substituents independently selected from the group consisting of of -OR 105 , -C(O)R 105 , -C(O)OR 105 , -NR 105 R 106 , -N(R 105 )C(O)R 106 , - N(R 105 )C(O)OR 106 , -C(O)NR 105 R
  • R 9 , R 10 and R 13 are hydrogen
  • R 8 is selected from the group consisting of ethoxyethyl and propoxyethyl
  • R 6 is selected from the group consisting of 5 to 6 membered ring heteroaryl, 5 to 6 membered ring heteroaryl-C(O)-, and 5 to 6 membered ring heteroaryl- C(O)-NH, optionally substituted with one or more substituents independently selected from the group consisting of alkyl, -OR 105 , and -C(O)R 105 , wherein R 105 is selected from the group consisting of hydrogen, methyl, and ethyl.
  • R 9 , R 10 and R 13 are hydrogen, R 8 is selected from the group consisting of ethoxyethyl and propoxyethyl, and R 6 is selected from the group consisting of 5 to 6 membered ring fully saturated heterocyclyl, 5 to 6 membered ring fully saturated heterocyclyl-C(O)-, and 5 to 6 membered ring fully saturated heterocyclyl-C(O)-NH, optionally substituted with one or more substituents independently selected from the group consisting of alkyl, -OR 105 , and -C(O)R 105 , wherein R 105 is selected from the group consisting of hydrogen, methyl, and ethyl.
  • the present invention is directed, in part, to a class of compounds having the structure of Formula l-l:
  • R 9 , R 10 , R 11 _ R 12 and R 13 are independently selected from the group consisting of hydrogen, halogen, oxo, alkyl, -OR 100 , -C(O)R 100 , -OC(O)R 100 , -C(O)OR 100 , -NR 100 R 101 and -C(O)NR 100 R 101 , wherein the alkyl substitutent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OR 102 , and -C(O)OR 102 ; wherein R 100 , R 101 , and R 102 are independently selected from the group consisting of hydrogen and Ci to C 4 alkyl;
  • Y 6 represents a bond or is selected from the group consisting of alkyl, alkenyl and alkynyl, wherein (a) the Y 6 alkyl, alkenyl and alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo,
  • R 103 and R 104 are independently selected from the group consisting of hydrogen and alkyl, wherein the alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy;
  • R 6 is selected from the group consisting of aryl, aryl-C(O)-, heterocyclyl, aryl-C(O)-NR 105 -, heterocyclyl-C(O)-, and heterocyclyl-C(O)-NR 105 - wherein R 6 may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -OR 106 , -C(O)R 106 , -C(O)OR 106 , -
  • alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl susbstituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy;
  • R 105 is independently selected from the group consisting of hydrogen and alkyl
  • R 106 and R 107 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl, wherein (a) the R 106 and R 107 alkyl and alkenyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy, and (b) the R 106 and R 107 alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy;
  • R 8 is alkoxyalkyl, optionally substituted with halogen.
  • R 9 , R 10 , R 11 R 12 , and R 13 are selected from the group consisting of hydrogen, chloro, fluoro, methyl, ethyl, propyl, butyl, pentyl, hexyl, trif-luoromethyl, ⁇ hydroxy,-methoxy.,-ethoxy, propoxy, butoxy, amino, methylamino, dimethylamino, ethylamino, and diethylamino.
  • R 9 , R 10 , R 11 R 12 , and R 13 are selected from the group consisting of hydrogen, fluoro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, amino, methylamino, and dimethylamino.
  • R 9 , R 12 and R 13 are hydrogen, and R 10 and R 11 are selected from the group consisting of hydrogen, chloro, fluoro, methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluoromethyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, amino, methylamino, dimethylamino, ethylamino, and diethylamino.
  • R 9 , R 12 and R 13 are hydrogen, and R 11 and R 13 are selected from the group consisting of hydrogen, methoxy, trifluoromethyl, and fluoro.
  • R 9 , R 10 , R 12 and R 13 are hydrogen, and R 11 is fluoro.
  • Y 6 represents a bond or is selected from the group consisting of alkyl, alkenyl and alkynyl, wherein the Y 6 alkyl, alkenyl and alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, cycloalkyl, -OR 103 , -C(O)R 103 , -C(O)OR 103 , - OC(O)R 103 , -NR 103 R 104 , -N(R 103 )C(O)R 104 , and -C(O)NR 103 R 104 ; and wherein R 103 and R 104 are independently selected from the group consisting of hydrogen and alkyl, wherein the alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy,
  • Y 6 represents a bond or is alkyl, optionally substituted as described in Formula l-l. In another embodiment of Formula l-l, Y 6 represents a bond or is Ci to C 6 alkyl, optionally substituted as described in Formula l-l. In another embodiment of Formula I- I, Y 6 represents a bond or is selected from the group consisting of C-i to C 4 alkyl and hydroxyCi to C 4 .alkyl.
  • Y 6 represents a bond or is selected from the group consisting of methyl, ethyl, propyl, butyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, dihydroxyethyl, and dihydroxybutyl. In one embodiment of Formula l-l, Y 6 represents a bond or is selected from the group consisting of methyl, ethyl, propyl and butyl.
  • Y 6 is alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, cycloalkyl, -OR 103 , -C(O)R 103 , -C(O)OR 103 , -OC(O)R 103 , -NR 103 R 104 , -N(R 103 )C(O)R 104 , and -C(O)NR 103 R 104 ; wherein R 103 and R 104 are independently selected from the group consisting of hydrogen and C 1 to C 4 alkyl.
  • Y 6 is alkyl substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, oxo, cycloalkyl, hydroxy, and carboxy. In another embodiment of Formula l-l, Y 6 is alkyl substituted with one to three substituents independently selected from the group consisting of hydroxy and cyclohexyl. In another embodiment of Formula l-l, Y 6 is unsubstituted alkyl.
  • Ff Substituent Embodiments of Ff Substituent
  • R 6 is selected from the group consisting of phenyl, phenyl- C(O)-, 3 to 10 membered ring heterocyclyl, phenyl-C(O)-NR 105 -, 3 to 10 membered ring heterocyclyl-C(O)-, and 3 to 10 membered ring heterocyclyl-C(O)-NR 105 -, wherein R 6 is optionally substituted as described in Formula l-l, wherein R 105 is selected from the group consisting of hydrogen and C 1 to C 6 alkyl.
  • R 6 is selected from the group consisting of phenyl, phenyl-C(O)-, 5 to 7 membered ring heterocyclyl, phenyl-C(O)-NR 105 -, 5 to 7 membered ring heterocyclyl-C(O)-, and 5 to 7 membered ring heterocyclyl-C(O)-NR 105 -, wherein R 6 is optionally substituted as described in Formula l-l, wherein R 105 is selected from the group consisting of hydrogen and C 1 to C 4 alkyl.
  • R 6 is selected from the group consisting of phenyl, phenyl-C(O)-, 5 to 6 membered ring heterocyclyl, phenyl-C(O)-NR 105 -, 5 to 6 membered ring heterocyclyl-C(O)-, and 5 to 6 membered ring heterocyclyl-C(0)-NR 105 -, wherein R 6 is optionally substituted as described in Formula l-l wherein R 105 is hydrogen.
  • R 6 is selected from the group consisting of phenyl, pyridinyl, piperidinyl, piperizinyl, morpholino, pyrazinyl, tetrahydropyran, tetrahydrofuran, isoxazole, imidazole, pyrrolidine, wherein R 6 is optionally substituted as described in Formula l-l.
  • R 6 is selected from the group consisting of morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, and pyrrolidinyl, wherein R 6 is optionally substituted as provided in Formula l-l.
  • R 6 is selected from the group consisting of phenyl, phenyl C(O)NH-, and phenyl C(O)-.
  • R 6 is selected from the group consisting of 5 to 7 membered ring heteroaryl, 5 to 7 membered ring heteroaryl-C(O)-, and 5 to 7 membered ring heteroaryl-C(O)-NR 105 -, wherein R 6 is optionally substituted as described in Formula l-l, wherein R 105 is selected from the group consisting of hydrogen and C 1 to C 4 alkyl.
  • R 6 is a 3 to 10 membered ring heteroaryl, optionally substituted as described in Formula l-l.
