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WO2007020521A1 - Pyridoyrazinones comme inhibiteurs de la pde-5 - Google Patents

Pyridoyrazinones comme inhibiteurs de la pde-5 Download PDF

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Publication number
WO2007020521A1
WO2007020521A1 PCT/IB2006/002234 IB2006002234W WO2007020521A1 WO 2007020521 A1 WO2007020521 A1 WO 2007020521A1 IB 2006002234 W IB2006002234 W IB 2006002234W WO 2007020521 A1 WO2007020521 A1 WO 2007020521A1
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Prior art keywords
alkyl
group
optionally substituted
halogen
independently selected
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PCT/IB2006/002234
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English (en)
Inventor
David Louis Brown
Dafydd Rhys Owen
Christopher Phillips
Michael John Palmer
Andrew Simon Bell
John Nicholas Freskos
Yvette Marlene Fobjan
John Keith Walker
Robert Craig Hughes
Eric Jon Jacobsen
Michael Brent Tollefson
David Graham Brown
Brent Virgil Mischke
John Major Molyneaux
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Pharmacia & Upjohn Company Llc
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Publication of WO2007020521A1 publication Critical patent/WO2007020521A1/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 of pyridine pyrazinone compounds having the structure of Formula I or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising a compound of Formula I or pharmaceutically acceptable salts thereof.
  • 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).
  • Blood pressure is defined by a number of haemodynamic parameters taken either in isolation or in combination.
  • SBP stolic blood pressure
  • PP pulse pressure
  • Hypertension or elevated BP
  • SBP SBP of at least 140mmHg and/or a DBP of at least 90mmHg.
  • DBP blood pressure
  • ISH systolic hypertension
  • Hypertension is associated with an increased risk of stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease and renal impairment (Fagard, RH; Am. J. Geriatric Cardiology 11 (1 ), 23-28, 2002).
  • hypertension is the result of an imbalance between cardiac output and peripheral vascular resistance, and that most hypertensive subjects have abnormal cardiac output and increased peripheral resistance, there is uncertainty which parameter changes first (Beevers, G et al.; BMJ 322, 912-916, 2001).
  • drugs available in various pharmacological categories, including diuretics, alpha-adrenergic antagonists, beta-adrenergic antagonists, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors and angiotensin Il receptor antagonists, the need for an effective treatment of hypertension is still not satisfied.
  • ACE angiotensin converting enzyme
  • nitric oxide nitric oxide
  • This NO 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. This dilation reduces vascular resistance and so leads to a reduction in blood pressure.
  • cGMP is inactivated by hydrolysis to guanosine 5'-monophosphate (GMP) by a cGMP-specific phosphodiesterase.
  • GMP guanosine 5'-monophosphate
  • PDE5 phosphodiesterase type 5
  • Inhibitors of PDE5 decrease the rate of hydrolysis of cGMP to GMP and so potentiate the actions of nitric oxide.
  • Inhibitors of PDE5 have been reported in several chemical classes.
  • a class of pyrazolo[4,3-d]pyrimidin-7-ones is described in published international patent application WO 93/06104.
  • a class of pyrazolo[4,3-d]pyrimidin-7-ones is also described in WO 98/49166.
  • a class of pyrazolo[4,3-d]pyrimidin-7-ones is also described in WO 01/27113.
  • a class of pyrazolo[3,4-d]pyrimidin-4-ones is also described in published international patent application WO 93/07149.
  • a class of purin-6-ones is described in published international patent application WO 94/00453.
  • a class of hexahydropyrazino[2',1 ':6,1]pyrido[3,4-b]indole-1 ,4-diones is described in published international application WO 95/19978.
  • WO 99/24433 discloses a class of pyrazolo[4,3-d]pyrimidines and reports that such . compounds have a PDE-5 inhibiting effect, and can be used for treating disorders of the cardiovascular system.
  • the invention comprises compounds and pharmaceutically acceptable salts of the compounds, wherein the compounds have the structure of Formula I:
  • 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, but are not limited to, cardiovascular diseases, metabolic diseases, central nervous system diseases, pulmonary diseases, sexual dysfunction, pain and renal dysfunction.
  • the invention comprises a method for inhibiting PDE-5, and including 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.
  • a condition typically a pathological condition
  • the invention comprises intermediates useful in the synthesis of compounds having the structure of Formula I.
  • 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).
  • the abbreviation “m” refers to a multiplet 1 H NMR peak.
  • the abbreviation “q” refers to a quartet 1 H NMR peak.
  • 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-methylbutenyl;
  • 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
  • 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. Where there are more than one hydrogens replaced with halogens, the halogens may be the same or different.
  • haloalkyls include chloromethyl, dichloromethyl, difluorochloromethyl, dichlorofluoromethyl, trichloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 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, tetradydrofumayl, 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
  • 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-benzodiazinyl”)), benzopyranyl (including “chromanyl” or “isochromanyl) or
  • benzoxazolyl indoxazinyl (also known as “benzisoxazolyl”), anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also known as “coumaronyl"), isobenzofuranyl, benzothienyl (also known as “benzothiophenyl,” “thionaphthenyl,” or “benzothiofuranyl”), isobenzothienyl (also known as “isobenzothiophenyl,” “isothionaphthenyl,” or
  • isobenzothiofuranyl benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (including 1 ,3,2-benzoxazinyl , 1 ,4,2-benzoxazinyl , 2,3,1-benzoxazinyl , or 3,1 ,4-benzoxazinyl ), benzisoxazinyl (including 1 ,2-benzisoxazinyl or 1 ,4-benzisoxazinyl), tetrahydroisoquinolinyl , carbazolyl, xanthenyl, and acridinyl.
  • 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, pyrimidi ⁇ yl, and pyridazinyl; 5-membered ring substituents such as 1,3,5-, 1 ,2,4- or 1,2,3-triazinyl, 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-, 2,3- and 2, 1-benzopyr
  • heteroaryls include unsaturated 5 to 6 membered heteromonocyclyl 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, 1H-1 ,2,3- triazolyl, 2H-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 ,5-
  • benzoxazolyl, benzoxadiazolyl ; unsaturated 5 to 6-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,
  • 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-sulfonyl-alkyl refers to alkyl-S(O) 2 -alkyl.
  • examples of typically preferred alkylsulfonyl substituents 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 refers to any substituent.
  • 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 J 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 preclinical ⁇ 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 pyrazinone compounds. These compounds are useful as inhibitors of PDE-5.
  • the present invention is directed, in part, to a class of compounds (including pharmaceutically acceptable salts of the compounds) having the structure of Formula I:
  • R 2 is selected from the group consisting of aryl, aryloxy, heterocyclyl, and heterocyclyloxy, wherein the R 2 aryl and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -OR A , -C(O)R A , -OC(O)R A , 34
  • R A and R B are independently selected from the group consisting of hydrogen, alkyl, ' alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl, 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, cycloalkyl, -OR E , -C(O)OR E , and- C(O)NR E R F , (c) the alkynyl substituent may be optionally substituted with one or more substituents independently selected from halogen, cyano, oxo, -OR E , -C(O)OR E , and - C(O)NR E R F , and (d) the cycloalkyl, aryl, and hetero
  • R°, R D , R E and R F are independently selected from the group consisting of hydrogen and alkyl
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -OR G , -C(O)R G , -OC(O)R G , -C(O)OR 3 , -NR G R H , -N(R G )C(O) R H , -C(O)NR G R H -, -C(O)NR G C(O)R H , -SR G , -S(O)R G ,-S(O) 2 R G , - N(R G )S(O) 2 R H , and -S(O) 2 NR G R H , wherein (a) the R 3 and R 4 alkyl, alkenyl, and alkynyl substitutents may be optionally substituted with one or more substituents independently selected from the group consisting of
  • R G and R H are independently selected from the group consisting of hydrogen, alkyl, alkynyl, cycloalkyl, aryl, and heterocyclyl, 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 a substituent selected from one or more of the group consisting of halogen, cycloalkyl, -OR L , -C(O)OR M , and -C ⁇ O)NR L R M , (c) the R G and R H alkynyl substituents may be optionally substituted with one or more substituents independently selected from halogen, cyano, oxo, -OR L , -C(O)OR L , and -C(O)NR L R M , and (d) the R G and R H cycloalkyl
  • R J , R ⁇ , R L and R M are independently selected from the group consisting of hydrogen and alkyl;
  • X 6 represents a bond or is selected from the group consisting of -O-, -C(O)-, -C(O)O-, - OC(O)-, -N(R N )-, -N(R N )C(O)-, - C(O)N(R 1 Y, -S- -S(O)- -S(O) 2 -, -OS(O) 2 -, -N(R N )S(O) 2 -, and -S(O) 2 N(R N )-;
  • R N is selected from the group consisting of hydrogen and alkyl, wherein the R N alkyl comprising at least two carbon atoms may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and OR P ;
  • R p is alkyl wherein the alkyl may be optionally substituted with one or more halogen substituents
  • Y 6 represents a bond or is selected the group consisting of alkyl, alkynyl, cycloalkyl, aryl, and heterocyclyl, wherein (a) the Y 6 alkyl and alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, cycloalkyl, aryl, heterocyclyl, -0R Q , -C(0)R Q , -C(O)OR 0 , -OC(O)R 0 , -NR°R R , - N(R°)C(O)R R , -C(0)NR°R R , -C(O)NR 0 C(O) R R , -SR 0 , -S(O)R 0 , -S(O) 2 R 0 , -N(R°)S(O) 2 R R , and - S(O) 2
  • R° and R R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl, wherein (a) when the alkyl is methyl, the methyl may be optionally substituted by 1 , 2, or 3 fluoro substituents, (b) when the alkyl comprises at least two carbon atoms, 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, (c) the R° and R R alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, o
  • R 6 is selected from the group consisting of halogen, hydroxy, amino, alkyl, alkylamino, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein (a) the R 6 alkyl, alkylamino, and alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, cycloalkyl, aryl, heterocyclyl, -OR S , - C(O)R S , -C(O)OR S , -OC(O)R S , -NR S R T , -N(R S )C(O)R T , -C(O)NR S R T , -C(O)NR S C(O)R T , -SR S , - S(O)R S , -S(O) 2 R S , -
  • R s and R ⁇ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl, wherein (a) when the alkyl is methyl, the methyl may be optionally substituted by 1 , 2, or 3 fluoro substituents, (b) when the alkyl comprises at least two carbon atoms, 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, (c) the R s and R ⁇ alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy,
  • R 8 is selected from the group consisting of alkyl, cycloalkyl, aryl and heterocyclyl; wherein (a) the R 8 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, cycloalkyl, alkynyl, aryl, heterocyclyl, -OR ⁇ , -C(O)R U , -C(O)OR U , -OC(O)R U , -NR ⁇ R v , - N(R ⁇ )C(O)R v , -C(O)NRV, -C(O)NR U C(O)R V , -SR ⁇ , -S(O)R U , -S(O) 2 R ⁇ , -N(R U )S(O) 2 R V , and - S(O) 2 NR ⁇ R v , where
  • R ⁇ and R v are independently selected from the group consisting of hydrogen, alkyl, alkynyl, cycloalkyl, aryl and heterocyclyl, wherein (a) when the alkyl is methyl, the methyl may be optionally substituted with 1 , 2, or 3 fluoro substituents, (b) when the alkyl comprises at least two carbon atoms, 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, (c) the R ⁇ and R v alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, ox
  • R 2 is selected from the group consisting of aryl and 3- 10 membered ring heterocyclyl, optionally substituted as described in Formula I.
  • the R 2 aryl or 3-10 membered ring heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, oxo, alkyl, cycloalkyl, phenyl, 3-10 membered ring heterocyclyl, -OR A , -C(O)R A , - OC(O)R A , -C(O)OR A , -NR A R B , -N(R B )C(O) R c , -C(O)NR A R B , -C(O)NR A C(O)R B , -SR A , -S(O)R A , - S(O) 2 R A , -N(R A )S(O) 2 R B , and -S(O) 2 NR A R B , wherein (a) the alkyl substitutent may be optionally substituted with one or
  • the R 2 aryl or 3-10 membered ring heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, -OR C , -C(O)OR 0 , and -C(O)NR 0 R 0
  • the cycloalkyl, phenyl, and 5-7 membered ring heterocyclyl substitutents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, -OR 0 , -C(O)OR 0 , and -C(O)NR 0 R 0
  • R A and R B are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, and 5-7 membered ring heterocyclyl, wherein (a) when the alkyl is methyl, the
  • R 2 aryl or 3-10 membered ring heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, -OR A , -NR A R B , and -S(O) 2 R A , wherein the alkyl substitutent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, -OR 0 , -C(O)OR 0 , and -C(O)NR 0 R 0 ; wherein R A and R B are independently selected from the group consisting of hydrogen, alkyl, C 3 -C 6 -cycloalkyl, phenyl, and 5-6 membered ring heterocyclyl, 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
  • the R 2 aryl or 3-10 membered ring heterocyclyl 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, diethylamino, methylsulfonyl, and ethylsulfonyl.
  • 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, diethylamino, methylsulfony
  • the R 2 aryl or 3-10 membered ring heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, amino, methylamino, dimethylamino, and methylsulfonyl.
  • the R 2 aryl or 3-10 membered ring heterocyclyl is optionally substituted with one or more fluoro substituents.
  • the R 2 aryl or 3-10 membered ring heterocyclyl is optionally substituted with two fluoro substituents.
  • R 2 is selected from the group consisting of phe ⁇ iyl, napthyl, and 5-7 membered ring heterocyclyl, each optionally substituted as described in Formula I.
  • R 2 is phenyl (optionally substituted as described in Formula I), described in Formula I-A:
  • R 12 , R 13 , R 14 , R 15 , and R 16 are independently selected from the group consisting of hydrogen, halogen, cyano, oxo, alkyl, cycloalkyl, phenyl, 5-7 membered ring heterocyclyl, - OR A , -C(O)R A , -OC(O)R A , -C(O)OR A , -NR A R B , -N(R B )C(O) R c , -C(O)NR A R B , -C(O)NR A C(O)R B , - SR A , -S(O)R A , -S(O) 2 R A , -N(R A )S(O) 2 R B , and -S(O) 2 N R A R B , wherein (a) the alkyl substituted may be optionally substituted with one or more substituents independently selected from the group consisting of
  • R 2 is 5-7 membered ring heterocyclyl, optionally substituted as described in Formula I. In another embodiment, R 2 is a 5-7 membered ring heteroaryl, optionally substituted as described in Formula I.
  • R 2 is selected from the group consisting of phenyl, pyrrolyl, imidazolyl, pyrazolyl, tetrahydrofuryl, dihydrofuryl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, morpholinyl, and benzofuryl, each optionally substituted as described in Formula I.
  • R 2 is selected from the group consisting of phenyl, pyrazolyl, tetrahydrofuryl, furyl, isoxazolyl, thienyl, pyridinyl, pyrimidinyl, and benzofuryl, each optionally substituted as described in Formula I.
  • R 2 is pyridinyl, optionally substituted as described in Formula I.
  • R 2 is selected from the group consisting of 4- pyridinyl and 3-pyridinyl, (optionally substituted as described in Formula I), described in Formulas I-B and I-C:
  • R 9 , R 10 , R 12 and R 13 are independently selected from the group consisting of hydrogen, halogen, cyano, oxo, alkyl, cycloalkyl, phenyl, 5-7 membered ring heterocyclyl, -OR A , -C(O)R A , ⁇ OC(O)R A , -C(O)OR A , -NR A R B , -N(R B )C(O) R°, -C(O)NR A R B , -C(O)NR A C(O)R B , -SR A , -S(O)R A , - S(O) 2 R A , -N(R A )S(O) 2 R B , and -S(O) 2 NR A R B , wherein (a) the alkyl substituted may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, o
  • R 2 is pyrimidinyl (optionally substituted as described in Formula I), as described in Formula I-D:
  • R 9 , R 10 and R 12 are independently selected from the group consisting of hydrogen, halogen, cyano, oxo, alkyl, cycloalkyl, phenyl, 5-7 membered ring heterocyclyl, -OR A , -C(O)R A , - OC(O)R A , -C(O)OR A , -NR A R B , -N(R B )C(O) R°, -C(O)NR A R B , -C(O)NR A C(O)R B , -SR A , -S(O)R A , - S(O) 2 R A , -N(R A )S(O) 2 R B , and -S(O) 2 NR A R B , wherein (a) the alkyl substitutent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo,
  • R is pyrazoyl (optionally substituted as described in Formula I), as described in Formula I-E:
  • R 9 , R 10 , R 11 and R 12 are as described in Formula I-D.
  • R is isoxazolyl (optionally substituted as described in Formula I), as described in Formula I-F:
  • the R substituent is selected from the group consisting of the substituents listed in Table B: Table B
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, phenyl, amino, alkylamino, haloalkylamino, hydroxyalkylamino, mercapto, alkylthio, haloalkylthio, and hydroxyalkylthio.
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, cyano, hydroxy, carboxy, methyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, ethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoroethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, propyl, methoxy, ethoxy, propoxy, phenyl, amino, methylamino, dimethylamino, mercapto, and methylthio.
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, fluoro, methyl, ethyl, trifluoromethyl, and methoxy.
  • At least one of R 3 and R 4 is hydrogen.
  • both R 3 and R 4 are hydrogen, as described in Formula I-AA:
  • X 6 represents a bond or is selected from the group consisting -O-, and -N(R N )-; wherein R N is independently selected from the group consisting of hydrogen and alkyl, wherein the R N alkyl comprising at least two carbon atoms may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and -OR P ; and further wherein R p is alkyl wherein the alkyl may be optionally substituted with one or more fluoro radical substituents.
  • X 6 is -N(R N )-, wherein R N is selected from the group consisting of hydrogen and C 1 -C 4 alkyl; wherein the R N C 1 -C 4 alkyl comprising at least two carbon atoms may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and -OR P ; and R p is CrC 4 alkyl wherein the C 1 -C 4 alkyl may be optionally substituted with one or more fluoro radical substituents.
  • X 6 is -N(R N )-, wherein R N is hydrogen, as described in Formula I-K:
  • X 6 represents a bond, as described in Formula I-G:
  • Y 6 represents a bond or is selected from the group consisting of alkyl and -O-, wherein the Y 6 substitutent may be optionally substituted as described in Formula I.
  • Y 6 is alkyl, optionally substituted as described in Formula I. In another embodiment of Formula I, Y 6 is a C 1 -C 6 alkyl, optionally substituted as described in Formula I. In another embodiment of Formula I, Y 6 is selected from the group consisting of -CH 2 - , -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 (CH 3 )-, -CH 2 CH 2 (CH 3 )-, -CH 2 (CH 3 )CH 2 -, -0-CH 2 -, and - OCH 2 CH 2 -.
  • Y 6 represents a bond, as described in Formula I-X:
  • R is selected from the group consisting of halogen, hydroxy, amino, alkyl, alkylamino, cycloalkyl, aryl, and 3-10 membered ring heterocyclyl, wherein (a) the R 6 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, cycloalkyl, aryl, 3-10 membered ring heterocyclyl, -OR S , -C(O)R S , -C(O)OR S , -OC(O)R S , -NR S R T , -SR S and - S(O) 2 R S , and (b) the R 6 cycloalkyl, aryl, and 3-10 membered ring heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl
  • R 6 is alkyl, wherein the R 6 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, cycloalkyl, aryl, 3-10 membered ring heterocyclyl, -OR S , -C(O)R S , - C(O)OR 53 , -OC(O)R 53 , -NR 53 R 1" , -SR S and -S(O) 2 R 53 ; and wherein R s and R ⁇ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and 3-10 membered ring heterocyclyl, wherein (a) when the alkyl is methyl, the methyl may be optionally substituted by 1 , 2, or 3 fluoro substituents, (b) when the alkyl comprises at least two carbon atoms, the alkyl may be optionally substituted with one or more substituents independently selected from the
  • R 6 is alkyl, wherein the R 6 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 53 , -C(O)R S , -C(O)OR S , -OC(O)R 53 , -NR 53 R 1" , and -S(O) 2 R S ; and wherein R 55 and R ⁇ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and 3-10 membered ring heterocyclyl, wherein (a) when the alkyl is methyl, the methyl may be optionally substituted by 1 , 2, or 3 fluoro substituents, (b) when the alkyl comprises at least two carbon atoms, the alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkyny
  • R 6 is cycloalkyl, wherein the R 6 cycloalkyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, alkynyl, cycloalkyl, aryl, 3-10 membered ring heterocyclyl, -OR S , -C(O)R S , -C(O)OR S , -OC(O)R S , -NR S R T ,-SR S and -S(O) 2 R S ; and wherein R s and R ⁇ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and 3-10 membered ring heterocyclyl, wherein (a) when the alkyl is methyl, the methyl may be optionally substituted by 1 , 2, or 3 fluoro substituents, (b) when the alkyl comprises at least two carbon
  • R 6 is phenyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, alkynyl, cycloalkyl, aryl, 3-10 membered ring heterocyclyl, -OR S , -C(O)R S , -C(O)OR S , -OC(O)R S , -NR S R T ,-SR S and -S(O) 2 R S ; and wherein R s and R ⁇ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and 3-10 membered ring heterocyclyl, wherein (a) when the alkyl is methyl, the methyl may be optionally substituted by 1 , 2, or 3 fluoro substituents, (b) when the alkyl comprises at least two carbon atoms, the alkyl may be optionally substituted with one or more
  • R 6 is 5-6 membered ring heterocylyl, optionally substituted as described in Formula I. In another embodiment of Formula I, R 6 is 5-6 membered ring heteroaryl, optionally substituted as described in Formula I.
