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WO2006126081A2 - Pyridino [2 , 3-b] pyrazinones as pde-5 inhibitors - Google Patents

Pyridino [2 , 3-b] pyrazinones as pde-5 inhibitors Download PDF

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Publication number
WO2006126081A2
WO2006126081A2 PCT/IB2006/001386 IB2006001386W WO2006126081A2 WO 2006126081 A2 WO2006126081 A2 WO 2006126081A2 IB 2006001386 W IB2006001386 W IB 2006001386W WO 2006126081 A2 WO2006126081 A2 WO 2006126081A2
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group
alkyl
optionally substituted
independently selected
oxo
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PCT/IB2006/001386
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French (fr)
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WO2006126081A3 (en
Inventor
Andrew Simon Bell
Alan George Benson
David Graham Brown
David Louis Brown
Yvette Marlene Fobian
John Nicholas Freskos
Steven Edward Heasley
Robert Owen Hughes
Eric Jon Jacobsen
Brent Virgil Mischke
John Major Molyneaux
Joseph Blair Moon
Dafydd Rhys Owen
Michael John Palmer
Christopher Phillips
Donald Joseph Rogier, Jr.
John Keith Walker
Todd Michael Maddux
Michael Brent Tollefson
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Pharmacia & Upjohn Company Llc
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Priority to CA002603830A priority Critical patent/CA2603830A1/en
Publication of WO2006126081A2 publication Critical patent/WO2006126081A2/en
Publication of WO2006126081A3 publication Critical patent/WO2006126081A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention comprises a class of pyridine pyrazinone compounds having a structure of Formula I and pharmaceutical compositions comprising a compound of Formula I.
  • the present invention also comprises methods of treating a subject by administering a therapeutically effective amount of a compound of Formula I to the subject.
  • these compounds inhibit, in whole or in part, the enzyme: cyclic guanylate monophosphate-specific phosphodiesterase type 5 (PDE-5).
  • hypertension is associated with an increased risk of stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease and renal impairment.
  • anti-hypertensive drugs available in various pharmacological categories, additional agents useful for the treatment of hypertension are still needed.
  • nitric oxide nitric oxide
  • This acts on vascular smooth muscle cells and leads to the activation of guanylate cyclase and the accumulation of cyclic guanosine monophosphate (cGMP).
  • cGMP cyclic guanosine monophosphate
  • the accumulation of cGMP causes the muscles to relax and the blood vessels to dilate, leading to a reduction in blood pressure.
  • the cGMP is inactivated by hydrolysis to guanosine 5'-monophosphate (GMP) by a cGMP-specific phosphodiesterase.
  • GMP guanosine 5'-monophosphate
  • PDE5 Phosphodiesterase type 5
  • Inhibitors of PDE5 decrease the rate of hydrolysis of cGMP and potentiate the actions of nitric oxide.
  • Improved drug therapies for the treatment of subjects suffering from or susceptible to a cardiovascular condition are desirable.
  • the invention comprises compounds of Formula I: wherein R 2 , Y 6 , R 6 , R 6A and R 8 are as defined in the detailed description of the invention.
  • the invention comprises a pharmaceutical composition comprising a compound of Formula I.
  • the invention comprises methods of treating a condition in a subject by administering a therapeutically effective amount of a compound of Formula I to the subject.
  • the invention comprises a method for inhibiting PDE-5, and methods for treating a condition in a subject mediated by PDE-5 activity by administering a compound of Formula I to the subject.
  • the invention comprises intermediates useful in the synthesis of compounds having the structure of Formula I.
  • alkyl refers to a linear or branched-chain saturated hydrocarbyl substituent (i.e., a substituent 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.
  • 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.
  • aikynyl radicals include 1-propynyl, 2-propynyl, 1-butyne, 2-butynyl and 1-pentynyl.
  • amino alone or in combination with another term(s), refers to -NH2 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.
  • carbocyclyl refers to a saturated cyclic (i.e., "cycloalkyl"), partially saturated cyclic (i.e., “cycloalkenyl”), or completely unsaturated (i.e., "aryl”) hydrocarbyl substituent containing from 3 to 14 carbon ring atoms ("ring atoms” are the atoms bound together to form the ring or rings of a cyclic substituent).
  • a carbocyclyl may be a single ring, which typically contains from 3 to 6 ring atoms.
  • Examples of such single-ring carbocyclyls include cyclopropanyl, cyclobutanyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl.
  • a carbocyclyl alternatively may be 2 or 3 rings fused together, such as naphthalenyl, tetrahydronaphthalenyl (also known as “tetralinyl”), indenyl, isoindenyl, indanyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl (also known as “phenalenyl”), fluoreneyl, decalinyl, and norpinanyl.
  • carbonyl alone or in combination with another term(s), means
  • carboxy alone or in combination with another term(s), refers to a radical of the formula -C(O)OH.
  • 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.
  • compound refers to a material made up of two or more elements and includes tautomers and pharmaceutically acceptable salts of the compound.
  • cyano alone or in combination with another term(s), means -CN, which also
  • cycloalkyl alone or in combination with another term(s), 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.
  • the prefix "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 hydrogen 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 alone or in combination with another term(s), means a saturated (i.e., “heterocycloalkyl"), partially saturated (i.e., “heterocycloalkenyl”), or completely unsaturated (i.e., "heteroaryl”) 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, phosphorous, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, phosphorous, and sulfur.
  • heteroatom i.e., oxygen, nitrogen, phosphorous, or sulfur
  • 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, phosphorous, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
  • a heterocyclyl may be a single ring, which typically contains from 3 to 10 ring atoms, more typically from 3 to 7 ring atoms, and even more typically 5 to 6 ring atoms.
  • single-ring heterocyclyls include furanyl, dihydrofurnayl, tetradydrofurnayl, thiophenyl (also known as "thiofuranyl"), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazo
  • azinyl piperidinyi, diazinyl (including pyridazinyl (also known as “1 ,2-diazinyl”), pyrimidinyl (also known as “1 ,3-diazinyl” or “pyrimidyl”), or pyrazinyl (also known as “1 ,4-diazinyl”)), piperazinyl, triazinyl (including s-triazinyl (also known as “1 ,3,5-triazinyl”), as-triazinyl (also known 1,2,4-triazinyl), and v-triazinyl (also known as "1 ,2,3-triazinyl”)), oxazinyl (including 1 ,2,3-oxazinyl, 1 ,3,2-oxazinyl, 1 ,3,6-oxazinyl (also known as "pentoxazolyl”), 1 ,2,6-oxa
  • 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
  • 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, two, or three heteroatoms selected from sulphur, nitrogen, phosphorous, and oxygen, selected from thienyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl and pyrazinyl.
  • heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as 1 ,3,5-, 1 ,2,4- or 1 ,2,3-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-
  • 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, 1 H-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
  • thiazolyl, thiadiazolyl e.g., 1 ,2,4- thiadiazolyl, 1 ,3,4-thiadiazolyl, 1 ,2,5-thiadiazolyl
  • unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms e.g., benzothiazolyl, benzothiadiazolyl] and the like.
  • the term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like.
  • heterocyclylalkyl alone or in combination with another term(s), refers to alkyl substituted with a heterocyclyl.
  • hydroxy alone or in combination with another term(s), refers to -OH.
  • mercapto or "thiol” refers to a sulfhydryl substituent, which also may depicted as -SH.
  • nitro alone or in combination with another term(s), refers to -NO2.
  • alkyl-sulfonyl-alkyP refers to alkyl-S(O)2-alkyl.