  • R 6 is a 5 to 7 membered ring heteroaryl, optionally substituted as described in Formula l-l. In another embodiment of Formula l-l, R 6 is a 5 to 6 membered ring heteroaryl, optionally substituted as described in Formula l-l. In another embodiment of Formula l-l, R 6 is a 5 to 6 membered ring heteroaryl containing one to three heteroatoms selected from the group consisting of O and N, optionally substituted as described in Formula l-l.
  • R 6 is selected from the group consisting of imidazole, isoxazoie, pyridinyl and pyrazynyl, wherein R 6 is optionally substituted as described in Formula l-l.
  • R 6 is selected from the group consisting of imidazole, isoxazoie, pyridinyl and pyrazynyl, wherein R 6 is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, -OR 105 , and -C(O)R 105 , wherein R 105 is selected from the group consisting of hydrogen, methyl, and ethyl.
  • R is selected from the group consisting of O * ,
  • R 6 is a 5 to 7 membered ring fully or partially saturated heterocylyl, 5 to 7 membered ring fully or partially saturated heterocyclyl-C(O)-, 5 to 7 membered ring fully or partially saturated heterocyclyl-C(O)NH-, wherein R 6 is optionally substituted as described in Formula l-l.
  • R 6 is a 5 to 6 membered ring fully saturated heterocylyl, 5 to 6 membered ring fully saturated heterocyclyl-C(O)-, 5 to 6 membered ring fully saturated heterocyclyl-C(O)NH-, wherein R 6 is optionally substituted as described in Formula l-l.
  • R 6 is a 5 to 6 membered ring fully saturated heterocylyl, optionally substituted as described in Formula M.
  • R 6 is selected from the group consisting of tetrahydrofuran, tetrahydropyran, pyrrolidinyl, piperidinyl, piperazinyl, and morpholino, wherein R 6 is optionally substituted as described in Formula l-l.
  • R 6 is selected from the group consisting of tetrahydrofuran, tetrahydropyran, pyrrolidinyl, piperidinyl, piperazinyl, and morpholino, wherein R 6 is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, -OR 105 , -C(O)R 105 and -C(O)OR 105 wherein R 105 is selected from the group consisting of hydrogen, methyl, and ethyl. In another embodiment, R 6 is selected from the group consisting of
  • R 6 is optionally substituted with one or more substituents independently selected from the group consisting of -OR 105 , -C(O)R 105 , -C(O)OR 105 ,
  • R 105 and R 106 are independently selected from the group consisting of hydrogen, methyl, ethyl, methylethyl, tert-butyl, cyclopentyl, cyclohexyl, optionally substituted with one or more substituent selected from the group consisting of halogen, oxo, hydroxy, and methyl.
  • R 6 is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, -C(O)R 105 and - C(O)OR 105 , wherein R 105 is selected from the group consisting of hydrogen, methyl, and ethyl.
  • R 6 is optionally substituted with one or more substituents independently selected from the group consisting of -OH, -CH 3 , -CH 2 CH 3 , -C(O)CH 3 , - C(O)CH 2 CH 3 , -C(O)OCH 2 CH 3 .
  • substituents independently selected from the group consisting of -OH, -CH 3 , -CH 2 CH 3 , -C(O)CH 3 , - C(O)CH 2 CH 3 , -C(O)OCH 2 CH 3 .
  • R 8 is a (C 1 to C ⁇ aIkOXy(C 1 to C 4 )alkyl, optionally substituted with one to three substituents selected from fluoro and chloro.
  • R 8 is trifluroethoxyethyl.
  • R 8 is ethoxyethyl.
  • R 8 is propoxyethyl.
  • R 8 is trifluoroethoxyethyl.
  • R 8 is selected from the group consisting of propoxyethyl and ethoxyethyl.
  • Y 6 is a bond or is alkyl, optionally substituted as described in Formula l-l, R 9 , R 12 and R 13 are hydrogen and R 10 and R 11 are selected from the group consisting of hydrogen, methyl, methoxy, trifluoromethyl, and fluoro.
  • R 9 , R 10 , R 12 and R 13 are hydrogen, and R 11 is fluoro.
  • R 9 , R 10 , R 13 are hydrogen and R 8 is ethoxyethyl or propoxyethyl
  • R 9 , R 10 and R 13 are hydrogen
  • R 8 is selected from the group consisting of ethoxyethyl and propoxyethyl
  • R 9 , R 10 and R 13 are hydrogen and R 11 and R 12 are independently selected from the group consisting of hydrogen, methyl, methoxy, fluoro and trifluoromethyl
  • R 8 is selected from the group consisting of ethoxyethyl and propoxyethyl.
  • R 9 R 10 and R 13 are hydrogen
  • R 11 and R 12 are independently selected from the group consisting of hydrogen and fluoro
  • R 8 is selected from the group consisting of ethoxyethyl and propoxyethyl.
  • R 9 , R 10 , R 13 are hydrogen
  • R 8 is ethoxyethyl or propoxyethyl
  • R 6 is selected from various embodiments
  • R 9 , R 10 and R 13 are hydrogen
  • R 8 is selected from the group consisting of ethoxyethyl and propoxyethyl
  • R 6 is selected from the group consisting of phenyl, phenyl C(O)NH-, phenyl C(O)-, 5 to 7 membered ring heterocyclyl, phenyl-C(O)-NH-, 5 to 7 membered ring heterocyclyl-C(O)-, and 5 to 7 membered ring heterocyclyl-C(O)-NH
  • R 6 is optionally substituted with one or more substituents independently selected from the group consisting of of -OR 105 , -C(O)R 105 , -C(O)OR 105 , -NR 105 R 106 , -N(R 105 )C(O)R 106 , - N(R 105 )C(O)OR 106 , -C(
  • R 9 , R 10 and R 13 are hydrogen
  • R 8 is selected from the group consisting of ethoxyethyl and propoxyethyl
  • R 6 is selected from the group consisting of 5 to 6 membered ring heteroaryl, 5 to 6 membered ring heteroaryl-C(O)-, and 5 to 6 membered ring heteroaryl-C(O)- NH
  • R 6 is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, -OR 105 , and -C(O)R 105
  • R 105 is selected from the group consisting of hydrogen, methyl, and ethyl.
  • R 9 , R 10 and R 13 are hydrogen
  • R 8 is selected from the group consisting of ethoxyethyl and propoxyethyl
  • R 6 is selected from the group consisting of 5 to 6 membered ring fully saturated heterocyclyl, 5 to 6 membered ring fully saturated heterocyclyl-C(O)-, and 5 to 6 membered ring fully saturated heterocyclyl-C(O)-NH
  • R 6 is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, -OR 105 , and -C(O)R 105 , wherein R 105 is selected from the group consisting of hydrogen, methyl, and ethyl.
  • the present invention comprises optical isomers and mixtures, including racemic mixtures of the compounds of Formulae (I) through (I-UU).
  • the present invention comprises diastereomeric forms (individual diastereomers and mixtures thereof) of compounds of Formulae (I) through (I-UU).
  • the present invention comprises the tautomeric forms of compounds of Formulae (I) through (I-UU). For instance, a tautomeric form of the following compound:
  • the compounds of this invention may be used in the form of salts derived from inorganic or organic acids.
  • a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced
  • a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
  • the salt preferably is pharmaceutically acceptable.
  • “pharmaceutically acceptable salt” refers to a salt prepared by combining a compound of
  • Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound. For use in medicine, the salts of the compounds of this
  • salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric,
  • hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids.
  • Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic,
  • suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate
  • examples of suitable addition salts formed include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsyate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihidrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.
  • representative salts include benzenesulfonate, hydrobromide and hydrochloride.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed wJtfcLsuitable organic ligands,_e.g., quaternary ammonium.salts.
  • base salts are formed from bases which form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine and zinc salts.
  • Organic salts may be made from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
  • secondary, tertiary or quaternary amine salts such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
  • Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl (Ci to C 6 ) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • salts of the compounds of this invention include hydrochloric acid (HCI) salts, trifluoroacetate (CF 3 COOH or 'TFA”) salts, mesylate salts, and tosylate salts.
  • compositions of Formulae (I) to (I-UU) may be prepared by one or more of three methods:
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the resulting salt may vary from completely ionized to almost non-ionised.
  • the present invention further comprises methods for treating a condition in a subject having or susceptible to having such a condition, by administering to the subject a therapeutical Iy- effective amount of one or more compounds of Formulae (I) through (I-UU) as described above.