  • R 6 is 5-6 membered ring fully or partially saturated heterocyclyl, optionally substituted as described in Formula I.
  • R 6 is selected from the group consisting of pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, tetrahydrofuryl, dihydrofuryl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, and morpholinyl, each optionally substituted as described in Formula I.
  • R 6 is selected from the group consisting of pyrrolidinyl, imidazolyl, tetrahydrofuryl, furyl, piperidinyl, piperazinyl, pyridinyl, pyrazinyl, tetrahydropyranyl, and morpholinyl, each optionally substituted as described in Formula I.
  • R 6 is a 5-6 membered ring heterocyclyl, wherein the R 6 5-6 membered ring heterocyclyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, alkynyl, cycloalkyl, aryl, 3-10 membered ring heterocyclyl, -OR S , -C(O)R S , -C(O)OR S , -OC(O)R S , -NR S R T , -SR S and - 1 S(O) 2 R 3 ; and wherein R s and R ⁇ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and 3-10 membered ring heterocyclyl, wherein (a) when the alkyl is methyl, the methyl may be optionally substituted by 1 , 2, or 3 flu ⁇ ro substituents
  • R 6 is a 5-6 membered ring heterocyclyl, wherein the R 6 5-6 membered ring heterocyclyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, C 3 - C 6 -cycloalkyl, phenyl, 5-6 membered ring heterocyclyl, -OR S , -C(O)R S , -C(O)OR S , -OC(O)R S , - NR S R T ,-SR S and -S(O) 2 R S ; and wherein R s and R ⁇ are independently selected from the group consisting of hydrogen, alkyl, C 3 -C 6 -cycloalkyl, phenyl, and 5-6 membered ring heterocyclyl, wherein (a) when the alkyl is methyl, the methyl may be optionally substituted by 1, 2, or
  • R 6 substituent is selected from the group consisting of the substituents listed in Table C:
  • RR 88 iiss aallkkyl, optionally substituted as described in Formula I.
  • R 8 is C f C-io-alkyl, optionally substituted as described in Formula I.
  • R 8 is Ci-C 6 -alkyl, optionally substituted as described in Formula I.
  • R 8 is alkyl, wherein the R 8 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, C 3 -C 6 -cycloalkyl, phenyl, 3-10 membered ring heterocyclyl, -OR U , -C(O)R U , -C(0)0R u , -OC(O)R U , -NR U R V , -N(R U )C(O)R V , -C ⁇ O)NR U R V , -
  • R 8 is alkyl, wherein the R 8 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 3 -C 6 -cycloalkyl, phenyl, 5-7 membered ring heterocyclyl, -OR U , -NR U R V , and -SR U , wherein the C 3 -C 6 -cycloalkyl, phenyl, 5-7 membered ring heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkyl, phenyl, 5-7 membered ring heterocyclyl, and alkoxy; and wherein R u and R v are independently selected from the group consisting of hydrogen, alkyl, C 3 -C 6 -cycloalkyl, phenyl, and 5-7 membered ring
  • R 8 is selected from the group consisting of alkyl, cycloalkylalkyl, phenylalkyl, 3-10 membered ring heterocyclylalkyl, alkylthioalkyl, alkoxyalkyl, cycloalkoxyalkyl, phenoxyalkyl, 3-10 membered ring heterocyclyloxyalkyl, and alkoxyarylalkyl, 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, oxo, and alkoxy.
  • R 8 is alkoxyalkyl, optionally substituted as described in Formula I.
  • R 8 is a d-C ⁇ alkoxy-C ⁇ -alkyl, optionally substituted as described in Formula I.
  • R 8 is methoxyethyl, as described in Formula I-L:
  • R 8 is ethoxyethyl, as described in Formula I-M:
  • R 8 is isopropoxyethyl, as described in Formula I L N:
  • R 8 is propoxyethyl, as described in Formula I-O:
  • R 8 is trifluoroethylethoxy as described in Formula I-
  • R 8 is as described in Formula I-Q:
  • R is as described in Formula I-R:
  • R 8 is as described in Formula I-S:
  • R 8 is as described in Formula I-T:
  • R 8 is as described in Formula I-U:
  • R 8 is as described in Formula I-V:
  • R is as described in Formula I-W:
  • R 8 is cycloalkylalkyl, optionally substituted as described in Formula I.
  • R 8 is phenylalkyl, optionally substituted as described in Formula I.
  • R 8 is 5-6 membered ring heterocyclylalkyl, optionally substituted as described in Formula I.
  • R 8 substituent is selected from the group consisting of the substituents listed in Table D:
  • R 2 is selected from the group consisting of the substituents listed in Table B
  • R 6 is selected from the group consisting of the substituents listed in Table C
  • R 8 is selected from the group consisting of the substituents listed in Table D.
  • X 6 represents a bond or is selected from the group consisting of -O- and -N(R N )-, wherein R N is selected from the group consisting of select ⁇ dfrom the group consisting of hydrogen and alkyi, wherein the R N alkyl comprising at least two carbon atoms may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and -OR P ; and R p is alkyl wherein the alkyl may be optionally substituted with one or more f luoro radical substituents;
  • Y 6 represents a bond or is selected from the group consisting of alkyl and -O-, wherein the Y 6 substitutent may be optionally substituted as described in Formula I;
  • R 6 is selected from the group consisting of halogen, hydroxy, amino, alkyl, alkylamino, cycloalkyl, aryl, and 3-10 membered ring heterocyclyl, wherein ⁇ a) the R 6 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, cycloalkyl, aryl, 3-10 membered ring heterocyclyl, -OR S , -C(O)R S , - C(O)OR S , -OC(O)R S , -NR S R T , -SR S and -S(O) 2 R S , and (b) the R 6 cycloalkyl, aryl, and 3-10 membered ring heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, alkyn
  • X 6 represents a bond or is -N(R N )-; wherein R N is independently selected from the group consisting of hydrogen, alkyl, and haloalkyl; Y 6 represents a bond or is alkyl, optionally substituted as described in Formula I; and R 6 is as described in Embodiment 1.
  • Embodiment 3 :
  • X 6 , Y 6 , and R 6 are as described in Embodiment 2; and R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, phenyl, amino, alkylamino, haloalkylamino, hydroxyalkylamino, mercapto, alkylthio and hydroxyalkylthio.
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, phenyl, amino, alkylamino, haloalkylamino, hydroxyalkylamino, mercapto, alkylthio and hydroxyalkylthio.
  • X 6 , Y 6 , R 6 , R 3 and R 4 are as described in Embodiment 3; and R 8 is alkyl, wherein R 8 may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, C 3 -C 6 -cycloalkyl, phenyl, 3-10 membered ring heterocyclyl, -OR U , -C(O)R U , -C(O)OR U , - OC(O)R U , -NR U R V , -N(R U )C(O)R V , -C ⁇ O)NR U R V , -C(O)NR U C(O)R V , -SR ⁇ , -S ⁇ O)R U , -S(O) 2 R U , - N(R U )S(O) 2 R V , and -S(O)
  • X 6 , Y 6 , R 6 , R 3 and R 4 are as described in Embodiment 4; and R 8 is alkyl, wherein R 8 may be optionally substituted with one or, more substituents independently selected from the group consisting of -halogen, C 3 -C 6 -cycloalkyl, phenyl, 5-7 membered ring heterocyclyl, -OR U , -NR U R V , and -SR ⁇ , wherein the C 3 -C 6 -cycloalkyl, phenyl, 5-7 membered ring heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alky], phenyl, 5-7 membered ring heterocyclyl, and alkoxy; and R u and R v are independently selected from the group consisting of hydrogen, alkyl, C 3
  • Embodiment 6 In another embodiment of Formula I, X 6 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in
  • R 2 is selected from the group consisting of aryl and 3-10 membered ring heterocyclyl, wherein the aryl and 3-10 membered ring heterocyclyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -OR A , -C(O)R A , -OC(O)R A , - C(O)OR A , -NR A R B , -N(R B )C(O) R c , -C(O)NR A R B , -C(O)NR A C(O)R B , -SR A , -S(O)R A , -S(O) 2 R A , - N(R A )S(O) 2 R B , and --
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • X 6 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in Embodiment 5; and R 2 is selected from the group consisting of phenyl and 5-6 membered ring heterocyclyl, wherein R 2 is optionally substituted as described in Embodiment 6.
  • X 6 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in Embodiment 5; and R 2 is selected from the group consisting of phenyl, pyrrolyl, imidazolyl, pyrazolyl, tetrahydrofuryl, dihydrofuryl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and benzofuryl, wherein R 2 is optionally substituted as described in Embodiment 6.
  • X 6 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in , Embodiment 5; and R 2 is selected from the group consisting of phenyl, pyrrolyl, imidazolyl, pyrazolyl, tetrahydrofuryl, dihydrofuryl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and benzofuryl, wherein R 2 is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, oxo, alkyl, cycloalkyl, phenyl, 3-10 membered ring heterocyclyl, -OR A , -C(O)R A ,
  • R 2 is selected from the group consisting of phenyl, pyrrolyl, imidazolyl, pyrazolyl, tetrahydrofuryl, dihydrofuryl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and benzofuryl, wherein R 2 is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, alkyl, cycloalkyl, phenyl, 5-7 membered ring heterocyclyl, -OR A , -C(O)R A , -OC(O)R A , -C(O)OR A , - NR A R B , -N(R B )C(0) R°, -
  • R 2 , X 6 , Y 6 , R 6 , and R 8 are as described in Embodiment 9; and R 3 and R 4 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, cyano, hydroxy, carboxy, methyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, ethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoroethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, propyl, methoxy, ethoxy, propoxy, phenyl, amino, methylamino, dimethylamino, mercapto, and methylthio.
  • Embodiment 11 In another embodiment of Formula I, R 2 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in
  • Embodiment 10 and X 6 represents a bond or is -N(R N )-, wherein R N is hydrogen.
  • Embodiment 12 is a diagrammatic representation of Embodiment 12
  • X 6 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in Embodiment 11 , and R 2 is selected from the group consisting of phenyl, pyrazolyl, tetrahydrofuryl, furyl, isoxazolyl, thienyl, pyridinyl, pyrimidinyl, and benzofuryl, and wherein the R 2 substituted may be optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, -OR A , -NR A R B , and -S(O) 2 R A , wherein the alkyl substitutent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, -OR C , -C(O)OR 0 , and -C(O)NR 0 R 0 ; wherein R A and R B
  • Embodiment 13 In another embodiment of Formula I, R 2 , X 6 , Y 6 , R 6 , R 3 , and R 4 are as described in Embodiment 12, and R 8 is selected from the group consisting of alkyl, cycloalkylalkyl, phenylalkyl, 3-10 membered ring heterocyclylalkyl, alkylthioalkyl, alkoxyalkyl, cycloalkoxyalkyl, phenoxyalkyl, 3-10 membered ring heterocyclyloxyalkyl, and alkoxyarylalkyl, 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, oxo, and alkoxy.
  • Embodiment 14 is a diagrammatic representation of Embodiment 14:
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 8 are as described in > Embodiment 13, and R 6 is selected from the group consisting of alkyl, C 3 -C 6 -cycloalkyl, phenyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, tetrahydrofuryl, dihydrofuryl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, and morpholinyl, wherein (a) the R 6 alkyl substituent may be optionally substituted with one or more substituents independently selected
  • piperazinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, and morpholinyl substitutents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, alkynyl, C 3 -C 6 -cycloalkyl, phenyl, 3-10 membered ring heterocyclyl, -OR S , -C(O)R S , -C(O)OR S , -OC(O)R S , -NR S R T ,-SR S and -S(O) 2 R S ; wherein R s and R ⁇ are independently selected from the group consisting of hydrogen, alkyl, C 3 - C 6 -cycloalkyl, phenyl, and 3-10 membered ring heterocyclyl, wherein (a) when the al
  • Embodiment 15 In another embodiment of Formula I, R 2 , X 6 , Y 6 , R 3 , R 4 , and R 8 are as described in Embodiment 14, and R 6 is selected from the group consisting of alkyl, C 3 -C 6 -cycloalkyl, phenyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, tetrahydrofuryl, dihydrofuryl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, and morpholinyl, wherein -(a) the R 6 alkyl substituent may be optionally substituted with one
  • Embodiment 16 In another embodiment of Formula I, R 2 , X 6 , Y 6 , R 6 , and R 8 are as described in Embodiment 15, and R 3 and R 4 are independently selected from the group consisting of hydrogen, fluoro, methyl, ethyl, trifluoromethyl, and methoxy.
  • Embodiment 17 is a diagrammatic representation of Embodiment 17:
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 6 are as described in Embodiment 16, and R 8 is selected from the group consisting of alkyl, alkoxyalkyl, C 3 -C 6 - cycloalkylalkyl, phenylalkyl, 5-6 membered ring heterocyclylalkyl, and alkylthioalkyl, wherein ⁇ a) the R 8 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy, and (b) the R 8 alkoxyalkyl, cycloalkylalkyl, phenylalkyl, 5-6 membered ring heterocyclylalkyl, and alkylthioalkyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carb
  • Embodiment 18 is a diagrammatic representation of Embodiment 18:
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 6 are as described in Embodiment 17, and R 8 is selected from the group consisting of alkyl, alkoxyalkyl, C 3 -C 6 - cycloalkylalkyl, and alkylthioalkyl, wherein (a) the R 8 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy, and (b) the R 8 alkoxyalkyl, cycloalkylalkyl, and alkylthioalkyl 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.
  • PC33036A PC33036A
  • Embodiment 19 is a diagrammatic representation of Embodiment 19:
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 8 are as described in Embodiment 18, and R 6 is selected from the group consisting of alkyl, cyclohexyl, pyrrolidinyl, imidazolyl, tetrahydrofuryl, furyl, piperidinyl, piperazinyl, pyridinyl, pyrazinyl, tetrahydropyranyl, and morpholinyl, wherein (a) the R 6 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy, and (b) the R 6 cyclohexyl, pyrrolidinyl, imidazolyl, tetrahydrofuryl, furyl, piperidinyl, piperazinyl, pyridinyl, pyrazin
  • Embodiment 20 is a diagrammatic representation of Embodiment 20.
  • X 6 , Y 6 , R 3 , R 4 , R 6 , and R 8 are as described in Embodiment 19, and R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 phenyl and pyridinyl substitutents may be optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, alkoxy , ⁇ amino, alkylamino, and alkylsulfonyl.
  • R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 phenyl and pyridinyl substitutents may be optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, alkoxy , ⁇ amino, alkylamino, and alkylsulfonyl.
  • Embodiment 21
  • X 6 , Y 6 , R 3 , R 4 , R 6 , and R 8 are as described in Embodiment 20, and R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 phenyl and pyridinyl substitutents may be 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, diethylamino, m ethyls ulfonyl, and ethylsulfonyl.
  • R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 phenyl and pyridinyl substitute
  • X 6 , Y 6 , R 3 , R 4 , R 6 , and R 8 are as described in Embodiment 21 , and R 2 is selected from ' the group consisting of phenyl and pyridinyl, wherein the R 2 phenyl and pyridinyl substitutents may be optionally substituted with one or more substituents selected from the group consisting of fluoro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, amino, methylamino, dimethylamino, and methylsulfonyl.
  • R 2 is selected from ' the group consisting of phenyl and pyridinyl, wherein the R 2 phenyl and pyridinyl substitutents may be optionally substituted with one or more substituents selected from the group consisting of fluoro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, amino, methylamino, dimethylamino, and
  • X 6 , Y 6 , R 3 , R 4 , R 6 , and R 8 are as described in Embodiment 22, and R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 phenyl and pyridinyl substitutents may be optionally substituted with one or more fluoro substituents.
  • Embodiment 24 is a diagrammatic representation of Embodiment 24.
  • X 6 , Y 6 , R 3 , R 4 , R 6 , and R 8 are as described in Embodiment 22, and R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 phenyl and pyridinyl substitutents maybe optionally substituted with two fluoro substituents.
  • R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 phenyl and pyridinyl substitutents maybe optionally substituted with two fluoro substituents.
  • Embodiment 25 is a diagrammatic representation of Embodiment 25.
  • R 2 , X 6 , Y 6 , R 6 , and R 8 are as described in Embodiment 22, and both R 3 and R 4 are hydrogen.
  • Embodiment 26 In another embodiment of compounds, tautomers of the compound, or pharmaceutically acceptable salts of the compounds or tautomers Formula I,
  • R 2 is selected from the group consisting of phenyl, pyrrolyl, imidazolyl, pyrazolyl, tetrahydrofuryl, dihydrofuryl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and benzofuryl, and wherein the R 2 substitutent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, cycloalkyl, phenyl, 5-7 membered ring heterocyclyl, - OR A , -C(O)R A , -OC(O)R A , -C(O)OR A , -NR A R B , -N(R A )C(
  • R A and R B are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, phenyl, and 5-7 membered ring heterocyclyl, 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, cycloalkyl, -OR E , -C(O)OR E , and- C'(O)NR E R F , and (c) the cycloalkyl, phenyl, and 5-7 membered ring heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from halogen, cyano, oxo, alkyl, -OR E , -C(O)OR E , and -C(O)NR E R
  • R°, R D , R E and R F are independently selected from the group consisting of hydrogen and alkyl
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -OR G , -C(O)R G , -OC(O)R G , -C(O)OR G , -NR G R H , -N(R G )C(O) R H , -C(O)NR G R H -, -C(O)NR G C(O)R H , -SR G , -S(O)R G ,-S(O) 2 R G , - N(R G )S(O) 2 R H , and -S(O) 2 NR G R H , wherein (a) the R 3 and R 4 alkyl, alkenyl, and alkynyl substitutents may be optionally substituted with one or more substituents independently selected from the group consisting of
  • R J , R ⁇ , R L and R M are independently selected from the group consisting of hydrogen and alkyl;
  • X 6 represents a bond or is selected from the group consisting of -O-, -N(R N )- , and -
  • R N is selected from the group consisting of hydrogen and alkyl, wherein the R N alkyl comprising at least two carbon atoms may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and OR P ;
  • R p is alkyl wherein the alkyl may be optionally substituted with one or more halogen substituents
  • Y 6 represents a bond or is alkyl, wherein the Y 6 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, cycloalkyl, aryl, heterocyclyl, -OR Q , -C(O)R Q , -C(O)OR 0 , -OC(O)R 0 , - NR Q R R , -N(R Q )C(O)R R , -C(O)NR Q R R , -C(O)NR 0 C(O) R R , -SR 0 , -S(O)R 0 , -S(O) 2 R 0 , - N(R°)S(O) 2 R R , and -S(O) 2 NR°R R ;
  • R° and R R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl, wherein (a) when the alkyl is methyl, the methyl may be optionally substituted by 1 , 2, or 3 fluoro substituents, (b) when the alkyl comprises at least two carbon atoms, 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, (c) the R° and R R alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, o
  • R 6 is selected from the group consisting of halogen, hydroxy, amino, , ' aryl, and heterocyclyl, wherein (a) the R 6 alkyl, alkylamino, and alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, cycloalkyl, aryl, heterocyclyl, -OR S , -C(O)R S , -C(O)OR S , -OC(O)R S , - NR S R T , -N(R S )C(O)R T , -C(O)NR S R T , -C(O)NR S C(O)R T , -SR S , -S(O)R S , -S(O) 2 R S , - N(R S )S(O) 2 R T , and -S(O) 2 NR S
  • R s and R ⁇ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl, wherein (a) when the alkyl is methyl, the f I methyl may be optionally substituted by 1 , 2, or 3 fluoro substituents, (b) when the alkyl comprises at least two carbon atoms, 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, (c) the R s and R ⁇ alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carb
  • R 8 is alkyl, wherein the R 8 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, cycloalkyl, alkynyl, aryl, heterocyclyl, -OR U , -C(O)R U , -C(O)OR ⁇ , -OC(O)R U , - NR ⁇ R v , -N(R ⁇ )C(O)R v , -C(O)NR U R V , -C(O)NR U C(O)R V , -SR U , -S(O)R U , -S ⁇ O) 2 R U , - N(R U )S(O) 2 R V , and -S(O) 2 NR ⁇ R v , wherein the cycloalkyl, alkynyl, aryl, and heterocyclyl
  • X 6 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in Embodiment 26, and R 2 is selected from the group consisting of phenyl, pyrazolyl, tetrahydrofuryl, furyl, isoxazolyl, thienyl, pyridinyl, pyrimidinyl, and benzofuryl, optionally substituted as described in Embodiment 26.