  • examples of typically preferred alkylsulfonyl substituents include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.
  • thio or "thia”, alone or in combination with another term(s), refers to a thiaether substituent, i.e., an ether substituent wherein a divalent sulfur atom is in the place of the ether oxygen atom. Such a substituent may be depicted as -S-. This, for example, "alkyl-thio-alkyl” means alkyl-S-alkyl.
  • substituent may be either (1) not substituted, or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the carbon (to the extent there are any) may separately and/or together be replaced with an independently selected optional substituent.
  • substituent and “radical” interchangeably.
  • hypertensive subject refers to a subject having hypertension, suffering from the effects of hypertension or susceptible to a hypertensive condition if not treated to prevent or control such hypertension.
  • pharmaceutically acceptable carrier refers to a carrier that is compatible with the other ingredients of the composition and is not deleterious to the subject.
  • Such carriers may be pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a chemical agent.
  • the preferred composition depends on the method of administration.
  • prevention refers to either preventing the onset of a 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.
  • therapeutically 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 PDE5.
  • Formula I describes ring numbering that is not reflective of standard chemical nomenclature.
  • Compounds of 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:
  • R 2 is selected from the group consisting of aryl and 3 to 10 membered ring heterocyclyl
  • R 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, -OR 100 , - C(O)R 100 , -OC(O)R 100 , -C(O)OR 100 , -NR 100 R 101 , -N(R 100 )C(O)R 101 , -C(O)NR 100 R 101 , - C(O)NR 100 C(O)R 101 , -SR 100 -S(O)R 100 and -S(O) 2 R 100 , aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl wherein (a) the alkyl, alkenyl, alkylnyl and cycloalkyl substituents are optional
  • R 100 , R 101 and R 102 are independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, alkoxy, - C(O)OH and -C(O)NH 2 ;
  • Y 6 represents a bond or is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl, Y 6 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cyano, OXO, cycloalkyl, -OR 103 , -C(O)R 103 , -C(O)OR 103 , -OC(O)R 103 , -NR 103 R 104 , -N(R 103 )C
  • R 103 and R 104 are independently selected from the group consisting of hydrogen and alkyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy;
  • R 6 is selected from the group consisting of hydrogen, halogen, oxo, hydroxy, amino, aminoalkyl, alkyl, alkynyl, alkoxy, alkylamino, cycloalkyl, aryl, aryl-C(O)-, heterocyclyl, heteroaryl, mercapto, sulfonyl, aryl-C(O)-NR 105 -, heterocyclyl-C(O)-, and heterocyclyl-C(O)- NR 105 - , R 6 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, mercapto, oxo, alkyl, alkenyl, alkynyl, alkoxy, aminoalkyl, haloalkyl, hydroxyalkyl, hydroxyalkoxy, carboxyalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl,
  • R 106 and R 107 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and cycloalkyl wherein (a) the R 106 and R 107 alkyl and alkenyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy, and (b) the R 106 and R 107 alkynyl and cycloalkyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy;
  • R 6A is selected from the group consisting of hydrogen, alkyl, and aminoalkyl, R 6A is optionally substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, oxo, hydroxy, alkyl, and alkoxy;
  • R 8 is alkyl; R 8 is optionally substituted with one or more R 8 substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, alkynyl, cycloalkyl, heterocyclyl, -OR 108 , -C(O)R 108 , -C(O)OR 108 , -OC(O)R 108 , -NR 108 R 109 , -N(R 108 )C(O)R 109 , - C(O)NR 108 R 109 , -SR 108 , -S(O)R 108 , and -S(O) 2 R 108 , wherein the alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkyl, and alkoxy; and
  • R 108 and R 109 are independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl, wherein (a) when the alkyl is methyl, the methyl is optionally substituted with 1 , 2, or 3 fluoro substituents, (b) when the alkyl comprises at least two carbon atoms, the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy, and (c) the R 108 and R 109 alkynyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy,
  • R 8 is alkyl, R 8 is optionally substituted with one or more R 8 substituents independently selected from the group consisting of alkoxy, cycloalkyl, and heterocyclyl, said R 8 substituents are optional substituted with halogen.
  • R 2 is selected from the group consisting of aryl and
  • R 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, -OR 100 , -C(O)R 100 , -OC(O)R 100 , -C(O)OR 100 , -NR 100 R 101 , - N(R 100 )C(O)R 101 , -C(O)NR 100 R 101 , -C(O)NR 100 C(O)R 101 , and -S(O) m R 100 , aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl wherein (a) the alkyl, alkenyl, alkylnyl and cycloalkyl substitu
  • R 100 , R 101 and R 102 are independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, alkoxy, - C(O)OH and -C(O)NH 2 ;
  • R 6A is selected from the group consisting of hydrogen and alkyl wherein the R 6A alkyl substituent is optionally substituted with one or more substituents selected from the group consisting of chloro, fluoro, alkoxy and hydroxy;
  • Y 6 represents a bond or is selected from the group consisting of alkyl, alkenyl and alkynyl, wherein (a) the Y 6 alkyl, alkenyl and alkynyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, cycloalkyl, -OR 103 , -C(O)R 103 , -C(O)OR 103 , -OC(O)R 103 , -NR 103 R 104 , - N(R 103 )C(O)R 104 , and -C(O)NR 103 R 104 ;
  • R 103 and R 104 are independently selected from the group consisting of hydrogen and alkyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy;
  • R 6 is selected from the group consisting of aryl, aryl-C(O)-, heterocyclyl, aryl-C(O)-NR 105 - , heterocyclyl-C(O)-, and heterocyclyl-C(O)-NR 105 - wherein R 6 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -OR 106 , -C(O)R 106 , -C(O)OR 106 , - OC(O)R 106 , -NR 106 R 107 , -N(R 106 )C(O)R 107 , -C(O)NR 106 R 107 , -C(O)NR 106 C(O)R 107 , -SR 106 , - S(O)
  • R 105 is independently selected from the group consisting of hydrogen and alkyl
  • R 106 and R 107 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl, wherein (a) the R 106 and R 107 alkyl and alkenyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy, and (b) the R 106 and R 107 alkynyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy;
  • R 8 is alkyl; wherein R 8 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, alkynyl, -OR 108 , -C(O)R 108 , -C(O)OR 108 , -OC(O)R 108 , -NR 108 R 109 , -N(R 108 )C(O)R 109 , - C(O)NR 108 R 109 , and -C(O)NR 108 C(O)R 109 , wherein the alkynyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkyl, and alkoxy; and
  • R 108 and R 109 are independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl, wherein (a) when the alkyl is methyl, the methyl is optionally substituted with 1 , 2, or 3 fluoro substituents, (b) when the alkyl comprises at least two carbon atoms, the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy, and (c) the R 108 and R 109 alkynyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy,
  • R 2 is selected from the group consisting of aryl and 3 to 10 membered ring heterocycyl wherein R 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, -OR 100 , -C(O)R 100 , -OC(O)R 100 , -C(O)OR 100 , -NR 100 R 101 , - N(R 100 )C(O)R 101 , -C(O)NR 100 R 101 , -C(O)NR 100 C(O)R 101 , -SR 100 -S(O)R 100 and -S(O) 2 R 100 , aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperaz
  • R 6A is selected from the group consisting of hydrogen and alkyl wherein the R 6A alkyl substituent is optionally substituted with one or more substituents selected from the group consisting of chloro, fluoro, alkoxy and hydroxy;
  • Y 6 represents a bond or is selected from the group consisting of alkyl, alkenyl and alkynyl, wherein (a) the Y 6 alkyl, alkenyl and alkynyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, cycloalkyl, -OR 103 , -C(O)R 103 , -C(O)OR 103 , -OC(O)R 103 , -NR 103 R 104 , - N(R 103 )C(O)R 104 , and -C(O)NR 103 R 104 ; R 103 and R 104 are independently selected from the
  • R 106 and R 107 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and cycloalkyl wherein (a) the R 106 and R 107 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy, and (b) the R 106 and R 107 alkynyl and cycloalkyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy;
  • R 8 is alkyl; wherein the R 8 substituent are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkynyl, - OR 108 , -C(O)R 108 , -C(O)OR 108 , -OC(O)R 108 , -NR 108 R 109 , -N(R 108 )C(O)R 109 , -C(O)NR 108 R 109 , - C(O)NR 108 C(O)R 109 , -SR 108 , -S(O)R 108 , and -S(O) 2 R 108 , wherein the alkynyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkyl, and alkoxy; and R 108 and R 109 are independently selected from the group consisting
  • R 109 alkynyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy.