  • the treatment is preventative treatment.
  • the treatment is palliative treatment.
  • the treatment is restorative treatment.
  • the conditions that can be treated in accordance with the present invention include, but are not limited to, cardiovascular diseases, metabolic diseases, central nervous system diseases, pulmonary diseases, sexual dysfunction, and renal dysfunction.
  • the present invention further comprises methods for treating a condition in a subject having or susceptible to having such a condition, by administering to the subject a therapeutically- effective amount of one or more compounds of Formula (I) through (I-UU).
  • the condition is a cGMP-mediated condition.
  • the conditions that can be treated in accordance with the present invention are PDE-5 mediated conditions.
  • Such conditions include cardiovascular diseases, metabolic diseases, central nervous system diseases, pulmonary diseases, sexual dysfunction, and renal dysfunction.
  • the condition is a cardiovascular disease, particularly a cardiovascular disease selected from the group consisting of hypertension (such as essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, hypertension associated with diabetes, hypertension associated with atherosclerosis, and renovascular hypertension) ; complications associated with hypertension (such as vascular organ damage, congestive heart failure, angina, stroke, glaucoma and impaired renal function); valvular insufficiency; stable, unstable and variant (Prinzmetal) angina; peripheral vascular disease; myocardial infarct; stroke; thromboembolic disease; restenosis; arteriosclerosis; atherosclerosis; pulmonary arterial hypertension; angiostenosis after bypass; angioplasty (such as percutaneous transluminal angioplasty, or percutaneous transluminal coronary angioplasty); hyperlipidemia; hypoxic vasoconstriction; vasculitis, such as Kawasaki's syndrome; heart failure (such as congestive hypertension,
  • the condition is hypertension. In another embodiment, the condition is.pulm.onaLy_arieriaLhypectensioriJ ⁇ ja ⁇ Qther.embodiment, the condition is heart failure. In another embodiment, the condition is diastolic heart failure. In another embodiment, the condition is systolic heart failure. In another embodiment, the condition is angina. In another embodiment, the condition is thrombosis. In another embodiment, the condition is stroke.
  • the condition is a metabolic disease, particularly a metabolic disease selected from the group consisting of Syndrome X; insulin resistance or impaired glucose tolerance; diabetes (such as type I and type Il diabetes); syndromes of insulin resistance (such as insulin receptor disorders, Rabson-Mendenhall syndrome, leprechaunism, Kobberling- Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Gushing syndrome, acromegaly, pheochomocytoma, glucagonoma, primary aldosteronism, somatostatinoma, Lipoatrophic diabetes, ⁇ -cell toxin induced diabetes, Grave's disease, Hashimoto's thyroiditis and idiopathic Addison's disease); diabetic complications (such as diabetic gangrene, diabetic arthropathy, diabetic nephropathy, diabetic glomerulosclerosis, diabetic deramatopathy, diabetic neuropathy, peripheral diabetic neuropathy, diabetic cataract, and diabetic retinopathy); hyperglycemia; and obesity
  • the condition is insulin resistance. In another embodiment, the condition is nephropathy. In another embodiment, the condition is a disease of the central nervous system, particularly a disease of the central nervous system selected from the group consisting of vascular dementia; craniocerebral trauma; cerebral infarcts; dementia; concentration disorders; Alzheimer's disease; Parkinson's disease; amyolateral sclerosis (ALS); Huntington's disease; multiple sclerosis; Creutzfeld-Jacob; anxiety; depression; sleep disorders; and migraine. In one embodiment, the condition is Alzheimer's disease. In another embodiment, the condition is Parkinson's disease. In one embodiment, the condition is ALS. In another embodiment, the condition is a concentration disorder.
  • the condition is a pulmonary disease, particularly a pulmonary disease selected from the group consiting of asthma; acute respiratory distress; cystic fibrosis; chronic obstructive pulmonary disease (COPD); bronchitis; and chronic reversible pulmonary obstruction.
  • a pulmonary disease selected from the group consiting of asthma; acute respiratory distress; cystic fibrosis; chronic obstructive pulmonary disease (COPD); bronchitis; and chronic reversible pulmonary obstruction.
  • the condition is sexual dysfunction, particularly sexual dysfunction selected from the group consiting of impotence (organic or psychic); male erectile dysfunction; clitoral dysfunction; sexual dysfunction after spinal cord injury; female sexual arousal disorder; female sexual orgasmic dysfunction; female sexual pain disorder; and female hypoactive sexual desire disorder.
  • the condition is erectile dysfunction.
  • the condition is renal dysfunction, particularly a renal dysfunction selected from the group consisting of acute or chronic renal failure; nephropathy (such as diabetic nephropathy); glomerulopathy; and nephritis.
  • the condition is pain.
  • the condition is acute pain.
  • acute pain include acute pain associated with injury or surgery.
  • the condition is chronic pain.
  • chronic pain include neuropathic pain (including postherpetic neuralgia and pain associated with peripheral, cancer or diabetic neuropathyVcarpalitunnel syndrome ⁇ back-pain ⁇ including-pain associated with-hemiated or ruptured intervertebral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament), headache, cancer pain (including tumour related pain such as bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (including postchemotherapy syndrome, chronic postsurgical pain syndrome, post radiation syndrome, pain associated with immunotherapy, or pain associated with hormonal therapy), arthritic pain (including osteoarthritis and rheumatoid arthritis pain), chronic post- surgical pain, post herpetic neuralgia, trigeminal neuralgia, HIV neuropathy, phantom
  • the condition is nociceptive pain (including pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, post- operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain).
  • nociceptive pain including pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, post- operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain).
  • the condition is pain associated with inflammation (including arthritic pain (such as osteoarthritis and rheumatoid disease pain), ankylosing spondylitis, visceral pain (including inflammatory bowel disease, functional bowel disorder, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, functional abdominal pain syndrome, Crohn's disease, ileitis, ulcerative colitis, dysmenorrhea!, cystitis, pancreatitis and pelvic pain).
  • arthritic pain such as osteoarthritis and rheumatoid disease pain
  • ankylosing spondylitis visceral pain
  • visceral pain including inflammatory bowel disease, functional bowel disorder, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, functional abdominal pain syndrome, Crohn's disease, ileitis, ulcerative colitis, dysmenorrhea!, cystitis, pancreatitis and pelvic pain.
  • the condition is pain resulting from musculoskeletal disorders (including myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenosis, polymyositis and pyomyositis).
  • the condition is selected from the group consisting of heart and vascular pain (including pain caused by angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma and skeletal muscle ischemia).
  • the condition is selected from the group consisting of head pain (including migraine such as migraine with aura and migraine without aura), cluster headache, tension-type headache mixed headache and headache associated with vascular disorders; orofacial pain, including dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain).
  • head pain including migraine such as migraine with aura and migraine without aura
  • cluster headache tension-type headache mixed headache and headache associated with vascular disorders
  • orofacial pain including dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain.
  • condition is a urologic condition selected from the group consisting of bladder outlet obstruction; incontinence and benign prostatic hyperplasia.
  • the condition is an ophthalmic condition selected from retinal disease; macular degeneration and glaucoma.
  • the condition is selected from the group consisting of tubulointerstitial disorders; anal fissure; baldness; cancerous cachexia; cerebral apoplexy; disorders of gut motility; enteromotility disorders; dysmenorrhoea (primary and secondary); glaucoma; macular degeneration; antiplatelet; haemorrhoids; incontinence; irritable bowel syndrome (IBS); tumor metastasis; multiple sclerosis; neoplasia; nitrate intolerance; nutcracker oesophagus; osteoporosis; infertility; premature labor; psoriasis; retinal disease; skin necrosis; and urticaria.
  • the condition is osteoporosis.
  • the condition is associated with endothelial dysfunction, particularly conditions-selected from-the-group-e ⁇ nsisting-of-atherosclerotic-lesions, myocardial ischaemia, peripheral ischaemia, valvular insufficiency, pulmonary arterial hypertension, angina, vascular complications after vascular bypass, vascular dilation, vascular repermeabilisation, and heart transplantation.