  • Embodiment 28 :
  • R 2 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in Embodiment 27, and X 6 represents a bond or is selected from the group consisting of -O- and N(R N )-, wherein R N is independently selected from the group consisting of hydrogen and alkyl, wherein the R N alkyl comprising at least two carbon atoms may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and - OR P ; and R p is alkyl wherein the alkyl may be optionally substituted with one or more fluoro radical substituents.
  • R 2 , X 6 , Y 6 , R 6 , and R 8 are as described in Embodiment 28, and R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, phenyl, amino, alkylamino, haloalkylamino, hydroxyalkylamino, mercapto, alkylthio, haloalkylthio, and hydroxyalkylthio.
  • Embodiment 30 In another embodiment of Formula I, X 6 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in
  • Embodiment 29, and R 2 is phenyl.
  • Embodiment 31 is a diagrammatic representation of Embodiment 31.
  • X 6 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as .described in Embodiment 29, and R 2 is pyridinyl.
  • X 6 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and R 2 is pyridinyl-3-yl.
  • Embodiment 33 In another embodiment of Formula I, X 6 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in
  • Embodiment 29, and R 2 is selected from the group consisting of phenyl, pyrazolyl, tetrahydrofuryl, furyl, isoxazolyl, thienyl, pyridinyl, pyrimidinyl, and benzofuryl, optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, - OR A , -NR A R B , and -S(O) 2 R A , wherein the alkyl substitutent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, -OR C , -C(O)OR 0 , and -C(O)NR 0 R 0 ; wherein R A and R B are independently selected from the group consisting of hydrogen, alkyl, C 3 -C 6 -cycloalkyl, phenyl, and 5-6 membered ring heterocyclyl,
  • X 6 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and R 2 is selected from the group consisting of phenyl, pyrazolyl, tetrahydrofuryl, furyl, isoxazolyl, thienyl, pyridinyl, pyrimidinyl, and benzofuryl, optionally substituted with one or more substituents selected from the group consisting of chloro, fluoro, methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluorom ethyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, amino, methylamino, dimethylamino, ethylamino, diethylamino, methylsulfonyl, and ethylsulfonyl.
  • Embodiment 35 In another embodiment of Formula I, X 6 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in
  • Embodiment 29, and R 2 is selected from the group consisting of phenyl, pyrazolyl, tetrahydrofuryl, furyl, isoxazolyl, thienyl, pyridinyl, pyrimidinyl, and benzofuryl, optionally substituted with one or more substituents selected from the group consisting of fluoro, methyl, trifluoromethyl, methoxy, trifluorom ethoxy, amino, methylamino, dimethylamino, and methylsulfonyl.
  • Embodiment 36 is a diagrammatic representation of Embodiment 36.
  • X 6 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and R 2 is selected from the group consisting of phenyl, pyrazolyl, tetrahydrofuryl, furyl, isoxazolyl, thienyl, pyridinyl, pyrimidinyl, and benzofuryl, optionally substituted with one or more fluoro subsituents.
  • R 2 is selected from the group consisting of phenyl, pyrazolyl, tetrahydrofuryl, furyl, isoxazolyl, thienyl, pyridinyl, pyrimidinyl, and benzofuryl, optionally substituted with one or more fluoro subsituents.
  • Embodiment 37 :
  • X 6 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and R 2 is selected from the group consisting of phenyl, pyrazolyl, tetrahydrofuryl, furyl, isoxazolyl, thienyl, pyridinyl, pyrimidinyl, and benzofuryl, optionally substituted with two fluoro subsituents.
  • Embodiment 38 is a diagrammatic representation of Embodiment 38.
  • X 6 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and R 2 is 4-fluorophenyl.
  • Embodiment 39 In another embodiment of Formula I, X 6 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in
  • Embodiment 29, and R 2 is 3,4-difluorophenyl.
  • Embodiment 40 is a diagrammatic representation of Embodiment 40.
  • X 6 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and R 2 is 4-methoxy-pyridin-3-yl.
  • R 2 , X 6 , Y 6 , R 6 , and R 8 are as described in Embodiment 29, and R 3 and R 4 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, cyano, hydroxy, carboxy, methyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxym ethyl, ethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoroethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, propyl, methoxy, ethoxy, propoxy, phenyl, amino, methylamino, dimethylamino, mercapto, and methylthio.
  • Embodiment 43 is a diagrammatic representation of Embodiment 43.
  • R 2 , X 6 , Y 6 , R 6 , and R 8 are as described in Embodiment 29, and R 3 and R 4 are independently selected from the group consisting of hydrogen, fluoro, methyl, ethyl, trifluoromethyl, and methoxy.
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, fluoro, methyl, ethyl, trifluoromethyl, and methoxy.
  • R 2 , X 6 , Y 6 , R 6 , and R 8 are as described in Embodiment 29, and at least one of R 3 and R 4 is hydrogen.
  • Embodiment 45 is a diagrammatic representation of Embodiment 45.
  • R 2 , X 6 , Y 6 , R 6 , and R 8 are as described in Embodiment 29, and both R 3 and R 4 are hydrogen.
  • R 2 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and X 6 is -N(R N )-, wherein R N is selected from the group consisting of hydrogen and C 1 -C 4 alkyl; wherein the R N C 1 -C 4 alkyl comprising at least two carbon atoms may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and -OR P ; and wherein R p is C 1 -C 4 alkyi wherein the C1-C4 alkyl may be optionally substituted with one or more fluoro radical substituents.
  • Embodiment 47 is a diagrammatic representation of Embodiment 47.
  • R 2 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and X 6 is -N(R N )-, wherein R N is hydrogen.
  • Embodiment 48 is a diagrammatic representation of Embodiment 48.
  • R 2 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and X 6 represents a bond.
  • Embodiment 49 In another embodiment of Formula I, R 2 , Y 6 , R 6 , R 3 , R 4 , and R 8 are as described in
  • Embodiment 29, and X 6 is -O-.
  • Embodiment 50 is a diagrammatic representation of Embodiment 50.
  • R 2 , X 6 , R 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and Y 6 is alkyl, optionally substituted as described in Embodiment 26.
  • R 2 , X 6 , R 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and Y 6 is a C 1 -C 6 alkyl, optionally substituted as described in Embodiment 26.
  • Embodiment 52 is a diagrammatic representation of Embodiment 52.
  • R 2 , X 6 , R 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and Y 6 is selected from the group consisting of -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 (CH 3 )-, -CH 2 CH 2 (CH 3 )-, -CH 2 (CH 3 )CH 2 -, -0-CH 2 -, and -OCH 2 CH 2 -.
  • Embodiment 53 is a diagrammatic representation of Embodiment 53.
  • R 2 , X 6 , R 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and Y 6 represents a bond.
  • R 2 , R 6 , R 3 , R 4 , and R 8 are as described in .
  • Embodiment 29, and Y 6 taken together with X 6 represents a bond.
  • Embodiment 55 is a diagrammatic representation of Embodiment 55:
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and R 6 is selected from the group consisting of halogen, hydroxy, amino, alkyl, alkylamino, cycloalkyl, aryl, and 3-10 membered ring heterocyclyl, wherein (a) the R 6 alkyl and alkylamino substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, cycloalkyl, aryl, 3-10 membered ring heterocyclyl, -OR S , -C(O)R S , -C(O)OR S , -OC(O)R S , -NR S R T , -SR S and - S(O) 2 R S , and (b) the R 6 cycloalkyl, aryl, and 3-10 membered ring heterocyclyl, wherein
  • Embodiment 56 is a diagrammatic representation of Embodiment 56.
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and R 6 is selected from the group consisting of halogen, hydroxy, amino, alkylamino, cycloalkyl, and aryl, wherein the R 6 cycloalkyl and aryl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, alkynyl, cycloalkyl, aryl, 3-10 membered ring heterocyclyl, -OR S , -C(O)R S , - C(O)OR S , -OC(O)R S , -NR S R T ,-SR s and -S(O) 2 R S ; and wherein R s and R ⁇ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, ary
  • Embodiment 57
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and R 6 is selected from the group consisting of halogen, hydroxy, amino, and alkylamino.
  • Embodiment 58
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and R 6 is cyclohexyl, optionally susbtituted as provided in Embodiment 55.
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and R 6 is phenyl, optionally susbtituted as provided in Embodiment 55.
  • Embodiment 60 is a diagrammatic representation of Embodiment 60.
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and R 6 is alkyl, optionally susbtituted with one or more substituents independently selected from the group consisting of halogen, oxo, cycloalkyl, aryl, 3-10 membered ring heterocyclyl, -OR S , -C(O)R S , -C(O)OR S , -OC(O)R S , -NR s R ⁇ , -SR S and - S(O) 2 R S ; and wherein R s and R T are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and 3-10 membered ring heterocyclyl, wherein (a) when the alkyl is methyl, the methyl may be optionally substituted by 1 , 2, or 3 fluoro substituents, (b) when the
  • Embodiment 29, and R 6 is alkyl, optionally susbtituted with one or more substituents independently selected from the group consisting of halogen, -OR S , -C(O)R S , -C(O)OR S , - OC(O)R S , -NR S R T , and -S(O) 2 R S ; and wherein R s and R T are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and 3-10 membered ring heterocyclyl, wherein (a) when the alkyl is methyl, the methyl may be optionally substituted by 1 , 2, or 3 fluoro substituents, (b) when the alkyl comprises at least two carbon atoms, the alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkyn
  • Embodiment 29 and R 6 is a 5-7 membered ring heterocylyl, optionally substituted as described in Embodiment 26. .
  • Embodiment 63 In another embodiment of Formula I, R 2 , X 6 , Y 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and R 6 is a 5-6 membered ring heteroaryl, optionally substituted as described in Embodiment 26.
  • Embodiment 64 is a diagrammatic representation of Embodiment 64.
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and R 6 is a 5-6 membered ring fully or partially saturated heterocyclyl, optionally substituted as described in Embodiment 26.
  • Embodiment 65 :
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and R 6 is selected from the group consisting of pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, tetrahydrofuryl, dihydrofuryl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, and morpholinyl, optionally substituted as described in Embodiment 26.
  • Embodiment 66 :
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and R 6 is selected from the group consisting of pyrrolidinyl, imidazolyl, tetrahydrofuryl, furyl, piperidinyl, piperazinyl, pyridinyl, pyrazinyl, tetrahydropyranyl, and morpholinyl, optionally substituted as described in Embodiment 26.
  • Embodiment 67 :
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and R 6 is a 5-6 membered ring heterocylyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, alkynyl, cycloalkyl, aryl, 3-10 membered ring heterocyclyl, -OR S , -C(O)R S , -C(O)OR S , - OC(O)R S , -NR S R T ,-SR S and -S(O) 2 R 53 ; and wherein R s and R ⁇ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and 3-10 membered ring heterocyclyl, wherein (a) when the alkyl is methyl, the methyl may be optionally substitute
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and R 6 is a 5-6 membered ring heterocylyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, C 3 -C 6 -cycloalkyl, phenyl, 5-6 membered ring heterocyclyl, -OR S , -C(O)R S , -C ⁇ O)OR S , - OC(O)R S , -NR S R T ,-SR S and -S(O) 2 R S ; and wherein R s and R ⁇ are independently selected from the group consisting of hydrogen, alkyl, C 3 -C 6 -cycloalkyl, phenyl, and 5-6 membered ring heterocyclyl, wherein (a) when the alkyl is
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 6 are as described in .
  • Embodiment 29, and R 8 is C 1 -C 10 alkyl, optionally substituted as described in Embodiment 26.
  • Embodiment 71 :
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 6 are as described in Embodiment 29, and R 8 is alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, G 3 -C 6 - cycloalkyl, phenyl, 3-10 membered ring heterocyclyl, -OR U , -C(O)R U , -C(O)OR U , -OC(O)R ⁇ , - NR ⁇ R v , -N(R ⁇ )C(O)R v , -C(O)NR U R V , -C(O)NR U C(O)R V , -SR ⁇ , -S(O)R U , -S(O) 2 R U , - N(R U )S(O) 2 R V , and
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 6 are as described in Embodiment 29, and R 8 is alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 3 -C 6 -cycloalkyl, phenyl, 5-7 membered ring heterocyclyl, -OR U , -NR ⁇ R v , and -SR U , wherein the C 3 -C 6 -cycloalkyl, phenyl, 5-7 membered ring heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkyl, phenyl, 5-7 membered ring heterocyclyl, and alkoxy; and wherein R u and R v are independently selected from the group consisting of hydrogen, alkyl, C 3
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 6 are as described in Embodiment 29, and R 8 is selected from the group consisting of alkyl, C 3 -C 6 -cycloalkylalkyl, phenylalkyl, 3-10 membered ring heterocyclylalkyl, alkylthioalkyl, alkoxyalkyl, cycloalkoxyalkyl, phenoxyalkyl, 3-10 membered ring heterocyclyloxyalkyl, and alkoxyarylalkyl, 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, oxo, and alkoxy.
  • Embodiment 74
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 6 are as described in Embodiment 29, and R 8 is alkyl, optionally substituted as described in Embodiment 26.
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 6 are as described in Embodiment 29, and R 8 is alkyloxyalkyl, optionally substituted as described in Embodiment 26.
  • Embodiment 76
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 6 are as described in Embodiment 29, and R 8 is cycloalkylalkyl, optionally substituted as described in Embodiment 26.
  • Embodiment 77
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 6 are as described in Embodiment 29, and R 8 is phenylalkyl, optionally substituted as described in Embodiment 26.
  • Embodiment 78 ⁇
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 6 are as described in
  • Embodiment 29 and R 8 is a 5-6 membered ring heterocyclylalkyl, optionally substituted as described in Embodiment 26.
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 8 are as described in Embodiment 29, and R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl, and 3-10 membered ring heterocyclyl, wherein (a) the R 6 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, cycloalkyl, aryl, 3-10 membered ring heterocyclyl, -OR S , -C(O)R 53 , -C(O)OR S , -OC(O)R S , -NR S R T , -SR S and -S(O) 2 R S , and (b) the R 6 cycloalkyl, aryl, and 3-10 membered ring heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from
  • Embodiment 79, and X 6 represents a bond or is -N(R N )-; wherein R N is independently selected from the group consisting of hydrogen, alkyl, and haloalkyl.
  • Embodiment 81 In another embodiment of Formula I, R 2 , X 6 , Y 6 , R 6 , and R 8 are as described in Embodiment 80, and R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, phenyl, amino, alkylamino, haloalkylamino, hydroxyalkylamino, mercapto, alkylthio, haloalkylthio, and hydroxyalkylthio.
  • Embodiment 82 In another embodiment of Formula I, R 2 , X 6 , Y 6 , R 3 , R 4 , and R 6 are as described in
  • Embodiment 81 , and R 8 is alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, C 3 -C 6 - cycloalkyl, phenyl, 3-10 membered ring heterocyclyl, -OR U , -C(O)R U , -C(O)OR U , -OC(O)R U , - NR U R V , -N(R U )C(O)R V , -C(O)NR U R V , -C(O)NR ⁇ C(O)R v , -SR U , -S(O)R U , -S(O) 2 R U , - N(R U )S(O) 2 R V , and -S(O) 2 NR U R V , wherein the C 3 -C 6 -cycloalkyl, phenyl, and
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 6 are as described in Embodiment 82, and R 8 is alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 3 -C 6 -cycloalkyl, phenyl, 5-7 membered ring heterocyclyl, -OR U , -NR U R V , and -SR ⁇ , wherein the C 3 -C 6 -cycloalkyl, phenyl, '5-7 membered ring heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkyl, phenyl, 5-7 membered ring heterocyclyl, and alkoxy; and wherein R u and R v are independently selected from the group consisting of hydrogen, alkyl,
  • R u and R v C 3 -C 6 -cycloalkyl, phenyl, and 5-7 membered ring heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from halogen, cyano, oxo, alkyl, haloalkyl, haloalkoxy, -OR W , -C(O)OR W , and -C(O)NR W R X , wherein R w and R x are independently hydrogen or alkyl.
  • Embodiment 84
  • X 6 , Y 6 , R 3 , R 4 , R 6 , and R 8 are as described in Embodiment 83, and R 2 is selected from the group consisting of phenyl, pyrazolyl, tetrahydrofuryl, furyl, isoxazolyl, thienyl, pyridinyl, pyrimidinyl, and benzofuryl, R 2 substitutent may be optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, alkyl, cycloalkyl, phenyl, 5-7 membered ring heterocyclyl, -OR A , -C(O)R A , - OC(O)R A , -C(O)OR A , -NR A R B , -N(R B )C(O) R c , -C(O)NR A R B , and -S(O) 2 R
  • Embodiment 85 In another embodiment of Formula I, R 2 , X 6 , Y 6 , R 6 , and R 8 are as described in
  • Embodiment 84, and R 3 and R 4 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, cyano, hydroxy, carboxy, methyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, ethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoroethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, propyl, methoxy, ethoxy, propoxy, phenyl, amino, methylamino, dimethylamino, mercapto, and methylthio.
  • Embodiment 86
  • R 2 , Y 6 , R 3 , R 4 , R 6 , and R 8 are as described in Embodiment 85, and X 6 represents a bond or is -N(R N )-; wherein R N is hydrogen.
  • X 6 , Y 6 , R 3 , R 4 , R 6 , and R 8 are as described in Embodiment 86, and R 2 is selected from the group consisting of phenyl, pyrazolyl, tetrahydrofuryl, furyl, isoxazolyl, thienyl, pyridinyl, pyrimidinyl, and benzofuryl, R 2 substitutent may be optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, -OR A , -NR A R B , and -S(O) 2 R A , wherein the alkyl substitutent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, -OR C , -C(O)OR 0 , and -C(O)NR 0 R 0 ; wherein R A and R B are independently selected
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 6 are as described in Embodiment 87, and R 8 is selected from the group consisting of alkyl, C 3 -C 6 -cycloalkylalkyl, phenylalkyl, 3-10 membered ring heterocyclylalkyl, alkylthioalkyl, alkoxyalkyl, cycloalkoxyalkyl, phenoxyalkyl, 3-10 membered ring heterocyclyloxyalkyl, and alkoxyarylalkyl, 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, oxo, and alkoxy.
  • Embodiment 89 In another embodiment of Formula I, R 2 , X 6 , Y 6 , R 3 , R 4 , and R 8 are as described in Embodiment 88, and R 6 is selected from the group consisting of alkyl, C 3 -C 6 -cycloalkyl, phenyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, tetrahydrofuryl, dihydrofuryl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, and morpholinyl, wherein (a) the R 6 alkyl substituent may be optionally substituted with
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 8 are as described in Embodiment 89, and R 6 is selected from the group consisting of alkyl, C 3 -C 6 -cycloalkyl, phenyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, tetrahydrofuryl, dihydrofuryl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, and morpholinyl, wherein (a) the R 6 alkyl substituent may be optionally substituted with one or more substituents independently
  • R 2 , X 6 , Y 6 , R 6 , and R 8 are as described in Embodiment 90, and R 3 and R 4 are independently selected from the group consisting of hydrogen, fluoro, methyl, ethyl, trifluoromethyl, and methoxy.
  • Embodiment 92 In another embodiment of Formula I, R 2 , X 6 , Y 6 , R 3 , R 4 , and R 6 are as described in
  • Embodiment 91 and R 8 is selected from the group consisting of alkyl, alkoxyalkyl, C 3 -Ce- cycloalkylalkyl, phenylalkyl, 5-6 membered ring heterocyclylalkyl, and alkylthioalkyl, wherein (a) the R 8 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy, and (b) the R 8 alkoxyalkyl, cycloalkylalkyl, phenylalkyl, 5-6 membered ring heterocyclylalkyl, and alkylthioalkyl 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.
  • Embodiment 93 J
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 6 are as described in Embodiment 92
  • R 8 is selected from the group consisting of alkyl, alkoxyalkyl, C 3 -Ce- cycloalkylalkyl, and alkylthioalkyl, wherein (a) the R 8 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy, and (b) the R 8 alkoxyalkyl, cycloalkylalkyl, and alkylthioalkyl 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.
  • Embodiment 94
  • R 2 , X 6 , Y 6 , R 3 , R 4 , and R 8 are as described in Embodiment 93, and R 6 is selected from the group consisting of alkyl, cyclohexyl, pyrrolidinyl, imidazolyl, tetrahydrofuryl, furyl, piperidinyl, piperazinyl, pyridinyl, pyrazinyl, tetrahydropyranyl, and morpholinyl, wherein (a) the R 6 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy, and (b) the R 6 cyclohexyl, pyrrolidinyl, imidazolyl, tetrahydrofuryl, furyl, piperidinyl, piperazinyl, pyridinyl, pyr
  • Embodiment 95 In another embodiment of Formula I, X 6 , Y 6 , R 3 , R 4 , R 6 , and R 8 are as described in
  • Embodiment 94, and R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 phenyl and pyridinyl substitutents may be optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, alkoxy, amino, alkylamino, and alkylsulfonyl.