  • R 2 is selected from the group consisting of aryl and heterocyclyl, R 2 is optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, alkenyl, alkyl, alkynyl, cyano, cycloalkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, nitro, and oxo;
  • Y 6 represents a bond or is selected from the group consisting of alkenyl, alkyl, alkynyl, cycloalkyl, and heterocyclyl, Y 6 is optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, alkyl, alkenyl, alkynyl, cyano, cycloalkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, nitro, and oxo;
  • R 6 is selected from the group consisting of alkylamino, alkoxy, alkoxyalkyl, alkyl, alkenyl, alkynl, amino, aminoalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxy, hydroxyalkyl, mercapto, oxo, and sulfonyl; R 6 is optionally substituted with one or more R 6 substituents independently selected from the group consisting of alkyl, akylamino, alkoxy, aminoalkyl, aryl, cycloalkyl, halogen, heterocyclyl, heteroaryl, hydroxy, hydroxyalkyl, mercapto, oxo, and sulfonyl; said R 6 substituents is optionally substituted with one or more substituents independently selected from alkyl, alkylaminocarbonyl, alkylcarbonyl, alkoxy, halogen, oxo and -S(O)
  • R 6A is selected from the group consisting of alkyl, aminoalkyl, and hydrogen, R 6A is optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, alkyl, hydroxy, and oxo; and
  • R 8 is alkyl, R 8 is optionally substituted with one or more R 8 substituents independently selected from the group consisting of alkoxy, cycloalkyl, and heterocyclyl, said R 8 substituents may optional be substituted with halogen.
  • R 2 SUBSTITUENT I Inn oonnee eemmbbooddiment of Formula I, R 2 is a 5 to 7 membered ring aryl that is optionally substituted as provided in Formula I.
  • R is phenyl that is optionally substituted as provided in Formula I.
  • R 2 is substituted with one or more halogens. In another embodiment, R 2 is substituted with one or more fluoro. In another embodiment, R 2 is substituted with one or more fluoro and one or more chloro.
  • R 2 is selected from the group consisting of
  • R 2 is a 3 to 10 membered ring heteroaryl that is optionally substituted as provided in Formula I. In another embodiment, R 2 is a 5 to 7 membered ring heteroaryl that is optionally substituted as provided Formula I. In another embodiment, R 2 is a 5 to 6 membered ring heteroaryl that is optionally substituted as provided in Formula I. In another embodiment of Formula I, R 2 is a 5 to 6 membered ring heteroaryl that comprises 1, 2, or 3 ring heteroatoms selected from the group consisting of oxygen and nitrogen.
  • R 2 is selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, tetrahydrofuryl, dihydrofuryl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, pyridazinyl, and morpholinyl, said R 2 is optionally substituted as provided in Formula I.
  • R 2 is selected from the group consisting of pyrazolyl, isoxazolyl, pyridinyl, and pyrimidinyl, R 2 is optionally substituted as provided in Formula I. In another embodiment of Formula I, R 2 is selected from the group consisting of
  • R 2 is optionally substituted with one or more substituents independently selected from the group consisting of chloro, bromo, fluoro, methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluoromethyl, hydroxy, methoxy, trifluoromethoxy, ethoxy, propoxy, butoxy, amino, methylamino, dimethylamino, ethylamino, diethylamino, methylsulfonyl, and ethylsulfonyl.
  • R 2 is optionally substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, hydroxy, methoxy, and methyl.
  • R 2 is substituted with one or two halogens. In another embodiment, R 2 is substituted with one chloro and one fluoro. In another embodiment, R 2 is substituted with one methoxy.
  • R 2 is selected from the group consisting of
  • R 9 , R 10 , R 11 , R 12 and R 13 are independently selected from the group consisting of hydrogen, halogen, oxo, alkyl, -OR 100 , -C(O)R 100 , -OC(O)R 100 , -C(O)OR 100 , -NR 100 R 101 and - C(O)NR 100 R 101 , wherein the alkyl substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OR 102 , and - C(O)OR 102 ; and
  • R 100 , R 101 , and R 102 are independently selected from the group consisting of hydrogen and C 1 to C 4 alkyl.
  • R 9 , R 10 , R 11 , R 12 and R 13 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 10 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.
  • R 9 , R 11 and R 13 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.
  • the R 11 and R 13 substituents are independently selected from the group consisting of hydrogen, fluoro, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, amino, methylamino and dimethylamino. In another embodiment, the R 11 and R 13 substituents are independently selected from the group consisting of hydrogen, fluoro, methyl, methoxy, ethyl and hydroxy. In another embodiment, the R 11 substituent is methoxy.
  • R 2 is selected from the group consisting of wherein R 9 , R 10 , R 11 , R 12 and R 13 are independently selected from the group consisting of hydrogen, fluoro, methyl, trifluoromethyl, and methoxy.
  • R 2 is substituted at the para position with a substituent as described in Formula I.
  • R 2 has one or more substituents independently selected from the group consisting of fluoro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, amino, methylamino, and dimethylamino.
  • R 2 is substituted at a para position with a substituent as defined herein.
  • R 2 is substituted at a para position with a substituent selected from the group consisting of fluoro, methyl, trifluoromethyl, methoxy, and trifluoromethoxy.
  • R 2 is selected from the group consisting of 3-pyridinyl and 4- pyridinyl, described in Formulas H-A and H-G:
  • R 9 , R 10 , R 11 , 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 , -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 substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyan
  • R 2 is pyrimidinyl, as described in Formula U-L:
  • R 9 , R 11 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 substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, -
  • Y 6 represents a bond. In another embodiment of Formula I, Y 6 is C-i to C 6 -alkyl that is optionally substituted as provided in Formula I.
  • Y 6 is a 5 to 6 membered heterocycle with one or more heteroatoms independently selected from the group consisting of nitrogen and oxygen, said Y 6 is optionally substituted as provided in Formula I.
  • Y 6 represents a bond or is selected from the group consisting of alkyl and hydroxyalkyl, optionally substituted as described in Formula I.
  • Y 6 represents a bond or is selected from the group consisting of methyl, ethyl, propyl, butyl, tert-butyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, dihydroxyethyl,
  • 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 -, ⁇ C(O)CH2CH 2 -, - C(O)CH 2 -, -C(O)-, -C(O)CH(CH 3 )-, -CH 2 C(CHa) 2 CH-, -C(CH 3 ) 2 CH-, -CH 2 C(CH 3 )-, - C(O)C(CHg) 2 -, -C(O)CH(CH 3 )CH-, -CH 2 CH 2 CH 2 CH 2 -,
  • R 6A is selected from the group consisting of alkyl, alkylaminoalkyl, alkoxyalkyl, alkoxycarbonylalkyl, hydrogen, and hydroxycarbonylalkyl that are optionally substituted as set forth in Formula I.