  • the methods and compositions of the present invention are suitable for use with, for example, mammalian subjects such as humans, other primates (e.g., monkeys, chimpanzees), companion animals (e.g., dogs, cats, horses), farm animals (e.g., goats, sheep, pigs, cattle), laboratory animals (e.g., mice, rats), and wild and zoo animals (e.g., wolves, bears, deer).
  • the subject is a human.
  • Selected embodiments of the invention therefore, comprise methods for treating a cGMP- mediated condition via PDE-5 inhibition.
  • compounds of Formulae (I) through (I-UU) would be therapeutically useful in methods for treating hypertension by administering to a hypertensive subject a therapeutically-effective amount of a compound of Forumulae (I) through (I-UU).
  • Other examples of circulatory-related disorders which can be treated by compounds of the invention include congestive heart failure, renal failure, angina, and glaucoma.
  • One or more compounds of the present invention can be used, alone or in combination with other therapeutic agents, in the treatment of various conditions or disease states.
  • the compound(s) of the present invention and other therapeutic agent(s) may be may be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially.
  • one or more compounds of Formulae (I) through (I-UU) may be administered with aspirin.
  • one or more compounds of Formulae (I) through (I-UU) may be coadministered with one or more angiotensin converting enzyme (ACE) inhibitors.
  • ACE angiotensin converting enzyme
  • examples of the one or more ACE inhibitors for use with the one or morecompound of Formulae (I) - (I-UU) include quinapril (such as ACCUPRILTM), perindopril (such as ACEONTM), captopril (such as
  • CAPOTENTM CAPOTENTM
  • enalapril such as VASOTECTM
  • ENALAPR ILATTM ramipril (such as ALTACETM)
  • cilazapril delapril
  • fosenopril such as MONOPR1LTM
  • zofenopril indolapril
  • benazepril such as LOT-ENSIN- ⁇ lisinopril ⁇ such-as-PRINIV-IL ⁇ or-ZEST-RILTM-
  • spirapril r trandolapril such as
  • one or more compounds of Formulae (I) through (I-UU) may be coadministered with one or more alpha blockers such as dozazosin (such as CARDURATM), phenoxybenzamine (such as DIBENZYLINETM), or terazosin (such as HYTRINTM), CDRI-93/478 and CR-2991.
  • alpha blockers such as dozazosin (such as CARDURATM), phenoxybenzamine (such as DIBENZYLINETM), or terazosin (such as HYTRINTM), CDRI-93/478 and CR-2991.
  • one or more compounds of Formulae (I) through (I-UU) may be co- administered with one or more alpha-beta blockers such as labetalol (such as NORMODYNETM or TRANDATETM).
  • alpha-beta blockers such as labetalol (such as NORMODYNETM or TRANDATETM).
  • one or more compounds of Formulae (I) through (I-UU) may be coadministered with one or more angiotensin Il receptor blockers such as candesartan (such as ATACANDTM), eprosartan (such as TEVETENTM), irbesartan (such as AVEPROTM), losartan (such as COZAARTM), olmesartan, olmesartan medoxomil (such as BENICARTM), tasosartan, telmisartan (such as MICARDISTM), valsartan (such as DIOVANTM) or zolasartan, FI-6828K, RNH-6270, UR-7198, Way-126227, KRH-594, TAK-536, BRA-657, and TA-606.
  • angiotensin Il receptor blockers such as candesartan (such as ATACANDTM), eprosartan (such as TEVETENTM), irbesartan
  • one or more compounds of Formulae (I) through (I-UU) may be coadministered with one or more alpha-2-delta ligands such as gabapentin, pregabalin (such as LYRICATM), [(1 R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1-aminomethyl- cyclohexylmethyl)-4H-[1 ,2,4]oxadiazol-5-one, C-[1-(1 H-tetrazol-5-ylmethyl)-cycloheptyi]- methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (1 ⁇ ,3 ⁇ ,5 ⁇ )-(3- amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (SS. ⁇ RJ-S-aminomethyl- ⁇ -methyl
  • one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more beta blockers such as timolol (such as BLOCARDENTM), 5 carteolol (such as CARTROLTM), carvedilol (such as COREGTM), nadolol (such as
  • CORGARDTM propranolol (such as INNOPRAN XLTM), betaxolol (such as KERLONETM), penbutolol (such as LEVATOLTM), metoprolol (such as LOPRESSORTM or TOPROL-XLTM), atenolol (such as TENORMINTM), or pindolol (such as VISKENTM), and bisoprolol.
  • one or more compounds of Formulae (I) through (I-UU) may be co-
  • calcium channel blockers such as nifedipine (such as ADALATTM, ADALAT CCTM or PROCARDIATM), verapamil (such as CALANTM, COVERA-HSTM, ISOPTIN SRTM or VERELANTM), diltiazem (such as CARDIZEMTM CARDIZEM CDTM, CARDIZEM LATM, CARDIZEM SRTM, DILACORTM, TIAMATETM or TIAZACTM), isradipine (such as DYNACIRCTM or DYNACIRC CRTM), amlodipine (such as NORVASCTM), felodipine (such as PLENDILTM),
  • nifedipine such as ADALATTM, ADALAT CCTM or PROCARDIATM
  • verapamil such as CALANTM, COVERA-HSTM, ISOPTIN SRTM or VERELANTM
  • diltiazem such as CARDIZEMTM CARDIZEM CDTM, CARD
  • nisoldipine such as SULARTM
  • bepridil such as VASCORTM
  • vatanidipine such as clevidipine
  • lercanidipine dilitiazem
  • NNC-55-0396 nisoldipine
  • one or more compounds Formulae (I) through (I-UU) may be co-
  • — _ administered-with one-or-mor-e-central-antiadrenergics-such.as-raethyldopa-(such.as
  • clonidine such as CATAPRESTM or CATAPRES-TTSTM
  • guanfacine such as
  • TENEXTM TENEXTM
  • guanabenz such as WYTENSINTM
  • one or more compounds of Formulae (I) through (I-UU) may be coadministered with one or more diruretics such as hydroclorothiazide (such as MICROZIDETM or ORETICTM), hydroflumethiazide (such as SALURONTM), bemetanide (such as BUMEXTM), torsemide (such as DEMADEXTM), metolazone (such as ZAROXOLYNTM), chlorothiazide (such as hydroclorothiazide (such as MICROZIDETM or ORETICTM), hydroflumethiazide (such as SALURONTM), bemetanide (such as BUMEXTM), torsemide (such as DEMADEXTM), metolazone (such as ZAROXOLYNTM), chlorothiazide (such
  • DIURILTM ESIDRIXTM or HYDRODIURILTM
  • triamterene such as DYRENIUMTM
  • ethacrynic acid such as EDECRINTM
  • chlorthalidone such as HYGROTONTM
  • furosemide such as LASIXTM
  • indapamide such as LOZOLTM
  • amiloride such as MIDAMORTM or MODURETICTM
  • one or more compounds of Formulae (I) through (I-UU) may be co-
  • glycosides / inotropic agents such as digoxin (such as LANOXINTM).
  • one or more compounds of Formulae (I) through (I-UU) may be coadministered with one or more organic nitrates or an NO donors.
  • "Nitric oxide donor” or “NO donor” refers to a compound that donates, releases and/or directly or indirectly transfers a
  • NO donor also includes compounds that are substrates for nitric oxide synthase. Examples of the one or more NO donors for use with one or more compounds of Formulae (I) through (I-UU) include S-nitrosothiols, nitrites, nitrates, N-oxo-N-nitrosamines, SPM
  • one or more compounds of Formulae (I) through (I-UU) may be coadministered with one or more human B-type natriuretic peptides (hBNP) such as nesiritide (such as NATRECORTM).
  • hBNP human B-type natriuretic peptides
  • nesiritide such as NATRECORTM
  • one or more compounds of Formulae (I) through (I-UU) may be coadministered with one or more renin inhibitors such as Aliskiren (SPP 100), SPP-500/600 and YS-004-39.
  • renin inhibitors such as Aliskiren (SPP 100), SPP-500/600 and YS-004-39.
  • one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more soluble guanylate cyclase activator ("sGCa").
  • sGCa soluble guanylate cyclase activator
  • An example of a suitable soluble guanylate cyclase activator is BAY-41 -8543.
  • one or more compounds of Formulae (I) through (I-UU) may be coadministered with one or more neutral endopeptidase (NEP) inhibitors, such as, for example
  • one or more compounds of Formulae (I) through (I-UU) may be coadministered with one or more aldosterone receptor antagonists such as eplerenone (such as INSPRATM) or spironolactone (such as ALDACTONETM).