  • R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 phenyl and pyridinyl substitutents may be optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, alkoxy, amino, alkylamino, and alkylsulfonyl.
  • X 6 , Y 6 , R 3 , R 4 , R 6 , and R 8 are as described in Embodiment 95, and R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 phenyl and pyridinyl substitutents may be 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, diethylamino, methylsulfonyl, and ethylsulfonyl.
  • Embodiment 97
  • X 6 , Y 6 , R 3 , R 4 , R 6 , and R 8 are as described in Embodiment 96, and R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 phenyl and pyridinyl substitutents may be optionally substituted with one or more substituents selected from the group consisting of fluoro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, amino, methylamino, dimethylamino, and methylsulfonyl.
  • Embodiment 98
  • X 6 , Y 6 , R 3 , R 4 , R 6 , and R 8 are as described in Embodiment 97, and R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 phenyl and pyridinyl substitutents is substituted with one or more fluoro substituents.
  • Embodiment 99 is a diagrammatic representation of Embodiment 99:
  • X 6 , Y 6 , R 3 , R 4 , R 6 , and R 8 are as described in Embodiment 98, and R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 phenyl and pyridinyl substitutents is substituted with two fluoro substituents.
  • Embodiment 100 is a diagrammatic representation of Embodiment 100.
  • R 2 , X 6 , Y 6 , R 6 , and R 8 are as described in Embodiment 99, and both R 3 and R 4 are hydrogen.
  • the present invention comprises a class of compounds (including tautomers of the compounds and pharmaceutically acceptable salts of the compounds and tautomers) having the structure of Formula l-CC: wherein R 2 , R 3 , R 4 , R N , Y 6 , R 6 and R 8 are as described in Formula I.
  • the present invention is directed, in part, to a class of compounds (including tautomers of the compounds and pharmaceutically acceptable salts of the compounds and tautomers) having the structure of Formula I-CC:
  • R 2 is a 5 to 6 membered ring heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, cycloalkyl, phenyl, 5-7 membered ring heterocyclyl, -OR A , -C(O)R A , -OC(O)R A , -C(O)OR A , - NR A R B , -N(R A )C(O)R B , -C(O)NR A R B , -C(O)NR A C(O)R B , -SR A , -S(O)R A , -S(O) 2 R A , - N(R A )S(O) 2 R B , and -S(O) 2 NR A R B , wherein (a) the alkyl substitutent may be optionally substituted with one or more substituents independently selected from the
  • R A and R B are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, phenyl, and 5-7 membered ring heterocyclyl, 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, cycloalkyl, -OR E , -C(O)R 6 , - C(O)OR E , -NR E R F , and-C(O)NR E R F , and (c) the cycloalkyl, phenyl, and 5-7 membered ring heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from halogen, cyano, oxo, alkyl, -OR E , -C
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -OR G , -C(O)R G , -OC(O)R G , -C(O)OR G , -NR G R H , -N(R G )C(O) R H , -C(O)NR G R H -, -C(O)NR G C(O)R H , -SR G , -S(O)R G ,-S(O) 2 R G , - N(R G )S(O) 2 R H , and -S(O) 2 NR G R H , wherein (a) the R 3 and R 4 alkyl, alkenyl, and alkynyl substitutents may be optionally substituted with one or more substituents independently selected from the group consisting of
  • R G and R H are independently selected from the group consisting of hydrogen, alkyl, alkynyl, cycloalkyl, aryl, and heterocyclyl, 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 a substituent selected from one or more of the group consisting of halogen, cycloalkyl, -OR L , -C(O)OR M , and -C(O)NR L R M , (c) the R G and R H alkynyl substituents may be optionally substituted with one or more substituents independently selected from halogen, cyano, oxo, -OR L , -C(O)OR L , and -C(O)NR L R M , and (d) the R G and R H cycloalkyl
  • R J , R ⁇ , R L and R M are independently selected from the group consisting of hydrogen and alkyl;
  • R N is selected from the group consisting of hydrogen and alkyl, wherein the R N alkyl comprising at least two carbon atoms may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and -OR P ;
  • R p is alkyl wherein the alkyl may be optionally substituted with one or more halogen substituents
  • Y 6 represents a bond or is alkyl, wherein the Y 6 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, -OR Q , -C(O)R 0 , -C(O)OR Q , -OC(O)R 0 , -NR Q R R ,-SR Q , -S(O) R Q , and - S(O) 2 R 0 ;
  • R 0 and R R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl, wherein (a) when the alkyl is methyl, the methyl may be optionally substituted by 1 , 2, or 3 fluoro substituents, (b) when the alkyl -comprises at least two carbon atoms, 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, (c) the R Q and R R alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy,
  • R 8 is alkyl, wherein the R 8 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, cycloalkyl, alkynyl, aryl, heterocyclyl, -OR U , -C(O)R U , -C(O)OR U , -OC(O)R U , - NR U R V , -N(R U )C(O)R V , -C(O)NR U R V , -C(O)NR U C(O)R V , -SR U , -S(O)R U , -S(O) 2 R 0 , - N(R U )S(O) 2 R V , and -S(O) 2 NR U R V , wherein the cycloalkyl, alkynyl, aryl, and heterocyclyl substituents may be optional
  • R u and R v are independently selected from the group consisting of hydrogen, alkyl, alkynyl, cycloalkyl, aryl and heterocyclyl, wherein (a) when the alkyl is methyl, the methyl may be optionally substituted with 1 , 2, or 3 fluoro substituents, (b) when the alkyl comprises at least two carbon atoms, 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, (c) the R u and R v alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, ox
  • Embodiment 2 of the Compounds of Formula I-CC is a
  • R 2 , R 3 , R 4 , and R 8 are as described in Formula I-CC, and R N is selected from the group consisting of hydrogen and C C 1 -C 4 alkyl; wherein the R N C 1 -C 4 alkyl comprising at least two carbon atoms may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and - OR P ; wherein R p is C 1 -C 4 alkyl wherein the C 1 -C 4 alkyl may be optionally substituted with one or more fluoro radical substituents; Y 6 is a bond or alkyl; and R 6 is selected from the group consisting of alkylamino, alkylthio, alkylsulfonyl, cycloalkyl, phenyl, and heterocyclyl, wherein the R 6 alkylsulfonyl, cycloalkyl, aryl, and heterocyclyl substituent
  • R 2 , R 3 , R 4 , Y 6 , R 6 , and R 8 are as described in Embodiment 2 of the compounds of Formula I-CC, and R N is hydrogen.
  • Embodiment 4 of the Compounds of Formula I-CQ are as described in Embodiment 2 of the compounds of Formula I-CC, and R N is hydrogen.
  • R N , R 2 , Y 6 , R 6 , and R 8 are as described in Embodiment 3 of the Compounds of Formula I-CC, and R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, phenyl, amino, alkylamino, haloalkylamino, hydroxyalkylamino, mercapto, alkylthio, haloalkylthio, and hydroxyalkylthio.
  • R N , R 2 , Y 6 , R 6 , and R 8 are as described in Embodiment 4 of the Compounds of Formula I-CC, and both R 3 and R 4 are hydrogen.
  • Embodiment 6 of the Compounds of Formula I-CC In another embodiment of Formula I-CC, R N , R 3 , R 4 , Y 6 , R 6 , and R 8 are as described ih Embodiment 4 of the compounds of Formula I-CC, and the R 2 5-6 membered ring het ⁇ rocyclyl may be optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, -OR A , -NR A R B , and -S(O) 2 R A , wherein the alkyl substitutent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, -OR G , -C(
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 6 of the compounds of Formula I-CC, and R 6 is is selected from the group consisting of C 3 -C 6 cycloalkyl, phenyl, and 3-10 membered ring heterocyclyl, wherein the C 3 -C 6 cycloalkyl, phenyl, and 3-10 membered ring heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, C 3 -C 6 -cycloalkyl, phenyl, 3-10 membered ring heterocyclyl, -OR S , - C(O)R S , -C(O)OR S , -OC(O)R S , -NR S R T , -N(R S )C(O)
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 7 of the compounds of Formula I-CC, and R 8 is alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, C 3 -C 6 -cycloalkyl, phenyl, 3-10 membered ring heterocyclyl, -OR U , -C(O)R U , - C(O)OR U , -OC(O)R U , -NR U R V , -N(R U )C(O)R V , -C(O)NR U R V , -C(O)NR U C(O)R V , -SR U , -S(O)R ⁇ , - S(O) 2 R U , -N(R U )S(O) 2 R V , -SR U ,
  • Embodiment 9 of the Compounds of Formula I-CQ In another embodiment of Formula I-CC, R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 8 of the compounds of Formula I-CC, and R 8 is alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 3 -C 6 - cycloalkyl, phenyl, 5-7 membered ring heterocyclyl, -OR U , -NR U R V , and -SR ⁇ , wherein the C 3 -C 6 - cycloalkyl, phenyl, 5-7 membered ring heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkyl, phenyl, 5-7 membered ring heterocyclyl, and alkoxy
  • R N , R 2 , Y 6 , R 6 , and R 8 are as described in Embodiment 9 of the compounds of Formula I-CC, and R 3 and R 4 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, cyano, hydroxy, carboxy, methyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, ethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoroethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, propyl, methoxy, ethoxy, propoxy, phenyl, amino, methylamino, dimethylamino, mercapto, and methylthio.
  • Embodiment 11 of the Compounds of Formula l-CC is as described in
  • Embodiment 10 of the compounds of Formula l-CC, and both R 3 and R 4 are hydrogen.
  • Embodiment 12 of the Compounds of Formula l-CC is a diagrammatic representation of the Compounds of Formula l-CC:
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 10 of the compounds of Formula l-CC, and R 6 is cycloalkyl, optionally substituted as described in Embodiment 7 of Formula l-CC.
  • Embodiment 13 of the Compounds of Formula l-CC Embodiment 13 of the Compounds of Formula l-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 10 of the compounds of Formula l-CC, and R 6 is cyclohexyl, optionally substituted as described in Embodiment 7 of Formula l-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 10 of the compounds of Formula l-CC, and R 6 is phenyl, optionally substituted as described in Embodiment 7 of Formula l-CC.
  • Embodiment 15 of the Compounds of Formula l-CC In another embodiment of Formula l-CC, R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in
  • Embodiment 10 of the compounds of Formula l-CC, and R 6 is a 5-7 membered ring heterocyclyl, optionally substituted as described in Embodiment 7 of Formula l-CC.
  • Embodiment 16 of the Compounds of Formula l-CC is a diagrammatic representation of the Compounds of Formula l-CC:
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 10 of the compounds of Formula l-CC, and R 6 is a 5-7 membered ring heteroaryl, optionally substituted as described in Embodiment 7 of Formula l-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 10 of the compounds of Formula l-CC, and R 6 is a 5-7 membered ring fully or partially saturated heterocylyl, optionally substituted as described in Embodiment 7 of Formula I- CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 10 of the compounds of Formula l-CC, and R 6 is selected from the group consisting of pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, tetrahydrofuryl, dihydrofuryl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, and morpholinyl, and wherein the R 6 substitutent may be optionally substituted as described in Embodiment 7 of Formula l-CC.
  • Embodiment 19 of the Compounds of Formula l-CC In another embodiment of Formula I-CC, R N , R 2 , Y 6 , R 6 , and R 8 are as described in Embodiment 18 of the compounds of Formula I-CC, and both R 3 and R 4 are hydrogen.
  • Embodiment 20 of the Compounds of Formula I-CC In another embodiment of Formula I-CC, R N , R 2 , Y 6 , R 6 , and R 8 are as described in Embodiment 18 of the compounds of Formula I-CC, and both R 3 and R 4 are hydrogen.
  • Embodiment 20 of the Compounds of Formula I-CC Embodiment 20 of the Compounds of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 10 of the compounds of Formula I-CC, and R 6 is selected from the group consisting of pyrrolidinyl, imidazolyl, tetrahydrofuryl, furyl, piperidinyl, piperazinyl, pyridinyl, pyrazinyl, tetrahydropyranyl, and morpholinyl, and wherein the R 6 substitutent may be optionally substituted as described in Embodiment 7 of Formula I-CC.
  • Embodiment 21 of the Compounds of Formula I-CC In another embodiment of Formula I-CC, R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in
  • Embodiment 10 of the compounds of Formula I-CC, and R 6 is a 5-6 membered ring heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, C 3 -C 6 -cycloalkyl, phenyl, 3-10 membered ring heterocyclyl, -OR S , -C(O)R S , -C(O)OR S , -OC(O)R S , -NR S R T , -SR S and -S(O) 2 R S ; and wherein R s and R ⁇ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and 3-10 membered ring heterocyclyl, wherein (a) when the alkyl is methyl, the methyl may be optionally substituted by 1 , 2, or 3 fluoro substituents, (b) when the alkyl comprises at
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 10 of the compounds of Formula I-CC, and R 6 is a 5-6 membered ring heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, C 3 -C 6 -cycloalkyl, phenyl, 5-6 membered ring heterocyclyl, -OR S , -C(O)R S , -C(O)OR S , -OC(O)R S , -NR S R T ,-SR S and -S(O) 2 R S ; and wherein R s and R ⁇ are independently selected from the group consisting of hydrogen, alkyl, C 3 -C 6 -cycloalkyl, phenyl, and 5-6 membered ring heterocyclyl, wherein (
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 10 of the compounds of Formula I-CC, and R 6 is selected from the group consisting of methylamino, dimethylamino, methylsulfonyl, cyclohexyl, phenyl, pyrrolidinyl, imidazolyl, tetrahydrofuryl, furyl, piperidinyl, piperazinyl, pyridinyl, pyrazinyl, tetrahydropyranyl, and morpholinyl, and wherein the R 6 substitutent may be optionally substituted as described in Embodiment 7 of Formula I-CC.
  • Embodiment 24 of the Compounds of Formula I-CC :
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 23 of the compounds of Formula I-CC, and R 6 is methylsulfonyl, optionally substituted as described in Embodiment 7 of Formula I-CC.
  • Embodiment 25 of the Compounds of Formula I-CC In another embodiment of Formula I-CC, R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in
  • Embodiment 23 of the compounds of Formula I-CC, and R 6 is morpholinyl, optionally substituted as described in Embodiment 7 of Formula I-CC.
  • Embodiment 26 of the Compounds of Formula I-CC is a
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 23 of the compounds of Formula I-CC, and R 6 is tetrahydropyranyl, optionally substituted as described in Embodiment 7 of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 23 of the compounds of Formula I-CC, and R 6 is pyridinyl, optionally substituted as described in Embodiment 7 of Formula I-CC.
  • Embodiment 28 of the Compounds of Formula I-CC is a
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 23 of the compounds of Formula I-CC, and R 6 is tetrahydrofuryl, optionally substituted as described in Embodiment 7 of Formula I-CC.
  • R N , R 2 , Y 6 , R 6 , and R 8 are as described in Embodiment 23 of the compounds of Formula I-CC, and both R 3 and R 4 are hydrogen.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 23 of the compounds of Formula I-CC, and R 8 is CrC 10 alkyl, optionally substituted as described in Embodiment 9 of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 23 of the compounds of Formula I-CC, and R 8 is C 1 -C 6 alkyl, optionally substituted as described in Embodiment 9 of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 23 of the compounds of Formula I-CC, and R 8 is alkyoxyalkyl, optionally substituted as described in Embodiment 9 of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 23 of the compounds of Formula I-CC, and R 8 is cycloalkylalkyl, optionally substituted as described in Embodiment 9 of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in
  • Embodiment 23 of the compounds of Formula I-CC, and R 8 is phenylalkyl, optionally substituted as described in Embodiment 9 of Formula 1-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 23 of the compounds of Formula I-CC, and R 8 is 5-6 membered ring heterocyclyl, optionally substituted as described in Embodiment 9 of Formula I-CC.
  • R N , R 2 , Y 6 , R 6 , and R 8 are as described in Embodiment 23 of the compounds of Formula I-CC, and R 3 and R 4 are selected from the group consisting of hydrogen, fluoro, methyl, ethyl, trifluoromethyl, and methoxy.
  • R N , R 2 , R 3 , R 4 , R 6 , and R 8 are as described in Embodiment 36 of the compounds of Formula I-CC, and Y 6 represents a bond or is CrC 6 alkyl.
  • Embodiment 38 of the Compounds of Formula I-CC In another embodiment of Formula I-CC, R N , R 2 , R 3 , R 4 , R 6 , and R 8 are as described in
  • Embodiment 37 of the compounds of Formula I-CC, and Y 6 is selected from the group consisting of -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 (CH 3 )-, -CH 2 CH 2 (CH 3 )-, and -CH 2 (CH 3 )CH 2 -.
  • R N , R 2 , Y 6 , R 6 , and R 8 are as described in Embodiment 37 of the compounds of Formula I-CC, and at least one of R 3 and R 4 are hydrogen.
  • R N , R 2 , Y 6 , R 6 , and R 8 are as described in Embodiment 37 of the compounds of Formula I-CC, and both R 3 and R 4 are hydrogen.
  • Embodiment 41 of the Compounds of Formula I-CQ is as described in
  • Embodiment 40 of the compounds of Formula I-CC, and R 2 is selected from the group consisting of pyridinyl, pyridazine, pyrimidine, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isothiazolyl and isoxazolyl, wherein the R 2 substituent may be optionally substituted as described in Embodiment 5 of the compounds of Formula l-CC. .
  • Embodiment 42 of the Compounds of Formula I-CC In another embodiment of Formula I-CC, R N , R 3 , R 4 , Y 6 , R 6 , and R 8 are as described in Embodiment 40 of the compounds of Formula I-CC, and R 2 is a 5-6 membered ring heterocyclyl 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, diethylamino, methylsulfonyl, and ethylsulfonyl.
  • R N , R 3 , R 4 , Y 6 , R 6 , and R 8 are as described in Embodiment 40 of the compounds of Formula I-CC, and R 2 is a 5-6 membered ring heterocyclyl optionally substituted with one or more substituents selected from the group consisting of fluoro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, amino, methylamino, dimethylamino, and methylsulfonyl.
  • R N , R 3 , R 4 , Y 6 , R 6 , and R 8 are as described in Embodiment 40 of the compounds of Formula I-CC, and R 2 is a 5 membered ring heterocyclyl optionally substituted as described in Embodiment 40 of the compounds of Formula I-CC.
  • R N , R 3 , R 4 , Y 6 , R 6 , and R 8 are as described in Embodiment 44 of the compounds of Formula I-CC, and R 2 is selected from the group consisting
  • R 11 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl; and the R 9 and R 12 substituents are independently selected from the group consisting of hydrogen, cyano, oxo, halogen, hydroxy, alkyl, C 3 -C 6 -cycloalkyl, phenyl, alkoxy, alkylamino, alkylthio and alkylsulfonyl.
  • R N , R 2 , R 3 , R 4 , Y 6 , R 6 , R 8 , and R 11 are as described in Embodiment 45 of the compounds of Formula I-CC, and R 9 and R 12 substituents are independently 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, diethylamino, methylsulfonyl, and ethylsulfonyl.
  • Embodiment 47 of the Compounds of Formula I-CQ In another embodiment of Formula 1-CC, R N , R 2 , R 3 , R 4 , Y 6 , R 6 , R 8 , and R 11 are as described in Embodiment 46 of the compounds of Formula I-CC, and R 9 and R 12 substituents are independently selected from the group consisting of hydrogen, flouro, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, amino, methylamino and dimethylamino.
  • Embodiment 48 of the Compounds of Formula I-CC ' In another embodiment of Formula I-CC, R N , R 2 , R 3 , R 4 , Y 6 , R 6 , R 8 , and R 11 are as described in Embodiment 46 of the compounds of Formula I-CC, and R 9 and R 12 substituents are independently selected from the group consisting of hydrogen, flouro, methyl, ethyl and hydroxy.
  • R N , R 2 , R 3 , R 4 , Y 6 , R 6 , R 8 , and R 11 are as described in Embodiment 48 of the compounds of Formula I-CC, and both R 9 and R 12 substituents are methyl.