  • R 6A is selected from the group consisting of hydrogen, C 1 to C 4 alkyl, wherein said C 1 to C 4 alkyl is optionally substituted with one or more substituents selected from the group consisting of C 1 to C 4 alkoxy and hydroxy.
  • R 6A is selected from the group consisting of hydrogen, methyl, ethyl, methylaminomethyl, ethylaminoethyl, diethylaminoethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, and hydroxycarbonylmethyl.
  • R 6A is selected from the group consisting of hydrogen and ethyl.
  • R 6 SUBSTITUENT In one embodiment of Formula I, R 6 is selected from the group consisting of hydrogen, halogen, oxo, hydroxy, amino, aminoalkyl, alkyl, alkynyl, alkoxy, alkylamino, and cycloalkyl, wherein (a) the alkyl, alkynyl, alkoxy, aminoalkyl and alkylamino substituents are optionally substituted with one or more substituents independently selected from the group consisting of -OR 105 , -C(O)R 105 , -C(O)OR 105 , -NR 105 R 106 , -N(R 105 )C(O)R 106 , -N(R 105 )C(O)COR 106 , - N(R 105 )C(O)OR 106 , -C(O)NR 105
  • R 6 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, tert-butyl, and cyclohexyl, wherein (a) the methyl R 6 substituent is optionally substituted with one or more substituents independently selected from the group consisting of -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 (CH 3 )CH 31 -C(O)CH 2 CH 2 OH, -C(O)OH, - C(O)OCH 2 (CH 3 )(CH 3 )(CH 3 ), -NH 2 , -NH(CH 2 CH 3 ), -N(CH 3 )(CH 3 ), -N(CH 2 CH 3 )CH 2 CH 3 , - N(H)CH 2 (CH 3 )CH 3 , -N(H)CH 2 CH 2 CH 2 OH, -N(H)CH 2 C(O)CH 3 ,
  • R 6 is selected from the group consisting of phenyl, phenyl-C(O)NH-, phenyl -C(O)-, 5 to 6 membered ring fully saturated heterocyclyl, 5 to 6 membered ring fully saturated heterocyclyl-C(O)-, and 5 to 6 membered ring fully saturated heterocyclyl-C(O)-NH, optionally substituted with one or more substituents independently selected from the group consisting of alkyl, -OR 105 , and -C(O)R 105 , wherein R 105 is selected from the group consisting of hydrogen, methyl, and ethyl.
  • R 6 is selected from the group consisting of phenyl- C(O)NH-,
  • R 6 is selected from the group consisting of alkylamino, alkylaminoalkyl, alkoxy, alkoxyalkyl, alkyl, alkylsulfonyl, amino, aryl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydroxy, said R 6 is optionally substituted as provided in Formula I.
  • R 6 is optionally substituted with one or more substituents independently selected from aryl, cyano, cycloalkyl, halogen, heterocyclyl, oxo, - C(O)R T , -C(O)OR T , -C(O)NR T R U , -OR T , -OC(O)R T , -NR T R U , -N(R T )COR U , -N(R T )S(O) 2 R U , -SR T , -S(O)R T , and -S(O) 2 R 1 , R ⁇ and R u are independently selected from the group consisting of hydrogen and alkyl.
  • R 6 is selected from the group consisting of methylamino, ethylamino, propylamino, /so-propylamino, butylamino, fert-butylamino,
  • R is selected from the group consisting of aminocarbonyl
  • R 6 is selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butyloxy, and ferf-butyloxy.
  • R 6 is selected from the group consisting of tert- butylcarboxy and methoxyethyl. In another embodiment of Formula I, R 6 is selected from the group consisting of methylsulfonyl and ethylsulfonyl.
  • R 6 is a 5 to 7 membered ring aryl that is optionally substituted as provided in Formula I.
  • R 6 is selected from the group consisting of
  • R 6 is -NH 2 .
  • R 6 is selected from the group consisting of cyclopropanyl, cyclobutanyl, cyclopentanyl, and cyclohexanyl, said R 6 is optionally substituted as provided in Formula I.
  • R 6 is selected from the group consisting of fluoromethyl, difluoromethyl, and trifluoromethyl.
  • R 6 is a 5 to 7 ring membered heterocycle that is optionally substituted as provided in Formula I.
  • R 6 is a 5 to 7 ring membered heteroaryl that is optionally substituted as provided 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, and wherein said R 6 substituent is optionally substituted as provided in Formula I.
  • R 6 is selected from the group consisting of morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, and pyrrolidinyl, said R 6 is optionally substituted as provided in Formula I.
  • R 6 is selected from the group consisting of pyrazinyl and pyridinyl, said R 6 is optionally substituted as provided in Formula I.
  • R 6 is selected from the group consisting of
  • R 6 is selected from the group consisting of
  • R 6 is selected from the group consisting of
  • R 6 is selected from the group consisting of
  • R 6 is selected from the group consisting of
  • R 6 is selected from the group consisting of
  • R 6 is selected from the group consisting of
  • R 6 is -OH.
  • R 8 is C 1 to Ci O -alkyl, wherein said R 8 Ci to C 10 -alkyl is optionally substituted as provided in Formula I.
  • R 8 is C 1 to C 6 -alkyl, wherein said R 8 C 1 to C 6 -alkyl is optionally substituted as provided in Formula I.
  • R 8 is C 1 to C 4 -alkyl, wherein said R 8 C 1 to C 4 -alkyl is optionally substituted as provided in Formula I.
  • R 8 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, thiolalkyl, alkylthiol, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy.
  • R 8 alkoxyalkyl optionally substituted as described in Formula I.
  • R 8 is selected from the group consisting of dimethylbutyl, ethoxyethyl, ethoxypropyl, trifluoroethoxyethyl, isopropoxyethyl, and propoxyethyl.
  • R 2 is selected from the group consisting of phenyl and pyridinyl, optionally substituted as described in claim 1 ;
  • Y 6 represents a bond or is selected from the group consisting of methyl, ethyl, and propyl;
  • R 6A is selected from the group consisting of hydrogen, C 1 to C 4 alkyl, wherein said C 1 to C 4 alkyl is optionally substituted with one or more substituents selected from the group consisting of C 1 to C 4 alkoxy and hydroxy;
  • R 6 is as described in Formula I, and
  • R 8 is selected from the group consisting of ethoxyethyl and propoxyethyl.
  • R 2 is selected from the group consisting of and ;
  • R 9 , R 10 , R 11 , R 12 and R 13 are independently selected from the group consisting of hydrogen, fluoro, methyl, trifluorom ethyl, and methoxy;
  • Y 6 represents a bond or is selected from the group consisting of methyl, ethyl, and propyl;
  • R 6A is as described in Formula I;
  • R 8 is selected from the group consisting of propoxyethyl and ethoxyethyl;
  • R 6 is selected from the group consisting of is selected from the group consisting of phenyl, phenyl- C(O)NH-, phenyl -C(O)-, 5 to 6 membered ring fully saturated heterocyclyl, 5 to 6 membered ring fully saturated heterocyclyl-C(O)-, and 5 to 6 membered ring fully saturated heterocyciyl-C(O)-NH, optionally substituted with one or more substituents independently selected from the group consisting of alkyl, -OR 105 , and -C(O)R 105 , wherein R 105 is selected from the group consisting of hydrogen, methyl, and ethyl.