  • aldosterone receptor antagonists such as eplerenone (such as INSPRATM) or spironolactone (such as ALDACTONETM).
  • one or more compounds of Formulae (I) through (I-UU) may be co- administered with one or more bradykinin agonists.
  • one or more compounds of Formulae (I) through (I-UU) may be coadministered with one or more endothelian antagonists.
  • suitable endothelin antagonists include ambrisentan, darusentan, J-104132, SPP-301 , TBC-3711 , YM-62899, YM- 91746, and BMS-193884.
  • one or more compounds of Formulae (I) through (I-UU) may be coadministered with niacin or one or more nicotinic acid derivatives, such as NIACORTM, NIASPANTM, NICOLARTM, or SLO-NIACINTM.
  • one or more compounds of Formulae (I) through (I-UU) may be coadministered with one or more fibric acid derivatives, such as clofibrate (such as ATROMID-STM), gemfibrozil (such as LOPIDTM), or fenofibrate (such as TRICORTM).
  • fibric acid derivatives such as clofibrate (such as ATROMID-STM), gemfibrozil (such as LOPIDTM), or fenofibrate (such as TRICORTM).
  • one or more compounds of Formulae (I) through (I-UU) may be co- administered with one or more cholesteryl ester transport protein inhibitors (CETPi), such as torcetrapib.
  • CETPi cholesteryl ester transport protein inhibitors
  • one or more compounds of Formulae (I) through (I-UU) may be coadministered with one or more bile acid sequestants, such as colestipol (such as COLESTIDTM), cholestyramine (such as LOCHOLESTTM, PREVALITETM, QUESTRANTM, or QUESTRAN LIGHTTM), colesevelam (such as WELCHOLTM).
  • colestipol such as COLESTIDTM
  • cholestyramine such as LOCHOLESTTM, PREVALITETM, QUESTRANTM, or QUESTRAN LIGHTTM
  • colesevelam such as WELCHOLTM
  • one or more compounds of Formulae (I) through (I-UU) may be coadministered with an apical sodium-dependent bile acid cotransporter inhibitors, such as SD- 5613, AZD7806 or 264W94.
  • an apical sodium-dependent bile acid cotransporter inhibitors such as SD- 5613, AZD7806 or 264W94.
  • one or more compounds of Formulae (I) through (I-UU) may be co- administered with one or more cholesterol absorbtion inhibitors, such as ezetimibe (such as ZETIATM).
  • one or more cholesterol absorbtion inhibitors such as ezetimibe (such as ZETIATM).
  • one or more compounds of Formulae (I) through (I-UU) may be co- adminLs ⁇ emdj/yj.tb_one_or.r ⁇ reductase inhibitors (statins) such as fluvastatin (such as LESCOLTM), atorvastatin (such as LIPITORTM), lovastatin (such as ALTOCORTM or MEVACORTM), pravastatin (such as PRAVACHOLTM), rosuvastatin (such as CRESTORTM), or simvastatin (such as ZOCORTM).
  • statins such as fluvastatin (such as LESCOLTM), atorvastatin (such as LIPITORTM), lovastatin (such as ALTOCORTM or MEVACORTM), pravastatin (such as PRAVACHOLTM), rosuvastatin (such as CRESTORTM), or simvastatin (such as ZOCORTM).
  • one or more compounds of Formulae (I) through (I-UU) may be coadministered with one or more alpha glucosidase inhibitors, such as miglitol (such as GLYSETTM), or acarbose (such as PRECOSETM).
  • one or more compounds of Formulae (I) through (I-UU) may be coadministered with one or more biguanides, such as roseiglitazone (such as AVANDAMETTM), or metformin (such as GLUCOPHAGETM or GLUCOPHAGE XRTM).
  • one or more compounds of Formulae (I) through (I-UU) may be coadministered with one or more insulins, such as HUMALOGTM, HUMALOG 50/50TM, HUMALOG 75/25TM, HUMULIN 50/50TM, HUMALIN 75/25TM, HUMALIN LTM, HUMALIN NTM, HUMALIN RTM, HUMALIN R U-500TM, HUMALIN UTM, ILETIN Il LENTETM, ILETIN Il NPHTM, ILETIN Il REGULARTM, LANTUSTM, NOVOLIN 70/30TM, NOVILIN NTM, NOVILIN RTM, NOVOLOGTM, or VELOSULIN BRTM, and EXUBERATM.
  • insulins such as HUMALOGTM, HUMALOG 50/50TM, HUMALOG 75/25TM, HUMULIN 50/50TM, HUMALIN 75/25TM, HUMALIN LTM, HUMALIN NTM, HUMALIN R
  • one or more compounds of Formulae (I) through (I-UU) may be co- administered with one or more meglitnides, such as repaglinide (such as PRANDINTM) or nateglinide (such as STARLIXTM).
  • meglitnides such as repaglinide (such as PRANDINTM) or nateglinide (such as STARLIXTM).
  • one or more compounds of Formulae (I) through (I-UU) may be coadministered with one or more sulfonylureas, such as glimepiride (such as AMARYLTM), glyburide (such as DIABETATM, GLYNASE PRESTABTM or MICRONASETM), or glipizide (such as GLUCOTROLTM, or GLUCOTROL XLTM).
  • one or more compounds of Formulae (I) through (I-UU) may be coadministered with one or more thiazolidinediones, such as pioglitazone (such as ACTOSTM) or rosiglitazone (such as AVANDIATM).
  • a compound described in this specification is administered in an amount effective to inhibit PDE-5.
  • the compounds of the present invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • the dosage regimen for the compounds and/or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular
  • the dosage regimen may vary widely. Dosage levels of the order from about 0.01 mg to about 100 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions.
  • the total daily dose of a __ compound of Formulae40Jhriiu ⁇ h4LUil)4admMsterMJn_sin5leOLdividejcl doses is typically from about 0. 01 to about 100 mg/kg. In another embodiment, total daily dose of the compound
  • 20 of Formulae (I) through (IX) is from about 0.1 to about 50 mg/kg, and in another embodiment, from about 0.5 to about 30 mg/kg (i.e., mg compound of Formulae (I) through (I-UU) per kg body weight).
  • dosing is from 0.01 to 10 mg/kg/day. In another embodiment, dosing is from 0.1 to 1.0 mg/kg/day.
  • Dosage unit compositions may contain such amounts or submultiples thereof to make up the daily dose. In many instances, the administration of the
  • 25 compound will be repeated a plurality of times in a day (typically no greater than 4 times). Multiple doses per day typically may be used to increase the total daily dose, if desired.
  • compositions may be provided in the form of tablets containing 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1mg to about 100 mg of active ingredient.
  • doses may range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.
  • the present invention comprises methods for the preparation of a pharmaceutical composition (or "medicament) comprising the compounds of Formulae (I) through (I-UU) in combination with one or more pharmaceutically-acceptable carriers and/or other active ingredients for use in treating a cGMP-mediated condition.
  • the invention comprises the use of one or more compounds of Formulae (I) through (I-UU) in the preparation of a medicament for the treatment of hypertension.
  • the invention comprises the use of one or more compounds of Formulae (I) through (I-UU) in the preparation of a medicament for the treatment of angina. In another embodiment, the invention comprises the use of one or more compounds of
  • the invention comprises the use of one or more compounds of Formulae (I) through (I-UU) in the preparation of a medicament for the treatment of thrombosis. In another embodiment, the invention comprises the use of one or more compounds of
  • compositions for the treatment of the conditions referred to above, the compounds of Formulae (I) through
  • (I-UU) can be administered as compound per se.
  • pharmaceutically acceptable salts are suitable for medical applications because of their greater aqueous solubility relative to the ⁇ parenLcompound.
  • the present invention comprises pharmaceutical compositions.
  • Such pharmaceutical compositions comprise compounds of Formulae (I) through (I-UU) presented with a pharmaceutically-acceptable carrier.
  • the carrier can be a solid, a liquid, or both, and may be formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compounds.
  • Compounds of Formulae (I) through (I-UU) may be coupled with suitable polymers as targetable drug carriers. Other pharmacologically active substances can also be present.
  • the active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • the active compounds and compositions may be administered orally, rectally, parenterally, or topically.