  • R 2 , R 3 , and R 4 are as described in Embodiment 42 of the compounds of Formula I-CC, and R N is hydrogen;
  • Y 6 is C 1 -C 4 alkyl
  • R 6 is selected from the group consisting of methylsulfonyl, cyclohexyl, phenyl, pyrrolidinyl, imidazolyl, tetrahydrofuryl, furyl, piperidinyl, piperazinyl, pyridinyl, pyrazinyl, tetrahydropyranyl, and morpholinyl, wherein the R 6 substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -OR S , -C(O)R S , -C(O)OR S , -OC(O)R S , -NR S R T , - N(R S )C(O)R T , -C(O)NR S R T , -C(O)NR S C(O)R T
  • R 8 is C 1 -C 6 alkyl, wherein the R 8 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, cycloalkyl, alkynyl, aryl, heterocyclyl, -OR U , -C(O)R U , -C(O)OR U , -OC(O)R U , - NR U R V , -N(R ⁇ )C(O)R v , -C(O)NR ⁇ R v , -C(O)NR U C(O)R V , -SR U , -S(O)R U , -S(O) 2 R U , - N(R U )S(O) 2 R V , and -S(O) 2 NR U R V , wherein the cycloalkyl, alkynyl, aryl, and hetero
  • R u and R v cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from halogen, cyano, oxo, alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, haloalkoxy, hydroxyalkoxy, carboxyalkoxy, -OR W , -C(O)OR W , and -C(O)NR W R X , wherein R w and R x are independently hydrogen or alkyl.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 50 of the compounds of Formula I-CC
  • R 6 is selected from the group consisting of methylsulfonyl, pyrrolidinyl, imidazolyl, tetrahydrofuryl, furyl, piperidinyl, piperazinyl, pyridinyl, pyrazinyl, tetrahydropyranyl, and morpholinyl, and wherein the R 6 substitutent may be optionally substituted as described in Embodiment 50 of the compounds of Formula I-CC.
  • Embodiment 52 of the Compounds of Formula I-CC :
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 50 of the compounds of Formula I-CC, and R 6 is methylsulfonyl optionally substituted as described in Embodiment 50 of the compounds of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 50 of the compounds of Formula I-CC, and R 6 is pyrrolidinyl optionally substituted as described in Embodiment 50 of the compounds of Formula I-CC.
  • Embodiment 54 of the Compounds of Formula I-CC In another embodiment of Formula I-CC, R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 50 of the compounds of Formula I-CC, and R 6 is morpholinyl optionally substituted as described in Embodiment 50 of the compounds of Formula I-CC.
  • Embodiment 55 of the Compounds of Formula I-CQ is as described in
  • Embodiment 50 of the compounds of Formula I-CC, and R 6 is tetrahydropyranyl optionally substituted as described in Embodiment 50 of the compounds of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described' in Embodiment 50 of the compounds of Formula I-CC, and R 6 is pyridinyl optionally substituted as described in Embodiment 50 of the compounds of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 50 of the compounds of Formula I-CC, and R 6 is tetrahydrofuryl optionally substituted as described in Embodiment 50 of the compounds of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 50 of the compounds of Formula I-CC, and R 8 is C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • Embodiment 59 of the Compounds of Formula I-CC is a diagrammatic representation of the Compounds of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 50 of the compounds of Formula I-CC, and R 8 is C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 50 of the compounds of Formula I-CC, and R 8 is C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 60 of the compounds of Formula I-CC, and R 8 is alkoxyalkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • Embodiment 62 of the Compounds of Formula I-CC is a diagrammatic representation of the Compounds of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 60 of the compounds of Formula I-CC, and R 8 is cycloalkylalkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 60 of the compounds of Formula I-CC, and R 8 is phenylalkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 60 of the compounds of Formula I-CC, and R 8 is 5-6 membered ring heterocyclylalkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • R N , R 2 , R 3 , R 4 , R 6 , and R 8 are as described in Embodiment 64 of the compounds of Formula I-CC, and Y 6 is selected from the group consisting of -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 (CH 3 )-, -CH 2 CH 2 (CH 3 )-, and -CH 2 (CH 3 )CH 2 -.
  • R N , R 2 , R 3 , R 4 , R 6 , and R 8 are as described in Embodiment 50 of the compounds of Formula I-CC, and
  • R 2 is a five-membered ring heterocyclyl, wherein the R 2 substitutent may be optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, ethyl, and hydroxy;
  • Y 6 is selected from the group consisting of methyl, ethyl and propyl
  • R 6 is selected from the group consisting of methylsulfonyl, cyclohexyl, tetrahydrofuryl, pyridinyl, pyrazinyl, and morpholinyl, wherein the R methylsulfonyl, cyclohexyl, tetrahydrofuryl, pyridinyl, pyrazinyl, and morpholinyl substitutents may be 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; and
  • R 8 is C 1 -C 6 alkyl, wherein the R 8 C 1 -C 6 alkyl substituent maybe optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • Embodiment 67 of the Compounds of Formula l-CC is directed, in part, to a class of compounds (including tautomers of the compounds and pharmaceutically acceptable salts of the compounds and tautomers) having the structure of Formula I-CC: wherein:
  • R 2 is selected from the group consisting of phenyl and pyridinyl, and wherein the R 2 substitutents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen,' cyano, oxo, alkyl, cycloalkyl, phenyl, 5-7 membered ring heterocyclyl, -OR A , -C(O)R A , -OC(O)R A , -C(O)OR A , -NR A R B , -N(R A )C(O)R B , -C(O)NR A R B , - C(O)NR A C(O)R B , -SR A , -S(O)R A , -S(O) 2 R A , -N(R A )S(O) 2 R B , and -S(O) 2 NR A R B , wherein (a) the alkyl substitutent
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -OR G , -C(O)R G , -OC(O)R G , -C(O)OR 6 , -NR G R H , -N(R G )C(O) R H , -C(0)NR G R H -, -C(O)NR G C(O)R H , -SR G , -S(O)R G ,-S(O) 2 R G , - N(R G )S(O) 2 R H , and -S(O) 2 NR G R H , wherein (a) the R 3 and R 4 alkyl, alkenyl, and alkynyl substitutents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen
  • R N is selected from the group consisting of hydrogen and alkyl, wherein the R N alkyl comprising at least two carbon atoms may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and -OR P ; wherein R p is alkyl wherein the alkyl may be optionally substituted with one or more halogen substituents;
  • Y 6 represents a bond or is alkyl, wherein the Y 6 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, -OR Q , -C(O)R 0 , -C(O)OR 0 , -OC(O)R 0 , -NR°R R ,-SR Q , -S(O)R 0 , and -
  • R° and R R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl, wherein (a) when the alkyl is methyl, the methyl may be optionally substituted by 1 , 2, or 3 fluoro substituents, (b) when the alkyl comprises at least two carbon atoms, 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, (c) the R°and R R alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen,
  • R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heterocyclyl, wherein (a) the R 6 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, cycloalkyl, aryl, heterocyclyl, -OR S , -C(O)R S , -C(O)OR S , -OC(O)R S , -NR S R T , -N(R S )C(O)R T , -C ⁇ O)NR S R T , - C(O)NR S C(O)R T , -SR S , -S(O)R 8 , -S(O) 2 R S , -N(R S )S ⁇ O) 2 R T , and -S(O) 2 NR S R T , and ⁇ b) the R 6 cycloalky
  • R 8 is alkyl, wherein the R 8 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, cycloalkyl, alkynyl, aryl, heterocyclyl, -OR U , -C(O)R U , -C(O)OR U , -OC(O)R U , - NR U R V , -N(R ⁇ )C(O)R v , -C(O)NR U R V , -C(O)NR U C(O)R V , -SR ⁇ , -S(O)R U , -S(O) 2 R ⁇ , - N(R U )S(O) 2 R V , and -S(O) 2 NR ⁇ R v , wherein the cycloalkyl, alkynyl, aryl, and heterocyclyl substitu
  • R 2 , R 3 , R 4 , and R 8 are as described in Embodiment 67 of the compounds of Formula I-CC, and R N is selected from the group consisting of hydrogen and C 1 -C 4 alkyl; wherein the R N C 1 -C 4 alkyl comprising at least two carbon atoms may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and -OR P ; wherein R p is C 1 -C 4 alkyl wherein the C 1 -C 4 alkyl may be optionally substituted with one or more fluoro radical substituents;
  • Y 6 is a bond or alkyl
  • R 6 is selected from the group consisting of alkylamino, alkylthio, alkylsulfonyl, cycloalkyl, phenyl, and heterocyclyl, wherein the R 6 alkylsulfonyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted as described in Embodiment 67 of the compounds of Formula I-CC.
  • Embodiment 69 of the Compounds of Formula I-CC is a diagrammatic representation of the Compounds of Formula I-CC.
  • R 2 , R 3 , R 4 , Y 6 , R 6 , and R 8 are as described in Embodiment 68 of the compounds of Formula I-CC, and R N is hydrogen.
  • R N , R 2 , Y 6 , R 6 , and R 8 are as described in Embodiment 69 of the compounds of Formula I-CC, and R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, phenyl, amino, alkylamino, haloalkylamino, hydroxyalkylamino, mercapto, alkylthio, haloalkylthio, and hydroxyalkylthio.
  • R N , R 2 , Y 6 , R 6 , and R 8 are as described in Embodiment 69 of the compounds of Formula I-CC, and both R 3 and R 4 are hydrogen.
  • R N , R 3 , R 4 , Y 6 , R 6 , and R 8 are as described in Embodiment 69 of the compounds of Formula I-CC, and R 2 phenyl and pyridinyl substitutents may be optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, -OR A , -NR A R B , and -S(O) 2 R A , wherein the alkyl substitutent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, -OR C , -C(O)OR 0 , and -C(O)NR 0 R 0 ; wherein R A and R B are independently selected from the group consisting of hydrogen, alkyl, C 3 -C 6 -cycloalkyl, phenyl, and 5-6 membered ring heterocyclyl, wherein
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 72 of the compounds of Formula I-CC, and R 6 is selected from the group consisting of C 3 -C 6 -cycloalkyl, phenyl, and 3-10 membered ring heterocyclyl, wherein the R 6 C 3 -C 6 - cycloalkyl, phenyl, and 3-10 membered ring heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, C 3 -C 6 -cycloalkyl, phenyl, 3-10 membered ring heterocyclyl, -OR S , - C(O)R S , -C(O)OR S , -OC(O)R S , -NR S R T , -N(R S )
  • Embodiment 74 of the Compounds of Formula I-CC is a diagrammatic representation of the Compounds of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 73 of the compounds of Formula I-CC, and R 8 is alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, C 3 -C 6 -cycloalkyl, phenyl, 3-10 membered ring heterocyclyl, -OR U , -C(O)R U , - C(O)OR U , -OC(O)R U , -NRV, -N(R U )C(O)R V , -C(O)NR U R V , -C(O)NR U C(O)R V , -SR U , -S(O)R U , - S(O) 2 R U , -N(R U )S(O) 2 R V , and
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 74 of the compounds of Formula I-CC, and R 8 is alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 3 -C 6 - cycloalkyl, phenyl, 5-7 membered ring heterocyclyl, -OR ⁇ , -NR U R V , and -SR U , wherein the C 3 -C 6 - cycloalkyl, phenyl, 5-7 membered ring heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkyl, phenyl, 5-7 membered ring heterocyclyl, and alkoxy; and wherein R u and R v are independently selected from the
  • Embodiment 76 of the Compounds of Formula I-CC is a diagrammatic representation of the Compounds of Formula I-CC.
  • R N , R 2 , Y 6 , R 6 , and R 8 are as described in Embodiment 75 of the compounds of Formula I-CC, and R 3 and R 4 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, cyano, hydroxy, carboxy, methyl, chloromethyl, dichlorom ethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, ethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoroethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, propyl, methoxy, ethoxy, propoxy, phenyl, amino, methylaminb, dimethylamino, mercapto, and methylthio.
  • Embodiment 77 of the Compounds of Formula I-CC is as described in
  • Embodiment 76 of the compounds of Formula I-CC, and both R 3 and R 4 are hydrogen.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 76 of the compounds of Formula I-CC, and R 6 is cycloalkyl, optionally substituted as described in Embodiment 73.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 76 of the compounds of Formula I-CC, and R 6 is cyclohexyl, optionally substituted as described in Embodiment 73.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 76 of the compounds of Formula I-CC, and R 6 is phenyl, optionally substituted as described in Embodiment 73.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 76 of the compounds of Formula I-CC, and R 6 is 5-7 membered ring heterocyclyl, optionally substituted as described in Embodiment 73.
  • Embodiment 82 of the Compounds of Formula I-CC is as described in
  • Embodiment 76 of the compounds of Formula I-CC, and R 6 is 5-7 membered ring heteroaryl, optionally substituted as described in Embodiment 73.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 76 of the compounds of Formula I-CC, and R 6 is 5-7 membered ring fully or partially saturated heterocylyl, optionally substituted as described in Embodiment 73.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 76 of the compounds of Formula I-CC, and R 6 is selected from the group consisting of pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, tetrahydrofuryl, dihydrofuryl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, and morpholinyl, and wherein the R 6 substitutent may be optionally substituted as described in Embodiment 73.
  • Embodiment 85 of the Compounds of Formula I-CC In another embodiment of Formula I-CC, R N , R 2 , Y 6 , R 6 , and R 8 are as described in
  • Embodiment 84 of the compounds of Formula I-CC, and both R 3 and R 4 are hydrogen.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 76 of the compounds of Formula I-CC, and R 6 is selected from the group consisting of pyrrolidinyl, imidazolyl, tetrahydrofuryl, furyl, piperidinyl, piperazinyl, pyridinyl, pyrazinyl, tetrahydropyranyl, and morpholinyl, and wherein the R 6 substitutent may be optionally substituted as described in Embodiment 73.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 76 of the compounds of Formula I-CC, and R 6 is 5-6 membered ring heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, C 3 -C 6 -cycloalkyl, phenyl, 3-10 membered ring heterocyclyl, -OR S , -C(O)R S ,.-C(O)OR S , -OC(O)R S , -NR S R T , -SR S and -S(O) 2 R S ; and wherein R s and R ⁇ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and 3-10 membered ring heterocyclyl, wherein (a) when the alkyl is
  • R N , R 2 , R 3 , R 4 , Y 6 , and' R 8 are as described in Embodiment 76 of the compounds of Formula I-CC, and R 6 is a 5-6 membered ring heterocyclyl, wherein the R 6 5-6 membered ring heterocyclyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, C 3 -C 6 -cycloalkyl, phenyl, 5-6 membered ring heterocyclyl, -OR S , -C(O) R s , -C(O)OFT 3 , - OC(O)R S , -NR S R T -SR S and -S(O) 2 R S ; and wherein R s and R ⁇ are independently selected from the group consisting of hydrogen, alkyl, C 3 -C 6 -cycloal
  • Embodiment 89 of the Compounds of Formula I-CC is a diagrammatic representation of the Compounds of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 76 of the compounds of Formula I-CC, and R 6 is selected from the group consisting of methylamino, dimethylamino, methylsulfonyl, cyclohexyl, phenyl, pyrrolidinyl, imidazolyl, tetrahydrofuryl, furyl, piperidinyl, piperazinyl, pyridinyl, pyrazinyl, tetrahydropyranyl, and morpholinyl, and wherein the R 6 substitutent may be optionally substituted as described in Embodiment 73.
  • Embodiment 90 of the Compounds of Formula I-CC Embodiment 90 of the Compounds of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 89 of the compounds of Formula I-CC, and R 6 is methylsulfonyl, optionally substituted as described in Embodiment 73.
  • Embodiment 91 of the Compounds of Formula I-CC In another embodiment of Formula I-CC, R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 89 of the compounds of Formula I-CC, and R 6 is morpholinyl, optionally substituted as described in Embodiment 73.
  • Embodiment 92 of the Compounds of Formula I-CQ is as described in
  • Embodiment 89 of the compounds of Formula I-CC, and R 6 is tetrahydropyranyl, optionally substituted as described in Embodiment 73.
  • Embodiment 93 of the Compounds of Formula I-CQ is a diagrammatic representation of the Compounds of Formula I-CQ.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 89 of the compounds of Formula I-CC, and R 6 is pyridinyl, optionally substituted as described in Embodiment 73.
  • Embodiment 94 of the Compounds of Formula I-CQ is a diagrammatic representation of the Compounds of Formula I-CQ.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 89 of the compounds of Formula 1-CC, and R 6 is tetrahydrofuryl, optionally substituted as described in Embodiment 73.
  • R N , R 2 , Y 6 , R 6 , and R 8 are as described in Embodiment 89 of the compounds of Formula I-CC, and both R 3 and R 4 are hydrogen.
  • Embodiment 96 of the Compounds of Formula I-CQ is as described in
  • Embodiment 89 of the compounds of Formula I-CC, and R 8 is C 1 -Ci 0 alkyl, optionally substituted as described in Embodiment 75 of the compounds of Formula I-CC.
  • Embodiment 97 of the Compounds of Formula I-CQ is a diagrammatic representation of the Compounds of Formula I-CQ.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 89 of the compounds of Formula I-CC, and R 8 is C 1 -C 6 alkyl, optionally substituted as described in Embodiment 75 of the compounds of Formula I-CC.
  • Embodiment 98 of the Compounds of Formula I-CQ is a diagrammatic representation of the Compounds of Formula I-CQ.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 89 of the compounds of Formula I-CC, and R 8 is alkoxyalkyl, optionally substituted as described in Embodiment 75 of the compounds of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 89 of the compounds of Formula I-CC, and R 8 is cycloalkylalkyl, optionally substituted as described in Embodiment 75 of the compounds of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 89 of the compounds of Formula I-CC, and R 8 is phenylalkyl, optionally substituted as described in Embodiment 75 of the compounds of Formula l-CC.
  • Embodiment 101 of the Compounds of Formula I-CQ is as described in Embodiment 89 of the compounds of Formula I-CC, and R 8 is 5-6 membered ring heterocyclylalkyl, optionally substituted as described in Embodiment 75 of the compounds of Formula I-CC.
  • Embodiment 102 of the Compounds of Formula I-CC is described in Embodiment 89 of the compounds of Formula I-CC, and R 8 is 5-6 membered ring heterocyclylalkyl, optionally substituted as described in Embodiment 75 of the compounds of Formula I-CC.
  • R N , R 2 , Y 6 , R 6 , and R 8 are as described in Embodiment 101 of the compounds of Formula I-CC, and R 3 and R 3 are selected from the group consisting of hydrogen, fluoro, methyl, ethyl, trifluoromethyl, and methoxy.
  • Embodiment 103 of the Compounds of Formula I-CC is as described in
  • Embodiment 102 of the compounds of Formula I-CC, and Y 6 represents a bond or is Ci-C ⁇ alkyl.
  • R N , R 2 , R 3 , R 4 , R 6 , and R 8 are as described in Embodiment 103 of the compounds of Formula I-CC, and Y 6 is selected from the group consisting of -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 (CH 3 )-, -CH 2 CH 2 (CH 3 )-, and -CH 2 (CH 3 )CH 2 -.
  • R N , R 2 , Y 6 , R 6 , and R 8 are as described in Embodiment 103 of the compounds of Formula I-CC, and at least one of R 3 and R 3 is hydrogen.
  • Embodiment 106 of the Compounds of Formula I-CC In another embodiment of Formula I-CC, R N , R 2 , Y 6 , R 6 , and R 8 are as described in
  • Embodiment 103 of the compounds of Formula I-CC, and both R 3 and R 3 are hydrogen.
  • R N , R 3 , R 4 , Y 6 , R 6 , and R 8 are as described in Embodiment 106 of the compounds of Formula I-CC, and R 2 is phenyl, optionally substituted as described in Embodiment 72 of the compounds of Formula I-CC.
  • R N , R 3 , R 4 , Y 6 , R 6 , and R 8 are as described in Embodiment 106 of the compounds of Formula I-CC, and R 2 is pyridinyl, optionally substituted as described in Embodiment 72 of the compounds of Formula I-CC.
  • R N , R 3 , R 4 , Y 6 , R 6 , and R 8 are as described in Embodiment 106 of the compounds of Formula I-CC, and R 2 is pyridine-3-yl, optionally substituted as described in Embodiment 72 of the compounds of Formula I-CC.
  • Embodiment 110 of the Compounds of Formula I-CC In another embodiment of Formula I-CC, R N , R 3 , R 4 , Y 6 , R 6 , and R 8 are as described in
  • Embodiment 106 of the compounds of Formula I-CC, and R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 substituent 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, diethylamino, methylsulfonyl, and ethyls ulfonyl.
  • Embodiment 111 of the Compounds of Formula I-CC :
  • R N , R 3 , R 4 , Y 6 , R 6 , and R 8 are as described in Embodiment 103 of the compounds of Formula I-CC, and R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 substituent is optionally substituted with one or more substituents selected from the group consisting of fluoro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, amino, methylamino, dimethylamino, and methylsulfonyl.
  • R N , R 2 , Y 6 , R 6 , and R 8 are as described in i Embodiment 106 of the compounds of Formula I-CC, and both R 3 and R 4 are hydrogen.
  • R N , R 3 , R 4 , Y 6 , R 6 , and R 8 are as described in Embodiment 112 of the compounds of Formula I-CC, and R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 substituent is optionally substituted with one or more fluoro substituents.
  • R N , R 3 , R 4 , Y 6 , R 6 , and R 8 are as described in Embodiment 112 of the compounds of Formula I-CC, and R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 substituent is optionally substituted with two fluoro substituents.
  • R N , R 3 , R 4 , Y 6 , R 6 , and R 8 are as described in Embodiment 112 of the compounds of Formula I-CC, and R 2 is selected from the group consisting of 4-fluorophenyl, 3,4-difluorophenyl, pyridin-3-yl, 4-fluoropyridin-3-yl, and 4- methoxypyridin-3-yl.