  • R 2 is selected from the group consisting of phenyl and pyridinyl, optionally substituted as described in claim 1 ;
  • R 6A is hydrogen;
  • Y 6 represents a bond or is selected from the group consisting of methyl, ethyl, propyl, butyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, dihydroxyethyl,
  • R 6 is as described in Formula I, and R 8 is selected from the group consisting of ethoxyethyl and propoxyethyl.
  • R is selected from the group consisting of and ;
  • R 9 , R 10 , R 11 , R 12 and R 13 are independently selected from the group consisting of hydrogen, fluoro, methyl, trifluoromethyl, and methoxy;
  • ⁇ R 6A is hydrogen;
  • Y 6 represents a bond;
  • R 8 is selected from the group consisting of ethoxyethyl and propoxyethyl; and R 6 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, and cyclohexyl, optionally substituted with one or more substituents independently selected from the group consisting of -OR 105 , -C(O)R 105 , -C(O)OR 105 , -NR 105 R 106 , -N(R 105 )C(O)R 106 , - N(R 105 )C(O)OR 106 , -C(O)NR 105 R 106 , -NHC(O)NR 105 R 106 , -N(R 105 )S(O) 2 R 106 , wherein R 105 and R 106 are independently selected from the group consisting of hydrogen, methyl, ethyl, butyl, cyclopentyl, cyclohexyl
  • R 2 is ;
  • R 11 is selected from the group consisting of hydrogen, chloro, fluoro, methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluoromethyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, amino, methylamino, dimethylamino, ethylamino, and diethylamino;
  • R 6A is hydrogen;
  • Y 6 is selected from the group consisting of methyl and ethyl
  • R 8 is selected from the group consisting of ethoxyethyl and propoxyethyl; and R 6 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, and cyclohexyl, optionally substituted with one or more substituents independently selected from the group consisting of -OR 105 , -C(O)R 105 , -C(O)OR 105 , -NR 105 R 106 , -N(R 105 )C(O)R 106 , -
  • R 105 and R 106 are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, cyclopentyl, cyclohexyl, optionally substituted with one or more substituent selected from the group consisting of halogen, oxo, hydroxy, and methyl.
  • R z is methoxypyridinyl.
  • R 2 is
  • R 2 is methoxypyridinyl and Y 6 is -C(O)CH 2 -.
  • R 2 is methoxypyridinyl and R 8 is selected from the group consisting of ethoxyethyl, isopropoxyethyl and propoxyethyl.
  • R 2 is methoxypyridinyl and R 6A is hydrogen.
  • the compound has a formula:
  • R 6 is as defined in Formula I.
  • R 6 is selected from the group consisting of alkoxy, alkylamino, amino, heterocyclyl, and hydroxy. In another embodiment of Formula I-X, R 6 is selected from the group consisting of methoxy, ethoxy, isopropoxy, propoxy, butoxy, ferf-butoxy, methylamino, ethylamino, dimethylamino, diethylamino, morpholinyl, and hydroxy.
  • the present invention comprises optical isomers and mixtures, including racemic mixtures of the compounds of Formula (I) through (IV).
  • the present invention comprises diastereomeric forms (individual diastereomers and mixtures thereof) of compounds of Formula (I) through (IV).
  • the present invention comprises the tautomeric forms of compounds of Formula (I) through (IV).
  • the various ratios of the tautomers in solid and liquid form is dependent on the various substituents on the molecule as well as the particular crystallization technique used to isolate a 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 temperature and humidity, 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.
  • 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 Formula (I) - (I-CC) with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption.
  • Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound.
  • 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 suitable addition salts formed include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsyate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihidrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.
  • representative salts include benzenesulfonate, hydrobromide and hydrochloride.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with 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 quatemized with agents such as lower alkyl (C 1 to C 6 ) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • salts of the compounds of this invention include hydrochloric acid
  • HCI chloride
  • CF 3 COOH or 'TFA trifluoroacetate
  • mesylate salts and tosylate salts.
  • compositions of Formula (I) to (IV) may be prepared by one or more of three methods:
  • the degree of ionization in the resulting salt may vary from completely ionized to almost non- ionised.
  • F. Methods of Treatment further comprises methods for treating a condition in a subject having or susceptible to having such a condition, by administering to the subject a therapeutically-effective amount of one or more compounds of Formula (I) through (IV) 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. Conditions
  • the conditions that can be treated in accordance with the present invention are PDE-5 mediated conditions.
  • Such conditions include cardiovascular diseases, metabolic diseases, central nervous system diseases, pulmonary diseases, sexual dysfunction, and renal dysfunction.
  • the condition is a cardiovascular disease, particularly a cardiovascular disease selected from the group consisting of hypertension (such as essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, hypertension associated with diabetes, hypertension associated with atherosclerosis, and renovascular hypertension) ; complications associated with hypertension (such as vascular organ damage, congestive heart failure, angina, stroke, glaucoma and impaired renal function); valvular insufficiency; stable, unstable and variant (Prinzmetal) angina; peripheral vascular disease; myocardial infarct; stroke; thromboembolic disease; restenosis; arteriosclerosis; atherosclerosis; pulmonary arterial hypertension; angiostenosis after bypass; angioplasty (such as percutaneous transluminal angioplasty, or percutaneous transluminal coronary angioplasty); hyperlipidemia; hypoxic vasoconstriction; vasculitis, such as Kawasaki's syndrome; heart failure (such as congestive hypertension,
  • the condition is hypertension. In another embodiment, the condition is pulmonary arterial hypertension. In another embodiment, the condition is heart failure. In another embodiment, the condition is diastolic heart failure. In another embodiment, the condition is systolic heart failure. In another embodiment, the condition is angina. In another embodiment, the condition is thrombosis. In another embodiment, the condition is stroke.
  • the condition is a metabolic disease, particularly a metabolic disease selected from the group consisting of Syndrome X; insulin resistance or impaired glucose tolerance; diabetes (such as type I and type Il diabetes); syndromes of insulin resistance (such as insulin receptor disorders, Rabson-Mendenhall syndrome, leprechaunism, Kobberiing-Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Cushing 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;
  • diabetes
  • condition is insulin resistance. In another embodiment, the condition is nephropathy.
  • the condition is a disease of the central nervous system, particularly a disease of the central nervous system selected from the group consisting of vascular dementia; craniocerebral trauma; cerebral infarcts; dementia; concentration disorders; Alzheimer's disease; Parkinson's disease; amyolateral sclerosis (ALS); Huntington's disease; multiple sclerosis; Creutzfeld-Jacob; anxiety; depression; sleep disorders; and migraine.
  • 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, particularly a pulmonary disease selected from the group consiting of asthma; acute respiratory distress; cystic fibrosis; chronic obstructive pulmonary disease (COPD); bronchitis; and chronic reversible pulmonary obstruction.
  • a pulmonary disease selected from the group consiting of asthma; acute respiratory distress; cystic fibrosis; chronic obstructive pulmonary disease (COPD); bronchitis; and chronic reversible pulmonary obstruction.
  • the condition is sexual dysfunction, particularly sexual dysfunction selected from the group consiting of impotence (organic or psychic); male erectile dysfunction; clitoral dysfunction; sexual dysfunction after spinal cord injury; female sexual arousal disorder; female sexual orgasmic dysfunction; female sexual pain disorder; and female hypoactive sexual desire disorder.
  • the condition is erectile dysfunction.