  • Oral administration of a solid dose form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention.
  • the oral administration may be in a powder or granule form.
  • the oral dose form is sub-lingual, such as, for example, a lozenge.
  • the compounds of Formulae (I) through (I-UU) are ordinarily combined with one or more adjuvants.
  • the dosage forms also may comprise buffering agentsor may be prepared with enteric coatings.
  • oral administration may be in a liquid dose form.
  • Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water).
  • Such compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
  • the present invention comprises a parenteral dose form.
  • Parenteral administration includes, for example, subcutaneous injections, intravenous injections, intraperitoneal ⁇ , intramuscular injections, intrastemal injections, and infusion.
  • injectable preparations e.g., sterile injectable aqueous or oleaginous suspensions
  • suitable dispersing, wetting agents, and/or suspending agents may be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents.
  • Topical administration includes, for example, transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration.
  • Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams.
  • a topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas.
  • Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention is dissolved or suspended in suitable carrier.
  • the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant.
  • the present invention comprises a rectal dose form.
  • rectal dose form may be in the form of, for example, a suppository.
  • compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures.
  • effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences. Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, et al., Eds., Pharmaceutical Dosage Forms, Marcel
  • kits that are suitable for use in performing the methods of treatment or prevention described above.
  • the kit contains a first dosage form comprising one or more of the compounds of the present invention and a container for the dosage, in quantities sufficient to carry out the methods of the present invention.
  • the kit of the present invention comprises one or more compounds of Formulae (I) through (I-UU) and an ACE inhibitor.
  • the kit of the present invention comprises one or more compounds of Formulae (I) through (I-UU) and an angiotensin Il receptor antagonist.
  • the kit of the present invention comprises one or more compounds of Formulae (I) through (I-UU) and an aldosterone receptor antagonist. In another embodiment, the kit of the present invention comprises one or more compounds of Formulae (I) through (I-UU) and a NO donor.
  • the compounds of the present invention may be prepared using the methods illustrated in the general synthetic schemes and experimental procedures detailed below.
  • the general synthetic schemes are presented for purposes of illustration and are not intended to be limiting.
  • Scheme 1 outlines a general procedure for the preparation of 7-aryl, 1 , 3-disubstituted pyrido[3,4-b]pyrazin-2(1 H)-one of formula I.
  • the starting material is the commercially available 6- chloropyridin-3-amine II.
  • 6-chloropyridin-3-amine Il is converted to tert-butyl 6-chloropyridin-3- ylcarbamate III by treatment with reagents such as di-tert-butyl dicarbonate, (2E)- ⁇ [(tert- butoxycarbonyl)oxy]imino ⁇ (phenyl)acetonitrile and tert-butyl phenyl carbonate.
  • This reaction is carried out in solvents such as dioxane, tetrahydrofuran, water, ethyl acetate or dichloromethane, in the presence or absence of inorganic bases such as potassium carbonate or sodium bicarbonate or organic bases such as triethylamine, 4-methylmorpholine, pyridine or N 1 N- diisopropylethylamine at temperatures ranging from room temperature to 110 ° C.
  • tert-butyl 6- chloropyridin-3-ylcarbamate III is converted to tert-butyl 6-chioro-4-fluoropyridin-3-ylcarbamate IV by metallation followed by quenching with an electrophilic fluorine source.
  • Lithation could be achieved be treating tert-butyl 6-chloropyridin-3-ylcarbamate III with an organolithium such as n- butyl lithium or t-butyl lithium in the presence or absence of additives such as N,N,N',N'- tetramethylethylenediamine in solvents such as diethyl ether or tetrahydrofuran at temperatures ranging from -80 ° C to 0 ° C.
  • Suitable electrophilic fluorine sources include N- flurobenzenesulfonimide.
  • Amines of the formula V could be converted to diamines of the formula Vl by removing the carbamate protecting group under standard conditions, as described in Green, T., Wuts, P. Protecting Groups in Organic Synthesis, John Wiley & Sons, INC, Second edition, 1991 , pp 309-405.
  • the diamines of formula Vl could be converted to the diones of formula VII using various reaction procedures. In one procedure, this conversion is achieved by refluxing an aqueous solution of Vl in the presence of oxalic acid and a catalytic amount of a mineral acid such as HCI.
  • this conversion to structures of formula VII could be achieved by addition of either methyl chlorooxoacetate or oxalyl chloride to a solution of Vl in the presence of an organic base such as triethylamine, 4-methylmorpholine, or ⁇ /, ⁇ /-diisopropylethylamine, at O 0 C, followed by warming to either room temp or the reflux temperature of the solvent.
  • organic base such as triethylamine, 4-methylmorpholine, or ⁇ /, ⁇ /-diisopropylethylamine, at O 0 C, followed by warming to either room temp or the reflux temperature of the solvent.
  • Suitable solvents include toluene, dichloromethane, dicholroethane, dioxane, or tetrahydrofuran.
  • the chloroimidate of formula VIII could be prepared by a number of methods.
  • a dione of formula VII could be heated to reflux in the presence of phosphorous oxychloride and a phase transfer catalyst such as tetraethylammonium chloride.
  • Suitable solvents for this reaction include propionitrile or acetonitrile.
  • the formation of chloroimidate VII is achieved by dissolving VII in a suitable solvent such as dichloromethane, tetrahydrofuran, or dioxane and treating it with oxalyl chloride in the presence of a catalytic amount of dimethylformamide between 0 0 C and rt.
  • the 6-aminopyrazinones of formula IX could be prepared by the addition of various primary and secondary amines to chloroimidate VIII in the presence of an organic base such as triethylamine, 4-methylmorpholine, or ⁇ /, ⁇ /-diisopropylethylamine at temperatures ranging from 0 0 C to rt.
  • organic base such as triethylamine, 4-methylmorpholine, or ⁇ /, ⁇ /-diisopropylethylamine at temperatures ranging from 0 0 C to rt.
  • Suitable solvents include dichloromethane, tetrahydrofuran, and dioxane.
  • Formation of the desired pteridinone of formula I could be prepared through a standard palladium catalyzed Suzuki coupling between chloride IX and suitable boronic acids, as described in Miyaura, N., Suzuki, A; Chem Rev. 1995, 95, 2457- 2483.
  • Scheme 2 outlines an alternate conversion of tert-butyl 6-chloropyridin-3-ylcarbamate III to amines of formula V.
  • tert-butyl ⁇ -chloropyridin-S-ylcarbamate III is converted to tert-butyl 6- chloro-4-iodopyridin-3-ylcarbamate X by metallation followed by quenching with an electrophilic iodine source.
  • Lithation could be achieved be treating tert-butyl 6-chloropyridin-3-ylcarbamate III with an organolithium such as n-butyl lithium or t-butyl lithium in the presence or absence of additives such as ⁇ /, ⁇ /, ⁇ /', ⁇ /'-tetramethylethylenediamine in solvents such as diethyl ether or tetrahydrofuran at temperatures ranging from -80 ° C to 0 ° C.
  • Suitable electrophilic iodine sources include molecular iodine and 1-iodopyrrolidine-2,5-dione.
  • a solution of iodide, X, in a suitable solvent such as tetrahydrofuran, dioxane, toluene, benzene, N 1 N dimethylformamide, isopropanol, ethanol or propionitrile is stirred at temperatures ranging from room temperature to reflux in the presence of the desired amine, a base such as sodium carbonate, cesium carbonate, potassium phosphate, or sodium terf-butoxide and a palladium with ligand and/or a copper source.
  • a suitable solvent such as tetrahydrofuran, dioxane, toluene, benzene, N 1 N dimethylformamide, isopropanol, ethanol or propionitrile
  • Suitable sources of palladium include palladium(ll) acetate, tetrakis(triphenylphosphine)palladium, dichloro[1 ,1'- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct and tris(dibenzylideneacetone)dipalladium(0).
  • Suitable ligands include triphenylphosphine, tri-2- furylphosphine, 4,5-bis(diphenylphosphine)-9-9-dimethylxathene, tricyclohexylphospine, tert- butylphospine and 2,2'-bis(diphenylphosphino)-1 ,1'-binapthyl.
  • Suitable sources of copper include copper(ll) acetate, copper(l) iodide and copper(l) chloride.