  • Embodiment 116 of the Compounds of Formula I-CC :
  • R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, oxo', alkyl, C 3 -C 6 -cycloalkyl, phenyl, alkoxy, amino, alkylamino, alkylthio, and alkylsulfonyl;
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, halogeri, cyano, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, phenyl, amino, alkylamino, haloalkylamino, hydroxyalkylamino, mercapto, alkylthio, haloalkylthio, and hydroxyalkylthio;
  • R N is hydrogen
  • Y 6 is alkyl
  • R 6 is selected from the group consisting of alkylamino, alkylthio, alkylsulfonyl, cycloalkyl, aryl, and heterocyclyl, wherein the the R 6 cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -OR S , -C(O)R S , - C(O)OR S , -OC(O)R S , -NR S R T , -N(R S )C(O)R T , -C(O)NR S R T , -C(O)NR S C(O)R T , -SR S , -S(O)R S , - S(O) 2 R S , -N(R
  • R 8 is alkyl, wherein the R 8 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, cycloalkyl, alkynyl, aryl, heterocyclyl, -OR U , -C(O)R U , -C(O)OR U , -OC(O)R U , - NR ⁇ R v , -N(R U )C(O)R V , -C(O)NR U R V , -C(O)NR U C(O)R V , -SR U , -S(O)R ⁇ , -S(O) 2 R U , - N(R U )S(O) 2 R V , and -S(O) 2 NR U R V , wherein the cycloalkyl, alkynyl, aryl, and heterocyclyl substituents may
  • Embodiment 117 of the Compounds of Formula I-CO In another embodiment of Formula I-CC, R N , R 2 , Y 6 , R 6 , and R 8 are as described in Embodiment 116 of the compounds of Formula I-CC, and R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, phenyl, amino, alkylamino, haloalkylamino, hydroxyalkylamino, mercapto, alkylthio, haloalkylthio, and hydroxyalkylthio.
  • Embodiment 118 of the Compounds of Formula I-CC is a diagrammatic representation of the Compounds of Formula I-CC.
  • R N , R 2 , Y 6 , R 6 , and R 8 are as described in Embodiment 117 of the compounds of Formula I-CC, and R 3 and R 4 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, cyano, hydroxy, carboxy, methyl, chloromethyl, dichloromethyl, trichlorom ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, ethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoroethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, propyl, methoxy, ethoxy, propoxy, phenyl, amino, methylamino, dimethylamino, mercapto, and methylthio.
  • Embodiment 119 of the Compounds of Formula I-CC is as described in
  • Embodiment 118 of the compounds of Formula I-CC, and R 3 and R 4 are independently selected from the group consisting of hydrogen, fluoro, methyl, ethyl, trifluoromethyl, and methoxy.
  • R N , R 2 , Y 6 , R 6 , and R 8 are as described in Embodiment 119 of the compounds of Formula I-CC, and at least one of R 3 and R 4 is hydrogen.
  • R N , R 2 , Y 6 , R 6 , and R 8 are as described in Embodiment 119 of the compounds of Formula I-CC, and both R 3 and R 4 are hydrogen.
  • Embodiment 122 of the Compounds of Formula I-CC In another embodiment of Formula I-CC, R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in
  • Embodiment 119 of the compounds of Formula I-CC, and R 6 is selected from the group consisting of alkyisulfonyl, cyclohexyl, phenyl, pyrrolidinyl, imidazolyl, tetrahydrofuryl, furyl, piperidinyl, piperazinyl, pyridinyl, pyrazinyl, tetrahydropyranyl, and morpholinyl, and wherein the R substitutent may be optionally substituted as described in Embodiment 116 of the compounds of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 122 of the compounds of Formula I-CC, and R 6 is alkyisulfonyl, optionally substituted as described in Embodiment 116 of the compounds of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 122 of the compounds of Formula I-CC, and R 6 is cyclohexyl, optionally substituted as described in Embodiment 116 of the compounds of Formula I-CC.
  • Embodiment 125 of the Compounds of Formula I-CC In another embodiment of Formula I-CC, R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 122 of the compounds of Formula I-CC, and R 6 is morpholinyl, optionally substituted as described in Embodiment 116 of the compounds of Formula I-CC.
  • Embodiment 126 of the Compounds of Formula I-CC is as described in
  • Embodiment 122 of the compounds of Formula I-CC, and R 6 is tetrahydropyranyl, optionally substituted as described in Embodiment 116 of the compounds of Formula I-CC.
  • Embodiment 127 of the Compounds of Formula I-CC is a diagrammatic representation of the Compounds of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 122 of the compounds of Formula I-CC, and R 6 is pyridinyl, optionally substituted as described in Embodiment 116 of the compounds of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 8 are as described in Embodiment 122 of the compounds of Formula I-CC, and R 6 is tetrahydrofuryj, optionally substituted as described in Embodiment 116 of the compounds of Formula I-CC.
  • Embodiment 129 of the Compounds of Formula I-CC is a diagrammatic representation of the Compounds of Formula I-CC.
  • R N , R 2 , Y 6 , R 6 , and R 8 are as described in .
  • Embodiment 122 of the compounds of Formula I-CC, and both R 3 and R 4 are hydrogen.
  • Embodiment 130 of the Compounds of Formula I-CC is as described in
  • Embodiment 122 of the compounds of Formula I-CC, and R 8 is selected from the group consisting of alkyl, cycloalkylalkyl, phenylalkyl, 3-10 membered ring heterocyclylalkyl, alkylthioalkyl, alkoxyalkyl, cycloalkoxyalkyl, phenoxyalkyl, 3-10 membered ring heterocyclyloxyalkyl, and alkoxyarylalkyl, 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, oxo, and alkoxy.
  • Embodiment 131 of the Compounds of Formula I-CC is a diagrammatic representation of the Compounds of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 130 of the compounds of Formula I-CC, and R 8 is selected from the group consisting of alkyl, cycloalkylalkyl, alkylthioalkyl, alkoxyalkyl, and cycloalkoxyalkyl, 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, oxo, and alkoxy.
  • Embodiment 132 of the Compounds of Formula I-CC is a diagrammatic representation of the Compounds of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 131 of the compounds of Formula I-CC, and R 8 is alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • Embodiment 133 of the Compounds of Formula I-CC is a diagrammatic representation of the Compounds of Formula I-CC.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 131 of the compounds of Formula I-CC, and R 8 is C 1 -C 10 alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 131 of the compounds of Formula I-CC, and R 8 is CrC 6 alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 131 of the compounds of Formula I-CC, and R 8 is alkoxyalkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 131 of the compounds of Formula I-CC, and R 8 is cyloalkylalkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 131 of the compounds of Formula I-CC, and R 8 is phenylalkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • Embodiment 138 of the Compounds of Formula I-CO is a diagrammatic representation of the Compounds of Formula I-CO.
  • R N , R 2 , R 3 , R 4 , Y 6 , and R 6 are as described in Embodiment 131 of the compounds of Formula I-CC, and R 8 is 5-6 membered ring heterocyclylalkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • Embodiment 139 of the Compounds of Formula I-CO is a diagrammatic representation of the Compounds of Formula I-CO.
  • R N ,'R 2 , Y 6 , R 6 , and R 8 are as described in Embodiment 131 of the compounds of Formula I-CC, and both R 3 and R 4 are hydrogen.
  • Embodiment 140 of the Compounds of Formula l-CC Embodiment 140 of the Compounds of Formula l-CC.
  • R N , R 3 , R 4 , Y 6 , R 6 , and R 6 are as described in Embodiment 131 of the compounds of Formula I-CC, and R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 substituent is optionally substituted with one or more substituent selected from the group consisting of chloro, fluoro, methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluoromethyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, amino, methylamino, dimethylamino, ethylamino, diethylamino, methylsulfonyl, and ethylsulfonyl.
  • Embodiment 141 of the Compounds of Formula I-CC is a diagrammatic representation of the Compounds of Formula I-CC:
  • R N , R 3 , R 4 , Y 6 , R 6 , and -R 6 are as described in Embodiment 131 of the compounds of Formula I-CC, and R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 substituent is optionally substituted with one or more substituent selected from the group consisting of fluoro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, amino, methylamino, dimethylamino, and methylsulfonyl.
  • Embodiment 142 of the Compounds of Formula l-CC In another embodiment of Formula l-CC, R N , R 2 , R 3 , R 4 , R 6 , and R 6 are as described in
  • Embodiment 141 of the compounds of Formula l-CC, and Y 6 is a CrC 6 alkyl.
  • R N , R 2 , R 3 , R 4 , R 6 , and R 6 are as described in Embodiment 142 of the compounds of Formula l-CC, and Y 6 is selected from the group consisting of -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 (CH 3 )-, -CH 2 CH 2 (CH 3 )-, and -CH 2 (CH 3 )CH 2 -.
  • R N , R 2 , Y 6 , R 6 , and R 6 are as described in Embodiment 143 of the compounds of Formula l-CC, and at least one of R 3 and R 4 is hydrogen.
  • Embodiment 145 of the Compounds of Formula l-CC In another embodiment of Formula l-CC, R N , R 2 , Y 6 , R 6 , and R 6 are as described in
  • Embodiment 143 of the compounds of Formula l-CC, and both R 3 and R 4 are hydrogen.
  • R N , R 3 , R 4 , Y 6 , R 6 , and R 6 are as described in Embodiment 145 of the compounds of Formula l-CC, and R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 substituent is optionally substituted with one or more fluoro substituents.
  • R N , R 3 , R 4 , Y 6 , R 6 , and R 6 are as described in Embodiment 145 of the compounds of Formula l-CC, and R 2 is selected from the group consisting of phenyl and pyridinyl, wherein the R 2 substituent is substituted with two fluoro substituents.
  • R N is as described in Embodiment 116 of the compounds of Formula l-CC, and R 2 is phenyl, wherein the R 2 phenyl may be optionally substituted with one or more fluoro substituents;
  • R 3 and R 4 are hydrogen
  • Y 6 is selected from the group consisting of methyl, ethyl and propyl;
  • R 6 is selected from the group consisting of methylsulfonyl, cyclohexyl, tetrahydrofuryl, pyridinyl, pyrazinyl, and morpholinyl, wherein the R 6 methylsulfonyl, cyclohexyl, tetrahydrofuryl, pyridinyl, pyrazinyl, and morpholinyl substitutents may be 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; and R 8 is selected from the
  • R N , R 3 , R 4 , Y 6 , R 6 , and R 6 are as described in Embodiment 148 of the compounds of Formula I-CC, and R 2 is phenyl substituted with one or more fluoro substituents.
  • Embodiment 150 of the Compounds of Formula I-CC In another embodiment of Formula I-CC, R N , R 3 , R 4 , Y 6 , R 6 , and R 6 are as described in
  • Embodiment 148 of the compounds of Formula I-CC, and R 2 is phenyl substituted with two fluoro substituents.
  • Embodiment 151 of the Compounds of Formula I-CC is a diagrammatic representation of the Compounds of Formula I-CC:
  • R N , R 3 , R 4 , Y 6 , R 6 , and R 6 are as described in Embodiment 148 of the compounds of Formula I-CC, and R 2 is selected from the group consisting of 4-fluorophenyl and 3,4-difluorophenyl.
  • R N is as described in Embodiment 116 of the compounds of Formula I-CC, and R 2 is pyridinyl, wherein the R 2 pyridinyl may be optionally substituted with one or more substituents selected from the group consisting of fluoro and methoxy; R 3 and R 4 are hydrogen;
  • Y 6 is selected from the group consisting of methyl, ethyl and propyl; R 6 is selected from the group consisting of methylsulfonyl, cyclohexyl, tetrahydrofuryl, pyridinyl, pyrazinyl, and morpholinyl, wherein the R 6 methylsulfonyl, cyclohexyl, tetrahydrofuryl, pyridinyl, pyrazinyl, and morpholinyl substitutents may be optionally substituted with one or more substituents selected from the group consisting of chloro, fluoro, methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluorom ethyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, amino, methylamino, dimethylamino, ethylamino, and diethylamino; and R 8 is selected
  • Embodiment 153 of the Compounds of Formula I-CC In another embodiment of Formula I-CC, R N , R 3 , R 4 , Y 6 , R 6 , and R 6 are as described in
  • Embodiment 152 of the compounds of Formula I-CC, and R 2 is pyridin-3-yl, optionally substituted as described in Embodiment 70 of the compounds of Formula I-CC.
  • Embodiment 154 of the Compounds of Formula l-CC In another embodiment of Formula I-CC, R N , R 3 , R 4 , Y 6 , R 6 , and R 6 are as described in Embodiment 152 of the compounds of Formula I-CC, and R 2 is pyridinyl substituted with one or more fluoro substituents.
  • R N , R 3 , R 4 , Y 6 , R 6 , and R 6 are as described in Embodiment 152 of the compounds of Formula I-CC, and R 2 is pyridinyl substituted with one or more methoxy substituents.
  • the present invention is directed, in part, to a class of compounds (including tautomers of the compounds and pharmaceutically acceptable salts of the compounds and tautomers) having the structure of Formula I-X:
  • R 2 is selected from the group consisting of
  • R 11 is selected from hydrogen and C 1 -C 4 alkyl
  • R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , and R 16 are independently selected from the group consisting of hydrogen, halogen, cyano, oxo, alkyl, cycloalkyl, phenyl, 5-7 membered ring heterocyclyl, - OR A , -C(O)R A , -OC(O)R A , -C(O)OR A , -NR A R B , -N(R B )C(O) R c , -C(O)NR A R B , -C(O)NR A C(O)R B , - SR A , -S(O)R A , -S(O) 2 R A , -N(R A )S(O) 2 R B , and -S(O) 2 NR A R B , wherein (a) the alkyl substitutent may be optionally substituted with one or more substituents independently
  • R c , R D , R E and R F are independently selected from the group consisting of hydrogen and alkyl;
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -OR G , -C(O)R G , -OC(O)R G , -C(O)OR G , -NR G R H , -N(R G )C(O) R H , -C(O)NR G R H -, -C(O)NR G C(O)R H , -SR G , -S(O)R G ,-S(O) 2 R G , - N(R G )S(O) 2 R H , and -S(O) 2 NR G R H , wherein (a) the R 3 and R 4 alkyl, alkenyl, and alkynyl substitutents may be optionally substituted with one or more substituents independently selected from the group consisting of
  • R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heterocyclyl, wherein (a) the R 6 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, cycloalkyl, aryl, heterocyclyl, -OR S , -C(O)R S , -C(O)OR S , -OC(O)R S , -NR S R T , -N(R S )C(O)R T , -C(O)NR S R T , - C(O)NR S C(O)R T , -SR S , -S(O)R S , -S(O) 2 R 55 , -N(R S )S(O) 2 R T , and -S(O) 2 NR S R T , and (b) the R 6 cycloalkyl
  • R 8 is alkyl, wherein the R 8 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, cycloalkyl, alkynyl, aryl, heterocyclyl, -OR ⁇ , -C(O)R U , -C(O)OR ⁇ , -OC(O)R ⁇ , - NR U R V , -N(R U )C(O)R V , -C(O)NR ⁇ R v ,' -C(O)NR U C(O)R V , -SR ⁇ , -S(O)R U , -S(O) 2 R U , - N(R U )S(O) 2 R V , and -S(O) 2 NR U R V , wherein the cycloalkyl, alkynyl, aryl, and heterocyclyl
  • R 2 , R 6 , and R 8 are as described in Formula I-X, and R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, phenyl, amino, alkylamino, haloalkylamino, hydroxyalkylamino, mercapto, alkylthio, haloalkylthio, and hydroxyalkylthio.
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, phenyl, amino, alkylamino, haloalkylamino, hydroxyalkylamino, mercapto, alkylthio, haloalkylthio, and hydroxyalkylthio.
  • R 2 , R 6 , and R 8 are as described in Formula I-X, and both R 3 and R 4 are hydrogen.
  • R 2 , R 3 , R 4 , R 6 , and R 8 are as described in Formula I-X, wherein R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , and R 16 are independently selected from the group consisting of hydrogen, halogen, alkyl, -OR A , -NR A R B , and -S(O) 2 R A , wherein the alkyl substitutent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, -OR 0 , -C(O)OR 0 , and -C(O)NR 0 R 0 ; wherein R A and R B are independently selected from the group consisting of hydrogen, alkyl, C 3 -C 6 - cycloalkyl, phenyl, and 5-6 membered ring heterocyclyl, wherein (a) when the alkyl is methyl
  • Embodiment 4 of the Compounds of Formula I-X In another embodiment of Formula I-X, R 2 , R 3 , R 4 , and R 8 are as described in Embodiment 3 of the compounds of Formula I-X, wherein R 6 is selected from the group consisting of alkyl, C 3 -C 6 -cycloalkyl, phenyl, and 3-10 membered ring heterocyclyl, wherein (a) the R 6 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, C 3 -C 6 -cycloalkyl, phenyl, 3-10 membered ring heterocyclyl, -OR S , -C(O)R S , -C(O)OR S , -OC(O)R S , -NR S R T , - N(R S )C(O)R T , -C(O)NR S R T
  • R 2 , R 3 , R 4 , and R 6 are as described in Embodiment 4 of the compounds of Formula I-X, wherein R 8 is alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, C 3 -C 6 -cycloalkyl, phenyl, 3-10 membered ring heterocyclyl, -OR U , -C(O)R U , - C(O)OR U , -OC(O)R U , -NR U R V , -N(R U )C(O)R V , -C(O)NR U R V , -C(O)NR U C(O)R V , -SR U , -S(O)R U , - S(O) 2 R ⁇ , -N(R U )S(O) 2 R V , and -S(O) 2
  • Embodiment 6 of the Compounds of Formula I-X In another embodiment of Formula I-X, R 2 , R 3 , R 4 , and R 6 are as described in Embodiment 5 of the compounds of Formula I-X, wherein R 8 is alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 3 -C 6 - cycloalkyl, phenyl, 5-7 membered ring heterocyclyl, -OR U , -NR U R V , and -SR U , wherein the C 3 -C 6 - cycloalkyl, phenyl, 5-7 membered ring heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkyl, phenyl, 5-7 membered ring heterocyclyl, and alkoxy; and wherein R ⁇ and R
  • R 2 , R 6 , and R 8 are as described in Embodiment 6 of the compounds of Formula I-X, wherein R 3 and R 4 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, cyano, hydroxy, carboxy, methyl, chloromethyl, dichioromethyl, trichlorom ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, ethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoroethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, propyl, methoxy, ethoxy, propoxy, phenyl, amino, methylamino, dimethylamino, mercapto, and methylthio.
  • Embodiment 8 of the Compounds of Formula I-X In another embodiment of Formula I-X, R 2 , R 6 , and R 8 are as described in Embodiment 7 of the compounds of Formula I-X, wherein both R 3 and R 4 are hydrogen.
  • R 2 , R 3 , R 4 , and R 8 are as described in Embodiment 7 of the compounds of Formula I-X, wherein R 6 is cycloalkyl optionally substituted as described in Embodiment 5 of the compounds of Formula I-X.
  • R 2 , R 3 , R 4 , and R 8 are as described in Embodiment 7 of the compounds of Formula I-X, wherein R 6 is cyclohexyl optionally substituted as described in Embodiment 5 of the compounds of Formula I-X.
  • R 2 , R 3 , R 4 , and R 8 are as described in Embodiment 7 of the compounds of Formula I-X, wherein R 6 is phenyl optionally substituted as described in Embodiment 5 of the compounds of Formula I-X.
  • Embodiment 12 of the Compounds of Formula I-X In another embodiment of Formula I-X, R 2 , R 3 , R 4 , and R 8 are as described in
  • Embodiment 7 of the compounds of Formula I-X wherein R 6 is alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, cycloalkyl, aryl, 3-10 membered ring heterocyclyl, -OR S , -C(O)R S , -C(O)OR S , -OC(O)R S , -NR S R T , -SR S and -S(O) 2 R S ; and wherein R s and R ⁇ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and 3-10 membered ring heterocyclyl, wherein (a) when the alkyl is methyl, the methyl may be optionally substituted by 1 , 2, or 3 fluoro substituents, (b) when the alkyl comprises at least two carbon atoms, the alkyl may be optionally substituted with one or more substituents independently selected from
  • R 2 , R 3 , R 4 , and R 8 are as described in Embodiment 7 of the compounds of Formula I-X, wherein R 6 is alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR S , - C(O)R S , -C(O)OR S , -OC(O)R S , -NR S R T , and -S(O) 2 R S ; and R s and R ⁇ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and 3-10 membered ring heterocyclyl, wherein (a) when the alkyl is methyl, the methyl may be optionally substituted by 1 , 2, or 3 fluoro substituents, (b) when the alkyl comprises at least two carbon atoms, the alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of
  • R 2 , R 6 , and R 8 are as described in Embodiment 13 of the compounds of Formula I-X, wherein both R 3 and R 4 are hydrogen.