  • the condition is renal dysfunction, particularly a renal dysfunction selected from the group consisting of acute or chronic renal failure; nephropathy (such as diabetic nephropathy); glomerulopathy; and nephritis.
  • the condition is pain.
  • the condition is acute pain.
  • acute pain include acute pain associated with injury or surgery.
  • the condition is chronic pain.
  • chronic pain include neuropathic pain (including postherpetic neuralgia and pain associated with peripheral, cancer or diabetic 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 such as bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (including postchemotherapy syndrome, chronic postsurgical pain syndrome, post radiation syndrome, pain associated with immunotherapy, or pain associated with hormonal therapy), arthritic pain (including osteoarthritis and rheumatoid arthritis pain), chronic post-surgical pain, post herpetic neuralgia, trigeminal neuralgia, HIV neuropathy, phantom limb pain, central post-stroke pain
  • the condition is nociceptive pain (including pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain).
  • nociceptive pain including pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain).
  • the condition is pain associated with inflammation (including arthritic pain (such as osteoarthritis and rheumatoid disease pain), ankylosing spondylitis, visceral pain (including inflammatory bowel disease, functional bowei disorder, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, functional abdominal pain syndrome, Crohn's disease, ileitis, ulcerative colitis, dysmenorrhea!, cystitis, pancreatitis and pelvic pain).
  • arthritic pain such as osteoarthritis and rheumatoid disease pain
  • ankylosing spondylitis visceral pain
  • visceral pain including inflammatory bowel disease, functional bowei disorder, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, functional abdominal pain syndrome, Crohn's disease, ileitis, ulcerative colitis, dysmenorrhea!, cystitis, pancreatitis and pelvic pain.
  • the condition is pain resulting from musculoskeletal disorders (including myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenosis, polymyositis and pyomyositis).
  • the condition is selected from the group consisting of heart and vascular pain (including pain caused by angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma and skeletal muscle ischemia).
  • the condition is selected from the group consisting of head pain (including migraine such as migraine with aura and migraine without aura), cluster headache, tension- type headache mixed headache and headache associated with vascular disorders; orofacial pain, including dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain).
  • head pain including migraine such as migraine with aura and migraine without aura
  • cluster headache tension- type headache mixed headache and headache associated with vascular disorders
  • orofacial pain including dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain.
  • condition is a urologic condition selected from the group consisting of bladder outlet obstruction; incontinence and benign prostatic hyperplasia.
  • condition is an ophthalmic condition selected from retinal disease; macular degeneration and glaucoma.
  • the condition is selected from the group consisting of tubulointerstitial disorders; anal fissure; baldness; cancerous cachexia; cerebral apoplexy; disorders of gut motility; enteromotility disorders; dysmenorrhoea (primary and secondary); glaucoma; macular degeneration; antiplatelet; haemorrhoids; incontinence; irritable bowel syndrome (IBS); tumor metastasis; multiple sclerosis; neoplasia; nitrate intolerance; nutcracker oesophagus; osteoporosis; infertility; premature labor; psoriasis; retinal disease; skin necrosis; and urticaria.
  • tubulointerstitial disorders anal fissure; baldness; cancerous cachexia; cerebral apoplexy; disorders of gut motility; enteromotility disorders; dysmenorrhoea (primary and secondary); glaucoma; macular degeneration; antiplatelet; haemorrh
  • the condition is osteoporosis.
  • the condition is associated with endothelial dysfunction, particularly 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 methods and compositions of the present invention are suitable for use with, for example, mammalian subjects such as humans, other primates (e.g., monkeys, chimpanzees), companion animals (e.g., dogs, cats, horses), farm animals (e.g., goats, sheep, pigs, cattle), laboratory animals (e.g., mice, rats), and wild and zoo animals (e.g., wolves, bears, deer).
  • the subject is a human.
  • (I) through (IV) 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 Formula (I) through (IV) would be therapeutically useful in methods for treating hypertension by administering to a hypertensive subject a therapeutically-effective amount of a compound of Forumulae (I) through (IV).
  • 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 (IV) may be administered with aspirin.
  • one or more compounds of Formulae (I) through (IV) 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) - (IV) include quinapril (such as ACCUPRILTM), perindopril (such as ACEONTM), captopril (such as CAPOTENTM), enalapril (such as VASOTECTM), ENALAPRILATTM, ramipril (such as
  • ALT ACETM ALT ACETM
  • cilazapril delapril
  • fosenopril such as MONOPRILTM
  • zofenopril indolapril
  • benazepril such as LOTENSINTM
  • lisinopril such as PRINIVILTM or ZESTRILTM
  • spirapril trandolapril (such as MAVIKTM)
  • pentopril such as UNIVASCTM
  • pivopril spirapril
  • trandolapril such as MAVIKTM
  • pentopril pentopril
  • moexipril such as UNIVASCTM
  • pivopril such as UNIVASCTM
  • one or more compounds of Formulae (I) through (IV) may be coadministered with one or more alpha blockers such as dozazosin (such as CARDURATM), phenoxybenzamine (such as DIBENZYLINETM), or terazosin (such as HYTRINTM), CDRI- 93/478 and CR-2991.
  • one or more compounds of Formulae (I) through (IV) may be coadministered with one or more alpha-beta blockers such as labetalol (such as NORMODYNETM or TRANDATETM).
  • one or more compounds of Formulae (I) through (IV) may be coadministered with one or more angiotensin Il receptor blockers such as candesartan (such as ATACANDTM), eprosartan (such as TEVETENTM), irbesartan (such as AVEPROTM), losartan (such as COZAARTM), olmesartan, olmesartan medoxomil (such as BENICARTM), tasosartan, telmisartan (such as MICARDISTM), valsartan (such as DIOVANTM) or zolasartan, FI-6828K, RNH-6270, UR-7198, Way-126227, KRH-594, TAK-536, BRA-657, and TA-606.
  • angiotensin Il receptor blockers such as candesartan (such as ATACANDTM), eprosartan (such as TEVETENTM), irbesartan (such as
  • one or more compounds of Formulae (I) through (IV) may be co- administered with one or more alpha-2-delta ligands such as gabapentin, pregabalin (such as LYRICATM), [(1 R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1- aminomethyl-cyclohexylmethyl)-4H-[1 ,2,4]oxadiazol-5-one, C-[1 -(1 H-tetrazol-5-ylmethyl)- 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, (3S,5R)-3-aminomethyl-5- methyl-octa
  • one or more compounds of Formulae (I) through (IV) may be coadministered 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), and bisoprolol.
  • one or more compounds of Formulae (I) through (IV) may be co- administered with one or more calcium channel blockers such as nifedipine ⁇ such as
  • ADALATTM, ADALAT CCTM or PROCARDIATM may be used with 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), vatanidipine, clevidipine, lercanidipine, dilitiazem, and NNC-55-0396.
  • verapamil such as CALANTM, COVERA- HSTM, ISOPTIN SRTM or VERELANTM
  • one or more compounds Formulae (I) through (IV) 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).
  • central antiadrenergics such as methyldopa (such as ALDOMETTM), clonidine (such as CATAPRESTM or CATAPRES-TTSTM), guanfacine (such as TENEXTM), or guanabenz (such as WYTENSINTM).
  • one or more compounds of Formulae (I) through (IV) may be coadministered 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, ES1DRIXTM or HYDRODIURILTM), 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 M1DAMORTM or MODURETICTM).
  • diruretics such as hydroclorothiazide (such
  • one or more compounds of Formulae (1) through (IV) may be coadministered with one or more glycosides / inotropic agents such as digoxin (such as LANOXINTM).