  • Scheme 3 outlines a one-pot procedure for the conversion of diaminopyridine of formula Vl to amino substituted pyrazinone of formula IX.
  • the pyridine Vl is dissolved in a solvent such as dichloromethane, tetrahydrofuran, or dioxane and cooled to 0 0 C.
  • the mixture is treated with oxalyl chloride and allowed to slowly warm to room temperature.
  • the reaction is typically mixed for 4-24 hours.
  • reaction mixture is then recooled to 0 0 C, treated with an organic base such as triethylamine, 4-methylmorpholine, or ⁇ /, ⁇ /-diisopropylethylamine, followed by addition of the requisite primary or secondary amine leading to isolation of the desired amine of formula IX.
  • organic base such as triethylamine, 4-methylmorpholine, or ⁇ /, ⁇ /-diisopropylethylamine
  • the preparation of substituted amine analogs in the C(6) position similar to compounds of formula XIII or XIV are shown in Scheme 5.
  • the starting amines Xl can be prepared by utilizing mono-protected diamines in the final step of Scheme 1.
  • the protecting groups used are typically carbamates which are removed using standard conditions to afford free amines of formula XII.
  • Derivatives of formula XIII can be prepared by adding the desired aldehyde to a solution of XII in the presence of a catalytic amount of acids such as hydrochloric or acetic acid.
  • a reducing agent such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride is then added to the mixture leading to amines of formula XIII.
  • Suitable solvents include tetrahydrofuran, dioxane, or dichloromethane.
  • Amide derivatives of formula XIV could be prepared by treatment of the amine XII with activated esters such a acid chlorides, or acid derivatives prepared from acids utilizing peptide .
  • Suitable solvents include dichloromethane, tetrahydrofuran, or dioxane.
  • Step 1 Preparation of tert-butyl ⁇ -chloropyridin-S-ylcarbamate.
  • TMEDA 39 ml_, 260.0 mmol
  • diethyl ether 700 mL
  • a 1.6M n-butyl lithium solution in hexane (193 mL, 308.8 mmol)
  • the reaction was stirred at -60 0 C for an additional 10 minutes after the addition was complete then warmed to -1O°C and stirred at -25° to -10 0 C for 2.0 hours.
  • Step 4 Preparation of 6-chloro-N 4 -(2-propoxvethvBpvridine-3.4-diamine.
  • Step 7 Preparation of 7-(6-methoxypyridin-3-yl)-3-f(2-morpholin-4-ylethyl)aminol-1-(2- 15 propoxyethyl)pyridor3,4-blpyrazin-2(1 H)-one.
  • step 7 in example 1 was performed using the following modified procedure.
  • a solution of 3-(2-(4-ethylpiperazin-1-yl)-2-oxoethylamino)-7-chloro-1-(2- propoxyethyl)pyrido[3,4-b]pyrazin-2(1 H)-one (306 mg, 0.70 mmol) in 1 ,4-dioxane (5.0 ml_) was treated with dichloro[1 ,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (54 mg, 0.066 mmol), 6-methoxypyridin-3-yl-3-boronic acid (250 mg, 1.6 mmol) and 2.5 ml_ of water containing Na 2 CO 3 (264 mg, 2.5 mmol).
  • the IC 50 of test compounds can be measured using an in vitro assay using PDE5 enzyme isolated from human platelets.
  • the IC 50 is the concentration of test compound required to inhibit the hydrolysis of cGMP to GMP by the PDE5 enzyme by 50% relative to the activity of uninhibited controls.
  • the PDE5 enzyme for use in the assay can be obtained from human platelets by appropriate modification of the method of Thompson, WJ etal.; Biochemistry 18(23), 5228-5237, 1979, as described by Ballard SA et al.; J. Urology 159(6), 2164-2171 , 1998.
  • the PDE5 enzyme so obtained can be used to catalyze the hydrolysis of [ 3 H]cGMP (Amersham Biosciences) to 5' nucleotide [ 3 H]GMP.
  • the [ 3 H]GMP binds to yttrium silicate SPA beads (Amersham Biosciences) and is detected by scintillation counting. More specifically, the effect of the test compound at different concentrations can be evaluated in the assay by contacting the compound with a fixed amount of PDE5 enzyme in the presence of substrate (cGMP or cAMP in a 3:1 ratio unlabelled to [ 3 H]-Iabeled). Scintillation counting can be used as described above to determine relative PDE5 enzyme activity. The inhibition of PDE5 enzyme activity is then calculated relative to total PDE5 enzyme activity of uninhibited controls.
  • Buffer A 20 mM Tris-HCI, 5 mM MgCI 2 , pH 7.4
  • Buffer B 2 mg/ml BSA in Buffer A (enzyme buffer)
  • cGMP substrate Final concentration of 500 nM in assay The amount of 3 H-labeled substrate added depends upon the specific activity of [ 3 H]cGMP, and the cGMP substrate is diluted with a 10 mM stock of cold cGMP in Buffer A for a final substrate concentration of 500 nM in the assay.
  • PDE enzyme Prepared in Buffer B. The dilution factor is determined by enzyme activity.
  • SPA beads 20 mg/ml suspension prepared in dH2O.
  • Stocks of standard and test compounds are prepared at 5 mM in 100% DMSO.
  • the compound is serially diluted in a dilution plate using a 10-point 1 /a log dilution format.
  • 2 ⁇ l of the compound dilution is added in duplicate to the wells of the assay plate.
  • 2 ⁇ l of 100% DMSO are added to designated control wells.
  • 25 ⁇ l of Buffer A are added to all wells.
  • 25 ⁇ l of Buffer B are added to the negative control wells.
  • 25 ⁇ l of enzyme are added to the remaining wells.
  • 50 ⁇ l of substrate are added to each well. Plates are sealed and incubated for 60 minutes on a plate shaker at 30 C. 50 ⁇ I of SPA beads are added to stop the reaction.
  • Inhibition (%) [(mean maximum - compound value/ (mean maximum - mean minimum)] x 100.
  • the IC 50 value is determined from sigmoid dose-response curves of enzyme activity versus compound concentration.
  • Method 2 Alternative Human Platelet PDE5 Enzyme Inhibition Scintillation Proximity Assay The IC 50 of test compounds also can be measured in an alternative in vitro assay that varies from Method 1 as described below:
  • Buffer A 20 mM Tris-HCI, 5 mM MgCI 2 , pH 7.4
  • Buffer B 2 mg/ml BSA in Buffer A (enzyme buffer)
  • cGMP substrate Final concentration of 50 n M in assay
  • the amount of 3 H-labeled substrate added depends upon the specific activity of [ 3 H]CGMP, and it is diluted in Buffer A.
  • PDE enzyme Prepared in Buffer B. The dilution factor is determined by enzyme activity.
  • SPA beads 4 mg/ml suspension prepared in dH 2 O.
  • Stocks of standard and test compound are prepared at 2 mM in 100% DMSO.
  • the test compound is serially diluted in a dilution plate using an 8-point 1/5 log dilution format such that the starting concentration in the assay is 2 ⁇ M for an initial IC 50 screen.
  • 27 ⁇ l of Buffer A are added to the wells of the assay plates.
  • 3 ⁇ l of diluted compound is delivered in duplicate or 3 ⁇ l of 100 % DMSO (for positive and negative controls) are added.
  • 30 ⁇ l of enzyme are added.
  • Buffer B is substituted in place of the enzyme.
  • 30 ⁇ l of labeled substrate are added to all wells.
  • the reaction is stopped with the addition of 30 ⁇ l of the yttrium silicate beads. These beads are dense and require constant agitation while being added to the plate. The plates are sealed and shaken on a plate shaker for fifteen minutes to allow the beads to bind the GMP product.
  • IC 50 values are shown in Table C for compounds tested in accordance with Method 2 above.
  • the effect of the test compound on systemic arterial blood pressure can be evaluated in a conscious pre-cannulated spontaneously hypertensive rat ("SHR") model.
  • This assay is conducted using an automated blood sampler ("ABS") system.
  • the CulexTM ABS system Bioanalytical System, Inc., West Lafayette, IN
  • the CulexTM ABS system comprises a laptop computer, four control units and metabolic cages.
  • This ABS system allows for the collection of multiple blood samples from a single rat without causing undue stress to the animal.
  • the ABS system allows for the collection of urine samples that can be potentially used for biomarker identifications.