  • R 2 , R 3 , R 4 , and R 8 are as described in Embodiment 13 of the compounds of Formula I-X, wherein R 6 is a 5-7 membered ring heterocylyl, optionally substituted as described in Embodiment 4 of the compounds of Formula I-
  • R 2 , R 3 , R 4 , and R 8 are as described in Embodiment 13 of the compounds of Formula I-X, wherein R 6 is a 5-7 membered ring heteroaryl, optionally substituted as described in Embodiment 4 of the compounds of Formula I-X.
  • Embodiment 17 of the Compounds of Formula I-X In another embodiment of Formula I-X, R 2 , R 3 , R 4 , and R 8 are as described in
  • Embodiment 18 of the Compounds of Formula I-X In another embodiment of Formula I-X, R 2 , R 3 , R 4 , and R 8 are as described in
  • Embodiment 8 of the compounds of Formula I-X wherein R 6 is selected from the group consisting of pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, tetrahydrofuryl, dihydrofuryl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, and morpholinyl, and wherein the R 6 substitutent may be optionally substituted as described in Embodiment 4 of the compounds of Formula I-X.
  • R 2 , R 6 , and R 8 are as described in Embodiment 18 of the compounds of Formula I-X, wherein both R 3 and R 4 are hydrogen.
  • Embodiment 20 of the Compounds of Formula I-X In another embodiment of Formula I-X, R 2 , R 3 , R 4 , and R 8 are as described in Embodiment 18 of the compounds of Formula I-X, wherein R 6 is selected from the group consisting of pyrrolidinyl, imidazolyl, tetrahydrofuryl, furyl, piperidinyl, piperazinyl, pyridinyl, pyrazinyl, tetrahydropyranyl, and morpholinyl, and wherein the R 6 substitutent may be optionally substituted as described in Embodiment 4 of the compounds of Formula I-X.
  • Embodiment 21 of the Compounds of Formula I-X is selected from the group consisting of pyrrolidinyl, imidazolyl, te
  • R 2 , R 3 , R 4 , and R 8 are as described in Embodiment 8 of the compounds of Formula I-X, wherein R 6 is a 5-6 membered ring heterocyclyl, wherein the R 6 5-6 membered ring heterocyclyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, alkynyl, cycloalkyl, aryl, 3-10 membered ring heterocyclyl, -OR S , - C(O)R S , -C(O)OR S , -OC(O)R S , -NR S R T -SR S and -S(O) 2 R 55 ; and wherein R s and R ⁇ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and 3-10 membered ring heterocyclyl, wherein (
  • Embodiment 22 of the Compounds of Formula I-X In another embodiment of Formula I-X, R 2 , R 3 , R 4 , and R 8 are as described in
  • R 2 , R 3 , R 4 , and R 8 are as described in Embodiment 7 of the compounds of Formula I-X, wherein R 6 is selected from the group consisting of alkyl, cyclohexyl, phenyl, pyrrolidinyl, imidazolyl, tetrahydrofuryl, furyl, piperidinyl, piperazinyl, pyridinyl, pyrazinyl, tetrahydropyranyl, and morpholinyl, and wherein the R 6 substitutent may be optionally substituted as described in Embodiment 4 of the compounds of Formula I-X.
  • Embodiment 24 of the Compounds of Formula I-X In another embodiment of Formula I-X, R 2 , R 3 , R 4 , and R 8 are as described in
  • R 2 , R 3 , R 4 , and R 8 are as described in Embodiment 23 of the compounds of Formula I-X, wherein R 6 is piperidinyl, optionally substituted as described in Embodiment 4 of the compounds of Formula I-X.
  • R 2 , R 6 , and R 8 are as described in Embodiment 23 of the compounds of Formula I-X, wherein both R 3 and R 4 are hydrogen.
  • R 2 , R 3 , R 4 , and R 6 are as described in Embodiment 23 of the compounds of Formula I-X, wherein R 8 is selected from the group consisting of alkyl, cycloalkylalkyl, phenylalkyl, 3-10 membered ring heterocyclylalkyl, alkylthioalkyl, alkoxyalkyl, cycloalkoxyalkyl, phenoxyalkyl, 3-10 membered ring heterocyclyloxyalkyl, and alkoxyarylalkyl, 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, oxo, and alkoxy.
  • Embodiment 28 of the Compounds of Formula I-X is a
  • R 2 , R 3 , R 4 , and R 6 are as described in Embodiment 27 of the compounds of Formula I-X, wherein R 8 is selected from the group consisting of alkyl, cycloalkylalkyl, alkylthioalkyl, alkoxyalkyl, and cycloalkoxyalkyl, 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, oxo, and alkoxy.
  • Embodiment 29 of the Compounds of Formula I-X In another embodiment of Formula I-X, R 2 , R 3 , R 4 , and R 6 are as described in
  • Embodiment 30 of the Compounds of Formula I-X In another embodiment of Formula I-X, R 2 , R 3 , R 4 , and R 6 are as described in Embodiment 27 of the compounds of Formula I-X, wherein R 8 is C r C 10 -alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • Embodiment 31 of the Compounds of Formula I-X :
  • R 2 , R 3 , R 4 , and R 6 are as described in Embodiment 27 of the compounds of Formula I-X, wherein R 8 is d-Ce-alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • R 8 is d-Ce-alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • R 2 , R 3 , R 4 , and R 6 are as described in Embodiment 27 of the compounds of Formula I-X, wherein R 8 is alkoxyalkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • R 8 is alkoxyalkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • R 2 , R 3 , R 4 , and R 6 are as described in Embodiment 27 of the compounds of Formula I-X, wherein R 8 is cycloalkylalkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • R 8 is cycloalkylalkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • R 2 , R 3 , R 4 , and R 6 are as described in Embodiment 27 of the compounds of Formula I-X, wherein R 8 is phenylalkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • R 8 is phenylalkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • R 2 , R 3 , R 4 , and R 6 are as described in Embodiment 27 of the compounds of Formula I-X, wherein R 8 is a 5-6 membered ring heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • R 8 is a 5-6 membered ring heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, and alkoxy.
  • R 2 , R 6 , and R 8 are as described in Embodiment 27 of the compounds of Formula I-X, wherein R 3 and R 4 are independently selected from the group consisting of hydrogen, fluoro, methyl, ethyl; trifluorom ethyl, and methoxy.
  • Embodiment 37 of the Compounds of Formula I-X In another embodiment of Formula I-X, R 2 , R 6 , and R 8 are as described in Embodiment .
  • R 2 , R 6 , and R 8 are as described in Embodiment 36 of the compounds of Formula I-X, wherein both R 3 and R 4 are hydrogen.
  • R 2 may be 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, diethylamino, methylsulfonyl, and ethylsulfonyl.
  • 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, diethylamino, methylsulfonyl, and ethylsulfonyl.
  • Embodiment 40 of the Compounds of Formula I-X is a
  • R 3 , R 4 , R 6 , and R 6 are as described in Embodiment 37 of the compounds of Formula I-X, wherein R 2 is selected from the group consisting of
  • R 11 is selected from the group consiting of hydrogen and CrC 4 alkyl
  • R 9 , R 10 and R 12 are independently 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, diethylamino, methylsulfonyl, and ethylsulfonyl.
  • R 3 , R 4 , R 6 , and R 6 are as described in Embodiment 37 of the compounds of Formula I-X, wherein R 2 is wherein
  • R 11 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl
  • R 9 , R 10 and R 12 are independently selected from the group consisting of chloro, fluoro, methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluoromethyl, hydroxy, methoxy, ethoxy, prop ⁇ xy, butoxy, amino, methylamino, dimethylamino, ethylamino, diethylamino, methylsulfonyl, and ethylsulfonyl.
  • R 3 , R 4 , R 6 , and R 6 are as described in Embodiment 37 of the compounds of Formula I-X, wherein R 2 is selected from the group consisting of 4-fluorophenyl, 3,4-difluorophenyl, 4-fluoropyridin-3-yl, and 4-methoxypyridin-3-yl.
  • R 2 , R 3 , R 4 , R 6 , and R 6 are as described in Embodiment 38 of the compounds of Formula I-X, wherein R 9 , R 10 and R 12 are independently 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, diethylamino, methylsulfonyl, and ethylsulfonyl.
  • R 2 , R 3 , R 4 , R 6 , and R 6 are as described in Embodiment 38 of the compounds of Formula I-X, wherein R 9 , R 10 and R 12 are independently selected from the group consisting of hydrogen, fluoro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, amino, methylamino, dimethylamino, and methylsulfonyl.
  • R 2 , R 3 , R 4 , R 6 , and R 6 are as described in Embodiment 44 of the compounds of Formula I-X, wherein R 9 , R 10 and R 12 are independently selected from the group consisting of hydrogen and fluoro.
  • R 2 , R 3 , R 4 , R 6 , and R 6 are as described in Embodiment 45 of the compounds of Formula I-X, wherein at least two of R 9 , R 10 and R 12 are fluoro.
  • Embodiment 47 of the Compounds of Formula I-X In another embodiment of Formula I-X, R 3 , R , R 6 , and R 6 are as described in Embodiment 44 of the compounds of Formula I-X, wherein R 2 is selected from the group consisting of 4-fluorophenyl, 3,4-difluorophenyl, 4-fluoropyridin-3-yl, and 4-methoxypyridin-3-yl.
  • X 6 is -NR N -, wherein R N is H and Y 6 represents a
  • X 6 is -NR N -, wherein R N is H and Y 6 is -CH 2 -, as
  • X 6 is -NR N -, wherein R N is H and Y 6 is -CH 2 CH 2 - (optionally substituted as described in Formula I), as described in Formula l-l:
  • X 6 is -N(R N )-, wherein R N is H and Y 6 is - CH 2 CH 2 CH 2 - (optionally substituted as described in Formula I), as described in Formula I-J: wherein R 2 , R 3 , R 4 , R 6 , and R 8 are as described in the various embodiments of Formula I.
  • the present invention comprises optical isomers and mixtures, including racemic mixtures of the compounds of Formulae (I) through (I-EE).
  • the present invention comprises diastereomeric forms (individual diastereomers and mixtures thereof) of compounds of Formulae (I) through (I-EE).
  • the present invention comprises the tautomeric forms of compounds of Formulae (I) through (I-CC). For instance, a tautomeric form of the following compound:
  • E. Salts The compounds of this invention may be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil. In some instances, a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound. Where a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context), the salt preferably is pharmaceutically acceptable.
  • pharmaceutically acceptable salt refers to a salt prepared by combining a compound of Formulae (I) - (I-CC) with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption.
  • Pharmaceutically acceptable salts are useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound.
  • the salts of the compounds of this invention are non-toxic "pharmaceutically acceptable salts.”
  • 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, araliphatic, heterocyclyl, carboxyic, and sulfonic classes of organic acids.
  • 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 (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, ⁇ -hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate, camphorate
  • examples of suitably 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 with suitable organic ligands, e.g., quaternary ammonium salts.
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands e.g., quaternary ammonium salts.
  • 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 (CrC 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.
  • lower alkyl (CrC 6 ) halides e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulfates e.g., dimethyl, die
  • 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)- (I-CC) 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.
  • prodrugs of the compounds of Formulae (1) through (I-CC).
  • certain derivatives of compounds of any of Formulae (I) through (I-EE) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of any of Formulae (I) through (I-EE) having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as "prodrugs”.
  • Further information on the use of prodrugs may be found in "Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of any of Formulae (I) through (I-EE) with certain moieties known to those skilled in the art as "pro-moieties” as described, for example, in “Design of Prodrugs” by H Bundgaard New York, NY (Elseview, 1985).
  • 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 Formulae (I) through (I-EE) 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 condition is a cardiovascular disease, including 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
  • the condition is a metabolic disease, including 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
  • the condition is a diseases of the central nervous system, including 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.
  • the condition is Alzheimer's disease.
  • the condition is Parkinson's disease.
  • the condition is ALS.
  • the condition is a concentration disorder.
  • the condition is a pulmonary disease, including a pulmonary disease selected from the group consisting 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 consisting of asthma; acute respiratory distress; cystic fibrosis; chronic obstructive pulmonary disease (COPD); bronchitis; and chronic reversible pulmonary obstruction.
  • the condition is sexual dysfunction, including sexual dysfunction selected from the group consisting 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, including a renal dysfunction selected from the group consisting of acute or chronic renal failure; nephropathy (such as diabetic nephropathy); glomerulopathy; and nephritis.
  • 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 acute pain associated with, for example, injury or surgery.
  • the condition is chronic pain including neuropathic pain (including postherpetic neuralgia and pain associated with peripheral, cancer or diabetic neuropathy), carpal tunnel syndrome, back pain (including pain associated with herniated 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 (e.g. bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (e.g.
  • 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 postsurgical pain post herpetic neuralgia, trigeminal neuralgia HIV neuropathy, phantom limb pain, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency.
  • the condition is nociceptive pain including pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, postoperative 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 (including osteoarthritis and rheumatoid disease pain), ankylosing spondylitis, visceral pain (including inflammatory bowel disease, functional bowel disorder, gastro-esophageal relux, dyspepsia, irritable bowel syndrome, functional abdominal pain syndrome, Crohn's disease, ileitis, ulcerative colitis, dysmenorrheal, cystitis, pancreaitis and pelvic pain).
  • arthritic pain including osteoarthritis and rheumatoid disease pain
  • ankylosing spondylitis visceral pain (including inflammatory bowel disease, functional bowel disorder, gastro-esophageal relux, dyspepsia, irritable bowel syndrome, functional abdominal pain syndrome, Crohn's disease, ileitis, ulcerative colitis, dysmenorrheal, cystitis, pancreaitis and pelvic pain).
  • the condition is pain resulting from musculo-skeletal 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, such as migraine (including 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 such as migraine (including 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.
  • the condition is selected from the group consisting of tubulointerstitial disorders; anal fissure; baldness; benign prostatic hyperplasia (BPH); bladder outlet obstruction; 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 assqciated with endothelial dysfunction, including conditions selected from the group consisting 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 condition is a cGMP-mediated condition.
  • the present invention additionally comprises methods for inhibiting the PDE-5 enzyme in a subject by administering to the subject a therapeutically-effective amount of one or more compounds of Formulae (I) through (I-EE) as described above.
  • the methods and compounds 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 human.
  • (I) through (I-EE) inhibit PDE-5 and increase intracellular cGMP levels. This increase in intracellular cGMP reduces intracellular calcium signaling, resulting in vascular smooth muscle relaxation, and a reduction in hypertension.
  • Selected embodiments of the invention therefore, comprise methods for treating a cGMP-mediated condition via PDE-5 inhibition.
  • compounds of Formulae (I) through (I-EE) would be therapeutically useful in methods for treating hypertension by administering to a hypertensive subject a therapeutical ly-effective amount of a compound, of Forumulae (I) through (I-CC).
  • 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-EE) may be administered with aspirin.
  • one or more compounds of Formulae (I) through (I-EE) 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-CC) include quinapril (such as ACCUPRILTM), perindopril (such as ACEONTM), captopril (such as
  • CAPOTENTM CAPOTENTM
  • enalapril such as VASOTECTM
  • ENALAPRILATTM ramipril
  • cilazapril delapril
  • fosenopril such as MONOPRILTM
  • zofenopril indolapril
  • benazepril such as LOTENSINTM
  • lisinopril such as PRINIVILTM or ZESTRILTM
  • spirapril trandolapril (such as MAVIKTM)
  • perindep pentopril
  • moexipril such as UNIVASCTM
  • pivopril april
  • trandolapril such as MAVIKTM
  • one or more compounds of Formulae (I) through (I-EE) may be co-administered with one or more alpha blockers such as dozazosin (such as CARDURATM), phenoxybenzamine (such as DIBENZYLINETM), or terazosin (such as HYTRINTM).
  • alpha blockers such as dozazosin (such as CARDURATM), phenoxybenzamine (such as DIBENZYLINETM), or terazosin (such as HYTRINTM).
  • one or more compounds of Formulae ⁇ l) through (I-EE) maybe co-administered with one or more alpha-beta blockers such as labetalol (such as NORMODYNETM or TRANDAT£TM).
  • alpha-beta blockers such as labetalol (such as NORMODYNETM or TRANDAT£TM).
  • one or more compounds of Formulae (I) through (I-EE) may be co-administered 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.
  • 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 BE
  • one or more compounds of Formulae (I) through (I-EE) may be co-administered with one or more alpha-2-delta ligands such as gabapentin, pregabalin, [(1R,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)-cycloheptyl]- 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, (SSj ⁇ RJ-S-aminomethyl- ⁇ -methyl-octanoic
  • one or more compounds of Formulae (I) through (I-EE) may be co-administered with one or more beta blockers such as timolol (such as BLOCARDENTM), 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).
  • beta blockers such as timolol (such as BLOCARDENTM), carteolol (such as CARTROLTM), carvedilol (such as COREGTM), nadolol (such as CORGARDTM
  • one or more compounds of Formulae (I) through (I-EE) may be co-administered with one or more 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), nisoldipine (such as SULARTM), or bepridil (such as VASCORTM).
  • nifedipine such as ADALATTM, ADALAT CCTM or PROCARDIATM
  • one or more compounds Formulae (I) through (I-EE) may be coadministered with one or more central antiadrenergics such as methyldopa (such as ALDOMETTM), clonidine (such as CATAPRESTM or CATAPRES-TTSTM), guanfacine ⁇ such as TENEXTM), or guanabenz (such as WYTENSINTM).
  • methyldopa such as ALDOMETTM
  • clonidine such as CATAPRESTM or CATAPRES-TTSTM
  • guanfacine ⁇ such as TENEXTM
  • guanabenz such as WYTENSINTM
  • one or more compounds of Formulae (I) through (1-EE) may be co-administered with one or more diruretics such as hydroclorothiazide (such as M1CROZIDETM or ORETICTM), hydroflumethiazide (such as SALURONTM), bemetanide (such as BUMEXTM), torsemide (such as DEMADEXTM), metolazone (such as ZAROXOLYNTM), chlorothiazide (such as DIURILTM, ESIDRIXTM or HYDROD1URILTM), triamterene (such as DYRENIUMTM), ethacrynic acid (such as EDECRINTM), chlorthalidone (such as HYGROTONTM), furosemide (such as LASIXTM), indapamide (such as LOZOLTM), or amiloride (such as MIDAMORTM or MODURETICTM).
  • one or more compounds of Formulae ⁇ I such as M1C
  • one or more compounds of Formulae (I) through (I-EE) may be co-administered 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 . nitrogen monoxide species, and/or stimulate the endogenous production of nitric oxide or endothelium-derived relaxing factor (EDRF) in vivo and/or elevate endogenous levels of nitric oxide or EDRF in vivo.
  • 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-EE) include S-nitrosothiols, nitrites, nitrates, N-oxo-N-nitrosamines, SPM 3672, SPM 5185, SPM 5186 and analogues thereof, sodium nitroprusside, nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, molsidomine, SIN-1 or substrates of the various isozymes of nitric oxide synthase.
  • one or more compounds of Formulae (I) through (I-EE) may be co-administered 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-EE) may be co-administered with one or more renin inhibitors such as Aliskiren (SPP 100).
  • one or more compounds of Formulae (I) through (I-EE) may be co-administered with one or more soluble guanylate cyclase activator ("sGCa").
  • one or more compounds of Formulae (I) through (1-EE) may be co-administered with one or more neutral endopeptidase (NEP) inhibitors, such as, for example
  • one or more compounds of Formulae (I) through (I-EE) may be co-administered 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-EE) may be co-administered with one or more endothelian antagonists, such as BMS-193884.
  • one or more compounds of Formulae (I) through (I-EE) may be co-administered with niacin or one or more nicotinic acid derivatives, such as NIACORTM, NIASPANTM, NICOLARTM, orSLO-NIACINTM.
  • one or more compounds of Formulae (I) through (I-EE) may be co-administered 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-EE) 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-EE) may be co-administered 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-EE) may be co-administered with an apical sodium-dependent bile acid cotransporter inhibitors, such as AZD7806 or 264W94.
  • one or more compounds of Formulae (I) through (I-EE) may be co-administered with one or more cholesterol absorbtion inhibitors, such as ezetimibe (such as ZETIATM).
  • one or more compounds of Formulae (I) through (I-EE) may be co-administered with one or more 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) 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).
  • HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors
  • one or more compounds of Formulae (I) through (I-EE) may be co-administered with one or more alpha glucosidase inhibitors, such as miglitol (such as GLYSETTM), or acarbose (such as PRECOSETM).
  • alpha glucosidase inhibitors such as miglitol (such as GLYSETTM), or acarbose (such as PRECOSETM).
  • one or more compounds of Formulae (I) through (I-EE) may be co-administered with one or more biguanides, such as roseiglitazone (such as AVANDAMETTM), or metformin (such as GLUCOPHAGETM or GLUCOPHAGE XRTM).
  • biguanides such as roseiglitazone (such as AVANDAMETTM), or metformin (such as GLUCOPHAGETM or GLUCOPHAGE XRTM).