  • digoxin such as LANOXINTM
  • one or more compounds of Formulae (I) through (IV) 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 (IV) 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 (IV) may be coadministered with one or more human B-type natriuretic peptides ⁇ hBNP) such as nesiritide (such as NATRECORTM).
  • ⁇ hBNP human B-type natriuretic peptides
  • nesiritide such as NATRECORTM
  • one or more compounds of Formulae (I) through (IV) may be coadministered with one or more renin inhibitors such as Aliskiren (SPP 100), SPP-500/600 and YS-004-39.
  • renin inhibitors such as Aliskiren (SPP 100), SPP-500/600 and YS-004-39.
  • one or more compounds of Formulae (I) through (IV) may be coadministered with one or more soluble guanylate cyclase activator ("sGCa").
  • sGCa soluble guanylate cyclase activator
  • An example of a suitable soluble guanylate cyclase activator is BAY-41-8543.
  • one or more compounds of Formulae (I) through (IV) may be co- administered with one or more neutral endopeptidase (NEP) inhibitors, such as, for example, omapatrilat, fasidotril, mixanpril, sampatrilat, Z13752A ,
  • NEP neutral endopeptidase
  • one or more compounds of Formulae (I) through (IV) may be coadministered with one or more aldosterone receptor antagonists such as eplerenone (such as INSPRATM) or spironolactone (such as ALDACTONETM).
  • aldosterone receptor antagonists such as eplerenone (such as INSPRATM) or spironolactone (such as ALDACTONETM).
  • one or more compounds of Formulae (I) through (IV) may be coadministered with one or more bradykinin agonists.
  • one or more compounds of Formulae (I) through (IV) may be coadministered with one or more endothelian antagonists.
  • suitable endothelin antagonists include ambrisentan, darusentan, J-104132, SPP-301 , TBC-3711 , YM-62899, YM-91746, and BMS-193884.
  • one or more compounds of Formulae (I) through (IV) may be coadministered with niacin or one or more nicotinic acid derivatives, such as NIACORTM, NIASPANTM, NICOLARTM, or SLO-NIACINTM.
  • one or more compounds of Formulae (I) through (IV) may be coadministered with one or more fibric acid derivatives, such as clofibrate (such as ATROMID- STM), gemfibrozil (such as LOPIDTM), or fenofibrate (such as TRICORTM).
  • one or more compounds of Formulae (I) through ⁇ IV) may be coadministered 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 (IV) may be coadministered with one or more bile acid sequestants, such as colestipol (such as COLESTIDTM), cholestyramine (such as LOCHOLESTTM, PREVALITETM, QUESTRANTM, or QUESTRAN LIGHTTM), colesevelam (such as WELCHOLTM).
  • one or more compounds of Formulae (I) through (IV) may be coadministered with an apical sodium-dependent bile acid cotransporter inhibitors, such as SD- 5613, AZD7806 or 264W94.
  • one or more compounds of Formulae (I) through (IV) may be coadministered with one or more cholesterol absorbtion inhibitors, such as ezetimibe (such as ZETIATM).
  • one or more compounds of Formulae (I) through (IV) 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 reductase inhibitors 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
  • one or more compounds of Formulae (I) through (IV) 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 (IV) may be coadministered 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 (IV) may be coadministered with one or more insulins, such as HUMALOGTM, HUMALOG 50/50TM, HUMALOG 75/25TM, HUMULIN 50/50TM, HUMALIN 75/25TM, HUMALIN LTM, HUMALIN NTM, HUMALIN RTM, HUMALIN R U-500TM, HUMALIN UTM, ILETIN Il LENTETM, ILETIN Il NPHTM, ILETIN Il REGULARTM, LANTUSTM, NOVOLIN 70/30TM, NOVILIN NTM, NOVILIN RTM, NOVOLOGTM, or VELOSULIN BRTM, and EXUBERATM.
  • insulins such as HUMALOGTM, HUMALOG 50/50TM, HUMALOG 75/25TM, HUMULIN 50/50TM, HUMALIN 75/25TM, HUMALIN LTM, HUMALIN NTM, HUMALIN RTM,
  • one or more compounds of Formulae (I) through (IV) may be coadministered 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 (IV) may be co- administered with one or more sulfonylureas, such as glimepiride (such as AMARYLTM), glyburide (such as DIABETATM, GLYNASE PRESTABTM or M1CRONASETM), or glipizide (such as GLUCOTROLTM, or GLUCOTROL XLTM).
  • glimepiride such as AMARYLTM
  • glyburide such as DIABETATM, GLYNASE PRESTABTM or M1CRONASETM
  • glipizide such as GLUCOTROLTM, or GLUCOTROL XLTM
  • one or more compounds of Formulae (I) through (IV) may be coadministered 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).
  • a compound described in this specification is administered in an amount effective to inhibit PDE-5.
  • the compounds of the present invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • 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 Formula (I) through (IV) is typically from about 0. 01 to about 100 mg/kg.
  • total daily dose of the compound of Formula (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 Formula (I) through (IV) per kg body weight).
  • dosing is from 0.01 to 10 mg/kg/day. In another embodiment, dosing is from 0.1 to 1.0 mg/kg/day.
  • Dosage unit compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • 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.
  • 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 1 mg 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 total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.
  • These dosages are based on an average human subject having a weight of about 60kg to about 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • references herein to "treatment” include references to curative, palliative, preventative, and prophylactic treatment.
  • the present invention comprises methods for the preparation of a pharmaceutical composition (or "medicament) comprising the compounds of Formula (I) through (IV) 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 Formula (I) through (IV) in the preparation of a medicament for the treatment of hypertension.
  • the invention comprises the use of one or more compounds of Formula (I) through (IV) in the preparation of a medicament for the treatment of angina. In another embodiment, the invention comprises the use of one or more compounds of Formula (I) through (IV) in the preparation of a medicament for the treatment of congestive heart failure.
  • the invention comprises the use of one or more compounds of Formula (I) through (IV) 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 Formula (I) through (IV) in the preparation of a medicament for the treatment of erectile dysfunction.
  • compositions for the treatment of the conditions referred to above the compounds of Formula (I) through (IV) can be administered as compound perse.
  • 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 Formula (I) through (IV) presented with a pharmaceutically-acceptable carrier.
  • the carrier can be a solid, a liquid, or both, and may be formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compounds.
  • Compounds of Formula (I) through (IV) 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 for example, 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 Formula (I) through ⁇ IV) are ordinarily combined with one or more adjuvants.
  • the dosage forms also may comprise buffering agents or 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.
  • compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures.
  • effective formulations and administration procedures are well known in the art and are described in standard textbooks.
  • Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, et al., Eds., Pharmaceutical Dosage Forms. Marcel Decker, New York, N.Y., 1980; and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients (3 rd Ed.), American Pharmaceutical Association, Washington, 1999. I. Kits
  • 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 Formula (I) through (IV) and an ACE inhibitor.
  • kit of the present invention comprises one or more compounds of Formula (I) through (IV) and an angiotensin Il receptor antagonist. In another embodiment, the kit of the present invention comprises one or more compounds of Formula (I) through (IV) and an aldosterone receptor antagonist.
  • the kit of the present invention comprises one or more compounds of Formula (I) through (IV) and a NO donor.
  • the compounds of the present invention may be prepared using the methods illustrated in the general synthetic schemes and experimental procedures detailed below.
  • the general synthetic schemes are presented for purposes of illustration and are not intended to be limiting.