  • connections are made between the right jugular catheter and the CulexTM sterile tubing set for blood sampling, and the left jugular catheter for compound administration, and the catheter in the right carotid artery is connected to a pressure transducer for monitoring blood pressure.
  • the right jugular cannula is maintained by the "tend" function of the CulexTM that flushes the catheter with 20 ⁇ l_ heparin saline (10 units/mL) every 12 minutes or between sampling events, and the left jugular cannula is filled with heparin saline (20 units/ml_).
  • the patency of the right carotid cannula is maintained by slow infusion of heparin saline either directly into the extend tubing when blood pressure is not recorded or through the pressure transducer during the blood pressure monitoring. Animals are allowed to acclimate for at least two hours before compound evaluation.
  • the test compound may be administered intravenously or by oral gavage. Blood sampling protocols (sampling time and volume) are programmed using the
  • CulexTM software The total amount of blood withdrawn from each animal will not exceed 750 ⁇ L/24 hrs and 10 ml_/kg within two weeks.
  • Heart rate, blood pressure, and drug concentration are monitored.
  • Systemic arterial blood pressure and heart rate are recorded by PONEMAH (Gould Instrument System, Valley View, OH), a pressure transducer through a data acquisition system for recording blood pressure and heart rate, for 6 to 24 hours based on experimental protocol.
  • Mean arterial blood pressure (primary endpoint) is analyzed for assessing the efficacy of the compound.
  • Blood samples are analyzed for measuring plasma drug concentration, using the LC/MS/MS method described below, and for evaluating potential biomarkers.
  • Plasma samples 50 ⁇ l_ unknown, control or blank
  • 10 ⁇ l_ acetonitrile:water or a standard solution of the test compound 150 ⁇ L of internal standard solution (100 ng/mL of the test compound in acetonitrile).
  • the mixture is centrifuged at 3000 rpm for 5 min, and 125 ⁇ L of the supernatant transferred to a 96 well plate.
  • the solvent is evaporated under a stream of nitrogen and the residue is reconstituted with 80 ⁇ L acetonitrile/0.1% aqueous formic acid (20:80 v/v).
  • a 20 ⁇ L volume of each prepared sample is injected onto a Phenomenex Synergi 4 ⁇ m MAX-RP 2.0 x 75 mm column and eluted at 0.4 mL/min using gradient elution from 0.1% aqueous formic acid (mobile phase A) to acetonitrile (mobile phase B).
  • the gradient program consists of initial application of 90% mobile phase A, followed by a linear gradient to 75% mobile phase B from 0.2 to 1.15 min after injection and held at 75% mobile phase B until 2.0 min. The mobile phase was linearly changed back to 90% mobile phase A from 2.00 to 2.10 minutes, and the next injection took place at 3.00 min.
  • Detection was performed by mass spectrometry using positive ion electrospray (ESI) with multiple reaction monitoring of the transitions m/z 454.00 (MH+ the Carboxypiperidine Compound) ⁇ m/z 408.00, m/z 466.24 (MH+ the Carboxypiperidine Compound) ⁇ 409.33 .
  • the ion spray voltagea is set at 5000.
  • a calibration curve is constructed by using peak area ratios of the analyte relative to the internal standard. Subject concentrations are determined by inverse prediction from their peak area ratios against the calibration curve.
  • Method 6 Implantation of Radio Transmitters and Subsequent Blood Pressure Screening by Telemetry in Spontaneously Hypertensive Rats
  • Rats are anesthetized with isoflurane gas via an isoflurane anesthesia machine that is calibrated to deliver isoflurane over a range of percentages as oxygen passes through the machine's inner chambers.
  • the animals are placed in an induction chamber and administered isoflurane at 4-5% to reach a surgical plane of anesthesia. They are then maintained at 1-2% during the surgical procedure via a nose cone, with isoflurane delivered via a smaller isoflurane anesthesia device on the surgical table.
  • the rats are implanted with transmitters using aseptic procedures with commercially available sterile radio-telemetry units (Data Sciences, International, Roseville, MN 55113-1136).
  • data Sciences International, Roseville, MN 55113-1136
  • the surgical field is shaved, scrubbed with DialTM brand antimicrobial solution (containing 4% chlorhexidine gluconate and 4% isopropyl alcohol) followed by an application of iodine (10%) spray solution.
  • DialTM brand antimicrobial solution containing 4% chlorhexidine gluconate and 4% isopropyl alcohol
  • iodine (10%) spray solution iodine (10%) spray solution.
  • a 2.5 to 3.0 cm laparotomy is preformed and the radio-telemetry units implanted into the abdomen, with the catheter tip inserted into the abdominal aorta. Baby Weitlaner retractors are used to retain soft tissue.
  • a 1 cm section of the abdominal aorta is partially dissected and that section cross-clamped briefly, punctured with a 21 -gauge needle and the transmitter catheter tip introduced into the vessel and secured by a single 4.0 silk suture anchored to the adjacent psoas muscle.
  • the transmitter body is then inserted into the abdominal cavity and simultaneously secured to the abdominal muscle wall while closing with running 4.0 silk suture.
  • the skin layer is closed with subdermal continuous 4.0 absorbable suture.
  • a subcutaneous (s.c.) administration of marcaine followed by a topical application of iodine is administered into and around the suture line, respectively, upon closing. All rats receive a postoperative injection of buprenorphine @ 0.05mg/kg, s.c. before regaining consciousness.
  • a typical dose volume for a 0.300kg rat will be 0.050ml.
  • the rats must be fully recovered from their operative anesthesia before the administration of buprenorphine. They then receive the same dose once daily for 2 consecutive days, unless the animal demonstrates that it is in compromising postoperative pain.
  • test compounds are administered intragastrically (i.g.) via gavage, using of a stainless steel, 2 1 /2 inch, 18 gauge gavage needle with a balled end.
  • the target volume is 3.33 ml/kg, i.g.
  • the dose volume for the test compound is approximately 1 ml/ rat.
  • Blood pressure data will be obtained using Data Sciences International's data acquisition program (Version 3.0). Blood pressure samples are recorded at 1.5-3 minute intervals for a 5 second duration 24 hours per day for the entire study. This data is processed by Data Science's data analysis software into averages of a desired time inervals. All other data reduction is performed in Microsoft ExcelTM spreadsheets.

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Abstract

Cette invention concerne des composés, des tautomères de ces composés, et des sels pharmaceutiquement acceptables de ces composés ou tautomères. Ces composés possèdent une structure représentée par la formule (I), dans laquelle R2, X6, Y6, R6 et R8 sont définis dans les pièces descriptives de la demande. Des compositions pharmaceutiques correspondantes, des procédés de traitement, des procédés de synthèse et des intermédiaires sont également divulgués.
PCT/IB2006/001387 2005-05-24 2006-05-17 Pyridine [3,4-b] pyrazinones Ceased WO2006126082A2 (fr)

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WO2007122466A1 (fr) * 2006-04-21 2007-11-01 Pfizer Products Inc. Pyridine[3,4-b]pyrazinones
FR2902009A1 (fr) * 2006-06-13 2007-12-14 Bioprojet Soc Civ Ile Utilisation d'un inhibiteur de vasopeptidase pour le traitement de l'hypertension arterielle pulmonaire
WO2009109341A1 (fr) 2008-03-05 2009-09-11 Merck Patent Gmbh Dérivés de pyridopyrazinone comme stimulateurs de la sécrétion d’insuline, leurs procédés d’obtention et leur utilisation pour le traitement du diabète
WO2012131539A1 (fr) 2011-03-31 2012-10-04 Pfizer Inc. Nouvelles pyridones bicycliques
WO2012172449A1 (fr) 2011-06-13 2012-12-20 Pfizer Inc. Lactames convenant comme inhibiteurs des bêta-sécrétases
WO2013030713A1 (fr) 2011-08-31 2013-03-07 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazine-2-amines
WO2014045156A1 (fr) 2012-09-21 2014-03-27 Pfizer Inc. Nouvelles pyridinones bicycliques
WO2014128585A1 (fr) 2013-02-19 2014-08-28 Pfizer Inc. Composés d'azabenzimidazole en tant qu'inhibiteurs d'isozymes pde4 pour le traitement de troubles du snc et d'autres affections
US8822456B2 (en) 2012-12-11 2014-09-02 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
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