  • one or more compounds of Formulae (I) through (I-EE) may be co-administered 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.
  • insulins such as HUMALOGTM, HUMALOG 50/50TM, HUMALOG 75/25TM, HUMULIN 50/50TM, HUMALIN 75/25TM, HUMALIN LTM, HUMALIN NTM ( , HUMALIN RTM,
  • one or more compounds of Formulae (I) through (I-EE) 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-EE) may be co-administered 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).
  • glimepiride such as AMARYLTM
  • glyburide such as DIABETATM, GLYNASE PRESTABTM or MICRONASETM
  • glipizide such as GLUCOTROLTM, or GLUCOTROL XLTM.
  • one or more compounds of Formulae (I) through (I-EE) may be co-administered with one or more thiazolidinediones, such as pioglitazone (such as ACTOSTM) or rosiglitazone (such as AVANDIATM).
  • thiazolidinediones such as pioglitazone (such as ACTOSTM) or rosiglitazone (such as AVANDIATM).
  • the compounds of the present invention are administered suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • Therapeutically effective doses of the compounds required to prevent or arrest the progress of or to treat the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts.
  • 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 compound employed. Thus 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 Formulae (I) through (I-EE) is typically from about 0. 01 to about 100 mg/kg.
  • total daily dose of the compound 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-EE) per kg body weight).
  • dosing is from 0.01 to 10 mg/kg/day.
  • 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.
  • the administration of the 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.
  • the 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 patient to be treated.
  • 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-EE) 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-EE) 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-EE) in the preparation of a medicament for the treatment of angina.
  • the invention comprises the use of one or more compounds of Formulae (I) through (I-EE) in the preparation of a medicament for the treatment of congestive heart failure.
  • the invention comprises the use of one or more compounds of Formulae (I) through (I-EE) 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 Formulae (I) through (I-EE) in the preparation of a medicament for the treatment of cognitive dysfunction. In another embodiment, the invention comprises the use of one or more compounds of Formulae (I) through (I-EE) in the preparation of a medicament for the treatment of pain.
  • compositions for the treatment of the conditions referred to above, the compounds of Formulae (I) through (I-EE) can be administered as compound per se.
  • pharmaceutically acceptable salts are suitable for medical applications because of their greater aqueous solubility relative to the parent compound.
  • the present invention comprises pharmaceutical compositions.
  • Such pharmaceutical compositions comprise compounds of Formulae (I) through (I-EE) presented with a pharmaceutically-acceptable carrier.
  • the carrier can b ⁇ 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-EE) 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-EE) 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, intraperitoneally, intramuscular injections, intrasternal 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.
  • Other carrier materials and modes of administration known in the pharmaceutical art may also be used.
  • Pharmaceutical compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. The above considerations in regard to 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.
  • 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-EE) and an ACE inhibitor.
  • the kit of the present invention comprises one or more compounds of Formulae (I) through (I-EE) and an angiotensin Il receptor antagonist.
  • the kit of the present invention comprises one or more compounds of Formulae (I) through (I-EE) and an aldosterone receptor antagonist.
  • the kit of the present invention comprises one or more compounds of Formulae (I) through (I-EE) and a NO donor.
  • the substituted pyrido[2,3-b]pyrazin-3(4H)-ones VII are prepared through two routes which diverge from a common intermediate prepared early in the synthesis as illustrated in Scheme 1 and Scheme 2.
  • 6-chloro-3-nitro-N-alkylsubstituted-pyridin-2-amine II is the common intermediate for the two outlined routes for preparation of the substituted pyrido[2,3-b]pyrazin-3(4H)-ones VII.
  • the first route described in Scheme I reduction of the nitro group utilizes reagents such as sodium bisulfite, borohydrides (such as sodium borohydride), dissolving metals (such as zinc or iron), or hydrogen with Raney Nickel to afford the 6-chloro-N ⁇ 2 ⁇ -alkylsubstitutedpyridine-2,3- diamine 111.
  • Refluxing of the diamine III compounds and oxalic acid in aqueous solvent in the presence of acids (such as hydrochloric or sulfuric) provides the 6-chloro-4-alkylsubstituted-1 ,4- dihydropyrido[2,3-b]pyrazine-2,3-dione IV.
  • agents for conversion of the amide to the chloropyrazine such as phosphorous oxychloride in the presence of tetraethylammonium chloride, oxalyl chloride, ' sulfonyl chloride
  • solvent such as acetonitrile
  • a second route as described in Scheme 2 to substituted pyrido[2,3-b]pyrazin-3(4H)- ⁇ nes VII commences with a typical palladium(O) couplings (utilizing catalysts such as palladium tetrakis) with substituted phenyl or heterocylic boronic acids, a base (such as sodium carbonate, potassium carbonate) and appropriate solvent (such as aqueous ethylene glycol dimethyl ether, aqueous ethers, aqueous toluene) with the substituted 6-choropyridine II.
  • a typical palladium(O) couplings utilizing catalysts such as palladium tetrakis
  • substituted phenyl or heterocylic boronic acids such as sodium carbonate, potassium carbonate
  • appropriate solvent such as aqueous ethylene glycol dimethyl ether, aqueous ethers, aqueous toluene
  • the nitro group of the resulting N-substituted-3-nitro-6-phenylpyridin-2-amine VIII could be reduced using standard hydrogenation conditions with palladium on carbon as the catalyst in solvent (such as methanol, ethanol, ethyl acetate) providing N ⁇ 2 ⁇ -substituted-6-phenylpyridine- 2,3-diamine IX.
  • solvent such as methanol, ethanol, ethyl acetate
  • oxalic acid in refluxing aqueous acid (such as hydrochloric acid or sulfuric acid ) providing the dihydropyrido[2,3-b]pyrazine-2,3-dione X.
  • chlorination reagents such as phosphorous oxychloride in the presence of tetraethylammonium chloride, oxalyl chloride, sulfonyl chloride
  • solvents such as acetonitrile, propionitrile, dichloromethane, toluene
  • chloropyrazine Xl is preparation of the alkyl sulfonates XII from the dihydropyrido[2,3-b]pyrazine-2,3-dione X which can be accomplished using alkylsulfonylchlorides (such as mesylchloride or tosylchloride) in an solvent (such as dichloromethane, tetrahydrofuran, acetonitrile) in the presence of organic bases (such as triethylamine, pyridine, n- methylmorpholine) or inorganic bases (aqueous bicarbonate, aqueous carbonate, aqueous hydroxide).
  • alkylsulfonylchlorides such as mesylchloride or tosylchloride
  • solvent such as dichloromethane, tetrahydrofuran, acetonitrile
  • organic bases such as triethylamine, pyridine, n- methyl
  • the alkylsulfonate can be displaced in solvent (such as dichloromethane, acetonitrile, tetrahydrofuran) in the presence of organic bases (such as triethylamine, n-methyl morpholine) providing the desired substituted pyrido[2,3-b]pyrazin-3(4H)-ones VII
  • solvent such as dichloromethane, acetonitrile, tetrahydrofuran
  • organic bases such as triethylamine, n-methyl morpholine
  • the carbon linked pyrido[2,3-b]pyrazin-3(4H)-ones XIV are prepared from intermediate IX as described in Scheme 4. Annulation of the phenylpyridine-2,3-diamine IX is accomplished using diethyl 2-oxopentanedioate XVI in a heated alcoholic solvent such as ethanol. The resulting ester XV is reduced using diisobutylaluminum hydride in solvents such as toluene or tetrahydrofuran to provide the aldehyde XVII.
  • Reductive aminations with the appropriate amine (HNR 1 R 2 ) using sodium triacetoxyborohydride or sodium cyanoborohyridie in an appropriate solvent such as ethanol, methanol, tetrahydrofuran, dichloromenthane, or 1 ,2-dichloroethane affords the desired carbon-linked pyrido[2,3-b]pyrazin-3(4H)-ones XIV.
  • Step 1 N-(5-chloro-2-nitrophenyl)-N-(2-ethoxyethyl)amine.
  • Step 2 Preparation of N-(2-ethoxyethyl)-6-(4-fluorophenyl)-3-nitropyridin-2-amine.
  • N-(5-chloro-2-nitrophenyl)-N-(2-ethoxyethyl)amine (11.6 g, 4.73 mmol), 4- fluorophenylboronic acid (7.8 g, 56.8 mmol), and tetrakis(triphenylphosphine)-palladium(0) (150 mg) were mixed in diglyme (90 ml) and 2.0 M aqueous sodium carbonate (30 mL). The solution was poured into ethyl acetate (300 mL) and vacuum filtered through celite. The layers were separated and the organic layer collected.
  • Step 3 Preparation of 4-(2-ethoxyethyl)-6-(4-f luorophenyl)-1 ,4-dihydropyrido-[2,3- b]pyrazine-2,3-dione.
  • Step 4 Preparation of 2-chloro-4-(2-ethoxyethyl)-6-(4-fluorophenyl)pyrido[2,3-b]pyrazin- 3(4H)-one:
  • Step 5 Preparation of 4-(2-ethoxyethyl)-6-(4-fluorophenyl)-2-[(tetrahydro-2H-pyran-4- ylmethyl)amino]pyrido[2,3-b]pyrazin-3(4H)-one
  • Example 2 was obtained from example 14 by treatment with sodium hydroxide in methanol.
  • Example 3 was prepared by a method similar to that described in Example 1 using 2- piperidin-1-ylethylamine in place of 2-tetrahydro-2H-pyran-4-ylmethylamine in step 5 and 3,4- difluorophenyl boronic acid in place of 4-fluorophenylboronic acid in step 2.
  • Example 4 was prepared by a method similar to that described in Example 1 using 2- tetrahydro-2H-pyran-4-ylethylamine in place of 2-tetrahydro-2H-pyran-4-ylmethylamine in step 5 and 3,4-difluorophenylboronic acid in place of 4-fluorophenylboronic acid in step 2.
  • Example 5 was prepared by a method similar to that described in Example 1 using 2- morpholin-4-ylethylamine in place of 2-tetrahydro-2H-pyran-4-ylmethylamine in step 5 and thien- 3-ylboronic acid in place of 4-fluorophenylboronic acid in step 2.
  • Example 6 was prepared by a method similar to that described in Example 1 using 2- piperidin-1-ylethylamine in place of 2-tetrahydro-2H-pyran-4-ylmethylamine in step 5 and thien-3- yiboronic acid in place of 4-fluorophenylboronic acid in step 2.
  • Example 7 was prepared by a method similar to that described in Example 1 using 2- tetrahydro-2H-pyran-4-ylethylamine in place of 2-tetrahydro-2H-pyran-4-ylmethylamine in step 5 and thien-3-ylboronic acid in place of 4-fluorophenylboronic acid in step 2.
  • Example 8 was prepared by a method similar to that described in Example 1 using 1-(3- aminopropyl)pyrrolidin-2-one in place of 2-tetrahydro-2H-pyran-4-ylmethylamine in step 5 and 3,4-difluorophenylboronic acid in place of 4-fluorophenylboronic acid in step 2.
  • Example 9 was prepared by a method similar to that described in Example 1 using 2-
  • Example 10 was prepared by a method similar to that described in Example 1 using 2- (methylsulfonyl)ethylamine in place of 2-tetrahydro-2H-pyran-4-ylmethylamine in step 5 and 3,4- difluorophenylboronic acid in place of 4-fluorophenylboronic acid in step 2.
  • Example 11 was prepared by a method similar to that described in Example 1 using 2- pyridin-2-ylethylamine in place of 2-tetrahydro-2H-pyran-4-ylmethylamine in step 5 and 3,4- difluorophenylboronic acid in place of 4-fluorophenylboronic acid in step 2.
  • Example 12 was prepared by a method similar to that described in Example 1 using ethyl piperidine-4-carboxylate in place of 2-tetrahydro-2H-pyran-4-ylmethylamine in step 5 and 3,4- difluorophenylboronic acid in place of 4-fluorophenylboronic acid in step 2.
  • Example 13 was prepared by a method similar to that described in Example 1 using N, N- diethylethane-1 ,2-diamine in place of 2-tetrahydro-2H-pyran-4-ylmethylamine in step 5 and 3,4- difluorophenylboronic acid in place of 4-fluorophenylboronic acid in step 2.
  • Example 14 was prepared by a method similar to that described in Example 1 using methyl beta-alaninate in place of 2-tetrahydro-2H-pyran-4-ylmethylamine in step 5 and 3,4- difluorophenylboronic acid in place of 4-fluorophenylboronic acid in step 2.
  • Example 15 was prepared by a method similar to that described in Example 1 using A- hydroxypiperidine in place of 2-tetrahydro-2H-pyran-4-ylmethylamine in step 5 and 3,4- difluorophenylboronic acid in place of 4-fluorophenylboronic acid in step 2.
  • Example 16 was prepared by a method similar to that described in Example 1 using 2- pyrrolidin-1-ylethylamine in place of 2-tetrahydro-2H-pyran-4-ylmethylamine in step 5 and 3,4- difluorophenylboronic acid in place of 4-fluorophenylboronic acid in step 2.
  • Example 17 was prepared by a method similar to that described in Example 1 using 2- pyridin-4-ylethylamine in place of 2-tetrahydro-2H-pyran-4-ylmethylamine in step 5 and 3,4- difluorophenylboronic acid in place of 4-fluorophenylboronic acid in step 2.
  • Example 18 was prepared by a method similar to that described in Example 1 using 2- morpholin-4-ylpropylamine in place of 2-tetrahydro-2H-pyran-4-ylmethylamine in step 5 and 3,4- difluorophenylboronic acid in place of 4-fluorophenylboronic acid in step 2.
  • Example 19 was prepared by a method similar to that described in Example 1 using 3-(4- methylpiperazin-1-yl)propylamine in place of 2-tetrahydro-2H-pyran-4-ylmethylamine in step 5 and 3,4-difluorophenylboronic acid in place of 4-fluorophenylboronic acid in step 2.
  • Example 20 was prepared by a method similar to that described in Example 1 using phenethylamine in place of 2-tetrahydro-2H-pyran-4-ylmethylamine in step 5 and 3,4- difluorophenylboronic acid in place of 4-fluorophenylboronic acid in step 2.
  • Example 21 was prepared by a method similar to that described in Example 1 using 2- cyclohex-1-en-1-ylethylamine in place of 2-tetrahydro-2H-pyran-4-ylmethylamine in step 5 and 3,4-difluorophenylboronic acid in place of 4-fluorophenylboronic acid in step 2.
  • Example 22 was prep by a method similar to that described in Example 1 using 1- [(2S)-tetrahydrofuran-2-yl]methanamine in place of 2-tetrahydro-2H-pyran-4-ylmethylamine in step 5 and 3,4-difluorophenylboronic acid in place of 4-fluorophenylboronic acid in step 2.
  • Example 23 was prepared by a method similar to that described in Example 1 using i- [(2R)-tetrahydrofuran-2-yl]methanamine in place of 2-tetrahydro-2H-pyran-4-ylmethylamirie in step 5 and 3,4-difluorophenylboronic acid in place of 4-fluorophenylboronic acid in step 2.

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Abstract

L'invention concerne des composés et des sels pharmaceutiquement acceptables de ceux-ci. Ces composés ont la structure représentée par formule I, dans laquelle R2, R3, R4, X6, Y6, R6 et R8 sont tels que définis dans le descriptif. Des compositions pharmaceutiques correspondantes, des méthodes de traitement, des procédés de synthèse et des produits intermédiaires sont également décrits.
PCT/IB2006/002234 2005-08-16 2006-08-16 Pyridoyrazinones comme inhibiteurs de la pde-5 WO2007020521A1 (fr)

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WO2010066111A1 (fr) 2008-12-10 2010-06-17 上海特化医药科技有限公司 Composés de phénylpyrimidone, compositions pharmaceutiques, leurs procédés de préparation et leurs utilisations
WO2014010732A1 (fr) * 2012-07-13 2014-01-16 武田薬品工業株式会社 Composé hétérocyclique
US9469637B2 (en) 2012-04-25 2016-10-18 Takeda Pharmaceutical Company Limited Nitrogenated heterocyclic compound
WO2016203335A1 (fr) * 2015-06-18 2016-12-22 Pfizer Inc. Nouvelles pyrido [2,3-b] pyrazinones utilisées en tant qu'inhibiteurs de bromodomaines de la famille bet
US9834520B2 (en) 2013-03-14 2017-12-05 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10053468B2 (en) 2013-07-03 2018-08-21 Takeda Pharmaceutical Company Limited Heterocyclic compound
CN109180691A (zh) * 2018-08-24 2019-01-11 武汉大学 一种c3-芳香型吡咯并吲哚类生物碱及其合成方法
US10472376B2 (en) 2013-07-03 2019-11-12 Takeda Pharmaceutical Company Limited Amide compound

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EP0784054A1 (fr) * 1994-09-27 1997-07-16 Yamanouchi Pharmaceutical Co. Ltd. Derive de 1,2,3,4-tetrahydroquinoxalindione
WO2002088123A1 (fr) * 2001-04-25 2002-11-07 Lilly Icos Llc Composes chimiques

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WO1994005661A1 (fr) * 1992-08-28 1994-03-17 Pfizer Limited Agents antiangineux a la pyridopyrimidinone
EP0784054A1 (fr) * 1994-09-27 1997-07-16 Yamanouchi Pharmaceutical Co. Ltd. Derive de 1,2,3,4-tetrahydroquinoxalindione
WO2002088123A1 (fr) * 2001-04-25 2002-11-07 Lilly Icos Llc Composes chimiques

Cited By (22)

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JP2011514896A (ja) * 2008-03-05 2011-05-12 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング ピリドピラジノン誘導体インスリン分泌刺激剤、それらを得る方法および糖尿病を治療するためのそれらの使用
US8178556B2 (en) 2008-03-05 2012-05-15 Merck Patent Gesellschaft Mit Beschraenkter Haftung Pyridopyrazinones derivatives insulin secretion stimulators, methods for obtaining them and use thereof for the treatment of diabetes
US8609689B2 (en) 2008-03-05 2013-12-17 Merck Patent Gmbh Pyridopyrazinones derivatives insulin secretion stimulators, methods for obtaining them and use thereof for the treatment of diabetes
US8642617B2 (en) 2008-03-05 2014-02-04 Merck Patent Gmbh Pyridopyrazinones derivatives insulin secretion stimulators, methods for obtaining them and use thereof for the treatment of diabetes
AU2009221213B2 (en) * 2008-03-05 2014-02-27 Merck Patent Gmbh Pyridopyrazinones derivatives insulin secretion stimulators, methods for obtaining them and use thereof for the treatment of diabetes
EA020372B1 (ru) * 2008-03-05 2014-10-30 Мерк Патент Гмбх Стимуляторы секреции инсулина - производные пиридопиразинонов, способы их получения и их применение для лечения диабета
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
WO2010066111A1 (fr) 2008-12-10 2010-06-17 上海特化医药科技有限公司 Composés de phénylpyrimidone, compositions pharmaceutiques, leurs procédés de préparation et leurs utilisations
US8871777B2 (en) 2008-12-10 2014-10-28 Topharman Shanghai Co., Ltd. Phenylpyrimidone compounds, the pharmaceutical compositions, preparation methods and uses thereof
US9469637B2 (en) 2012-04-25 2016-10-18 Takeda Pharmaceutical Company Limited Nitrogenated heterocyclic compound
US10017508B2 (en) 2012-04-25 2018-07-10 Takeda Pharmaceutical Company Limited Nitrogenated heterocyclic compound
JPWO2014010732A1 (ja) * 2012-07-13 2016-06-23 武田薬品工業株式会社 複素環化合物
US9527841B2 (en) 2012-07-13 2016-12-27 Takeda Pharmaceutical Company Limited Substituted pyrido[2,3-b]pyrazines as phosphodiesterase 2A inhibitors
WO2014010732A1 (fr) * 2012-07-13 2014-01-16 武田薬品工業株式会社 Composé hétérocyclique
US9834520B2 (en) 2013-03-14 2017-12-05 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10053468B2 (en) 2013-07-03 2018-08-21 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10472376B2 (en) 2013-07-03 2019-11-12 Takeda Pharmaceutical Company Limited Amide compound
US11053262B2 (en) 2013-07-03 2021-07-06 Takeda Pharmaceutical Company Limited Heterocyclic amide compounds having RORyT inhibitory action
US11851449B2 (en) 2013-07-03 2023-12-26 Takeda Pharmaceutical Company Limited Heterocyclic amide compounds having an RORvt inhibitory action
WO2016203335A1 (fr) * 2015-06-18 2016-12-22 Pfizer Inc. Nouvelles pyrido [2,3-b] pyrazinones utilisées en tant qu'inhibiteurs de bromodomaines de la famille bet
US20160368919A1 (en) * 2015-06-18 2016-12-22 Pfizer Inc. Novel pyridine pyrazinones as bet-family bromodomain inhibitors
CN109180691A (zh) * 2018-08-24 2019-01-11 武汉大学 一种c3-芳香型吡咯并吲哚类生物碱及其合成方法

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