  • the substituted pyrido[2,3-b]pyrazin-2(1 H)-ones VII are prepared through two routes which diverge from a common intermediate as described in Scheme 1 and Scheme 2.
  • the first intermediate preparation commences with the reaction of commercially available 5- bromopyridine-2,3-diamine I with activated esters such as an acid chloride or acid derivatives prepared under peptide coupling conditions utilizing peptide coupling reagents such as 1-[3- (dimethyl-aminopropy]-3-ethylcarbodiimide methiodide , 1.S-dicyclohexylcarbodiimide, or 0-(7- azabenzotriazol-1-yl)-1 ,1,3,3-tetramethyluromium hexafluorophosphate in the presence of an organic base such as triethylamine, N, ⁇ /-diisopropylethylamine, or 4-methylmorpholine in a solvent such as dichloromethane, tetrahydrofuran, ⁇ /, ⁇ /-dimethylformamide, or dioxane to provide the desired N-(2-amino-5-bromopyridin-3-
  • Conversion of the diamine III to the cyclic dione IV could be achieved by addition of ethyl chlorooxoacetate or oxalyl chloride to diamine III in an organic solvent such as toluene, dichloromethane, or tetrahydrofuran with organic bases such as triethylamine, 4- methylmorpholine, or ⁇ /, ⁇ /-diisopropylethylamine present at O 0 C followed by warming to room temp or the reflux temperature of the solvent.
  • organic solvent such as toluene, dichloromethane, or tetrahydrofuran
  • organic bases such as triethylamine, 4- methylmorpholine, or ⁇ /, ⁇ /-diisopropylethylamine present at O 0 C followed by warming to room temp or the reflux temperature of the solvent.
  • Conversion of the diamine III to the cyclic dione IV could be achieved by addition of ethyl chlorooxoacetate or oxalyl chloride to a solution of diamine III in an organic solvent such as toluene, dichloromethane, or tetrahydrofuran with organic bases such as triethylamine, 4-methylmorpholine, or ⁇ /, ⁇ /-diisopropylethylamine present at O 0 C followed by warming to room temp or the reflux temperature of the solvent.
  • organic solvent such as toluene, dichloromethane, or tetrahydrofuran
  • organic bases such as triethylamine, 4-methylmorpholine, or ⁇ /, ⁇ /-diisopropylethylamine present at O 0 C followed by warming to room temp or the reflux temperature of the solvent.
  • the desired pyrazinone Vl is prepared by displacement of the 3-chloro in 7-bromo-3-chloro-1-alkylsubstituted-pyrido[2,3-b]pyrazin- 2(1H)-one V with suitable primary or secondary amines in solvents such dichloromethane, tetrahydrofuran, or dioxane with organic bases such as triethylamine, 4-methylmorpholine, or ⁇ /, ⁇ /-diisopropylethylamine.
  • X Halogen, alkyl, OR, OH, etc.
  • a second route as described in Scheme 4 to substituted pyrido[2,3-b]pyrazin-2(1 H)-ones VlI commences with a palladium catalyzed Suzuki coupling between the bromide of the pyrazinedione IV and substituted phenyl or heterocylic boronic acids in solvents such as aqueous ethylene glycol dimethyl ether, aqueous ethers, or aqueous toluene utilizing typical palladium coupling reagents such as palladium(ll) acetate or tetrakis(triphenylphosphine)palladium with a base such as sodium carbonate or potassium carbonate.
  • solvents such as aqueous ethylene glycol dimethyl ether, aqueous ethers, or aqueous toluene
  • typical palladium coupling reagents such as palladium(ll) acetate or tetrakis(triphenylphosphine)
  • Conversion of the amide to the chloropyrazine IX utilizes chlorination reagents such as phosphorous oxychloride in the presence of tetraethylammonium chloride or oxalyl chloride in solvents such as acetonitrile, propionitrile, dichloromethane, or toluene at room temperature to reflux.
  • chlorination reagents such as phosphorous oxychloride in the presence of tetraethylammonium chloride or oxalyl chloride in solvents such as acetonitrile, propionitrile, dichloromethane, or toluene at room temperature to reflux.
  • Amide derivatives XII could be prepared by treatment of the amine Xl with activated esters such as acid chlorides or acid derivatives prepared from acids utilizing peptide coupling reagents such as 1-[3-(dimethylamino-propy]-3-ethylcarbo-diimide methiodide, 1 ,3- dicyclohexylcarbodiimide, or 0-(7-Azabenzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluromium hexafluorophosphate in the presence of an organic base such as triethylamine, N, N- diisopropylethyiamine, 4-methylmorpholine in a solvent such as dichloromethane, tetrahydrofuran, or dioxane as outlined in Scheme 6.
  • activated esters such as acid chlorides or acid derivatives prepared from acids utilizing peptide coupling reagents such as 1-[3-(di
  • substituted amines XIII can be prepared by the treatment of amine Xl with alkyl halides in solvents such as ⁇ /, ⁇ /-dimethylformamide or tetrahydrofuran with a base such as sodium hydride, potassium carbonate, or cesium carbonate.
  • Formation of sulfonamides XIV could be prepared through treatment of the the amine VII with sulfonyl chlorides in organic solvents such as tetrahydrofuran, dichloromethane, or dioxanes and organic bases such as triethylamine, N-methylmorpholines, or N, N- diisopropylethylamine as outlined in Scheme 8.
  • ureas XV could be prepared through treatment of the the amine VII with carbamyl chlorides in organic solvents such as tetrahydrofuran, dichloromethane, or dioxanes and organic bases such as triethylamine, N-methylmorpholines, or ⁇ /, ⁇ /-diisopropylethylamine as outlined in Scheme 9.
  • organic solvents such as tetrahydrofuran, dichloromethane, or dioxanes
  • organic bases such as triethylamine, N-methylmorpholines, or ⁇ /, ⁇ /-diisopropylethylamine as outlined in Scheme 9.
  • ureas XV can be prepared by treating amine VII with isocyanates in solvents such as dichloromethane, tetrahydrofuran, or dioxanes with organic bases such as triethylamine, N-methylmorpholines, or ⁇ /,/V-diisopropylethylamine as outlined in Scheme 9.
  • Acylation of the 3-amine in the pyrido[2,3-b]pyrazin-3(4H)-ones VII could be accomplished by treatment of VII with activated esters such as an acid chloride or acid derivatives prepared under peptide coupling conditions utilizing peptide coupling reagents such as 1-[3-(dimethylaminopropy]-3-ethylcarbodiimide methiodide , 1 ,3- dicyclohexylcarbodiimide, or 0-(7-azabenzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluromium hexafluorophosphate in the presence of an organic base such as triethylamine, N, N- diisopropylethylamine, or 4-methylmorpholine in a solvent such as dichloromethane, tetrahydrofuran, ⁇ /, ⁇ /-dimethylformamide, or dioxane to provide the desired acetamide
  • sulfonamides XVII could be prepared through treatment of the pyrido[2,3- b]pyrazin-3(4H)-ones VII with sulfonyl chlorides in organic solvents such as tetrahydrofuran, dichloromethane, or dioxanes and organic bases such as triethyl amine, N- methylmorpholines, or N, ⁇ /-diisopropylethylamine as outlined in Scheme 11.
  • organic solvents such as tetrahydrofuran, dichloromethane, or dioxanes
  • organic bases such as triethyl amine, N- methylmorpholines, or N, ⁇ /-diisopropylethylamine as outlined in Scheme 11.
  • Step 2 Preparation of 5-bromo-N ⁇ 3 ⁇ -(2-ethoxyethvhpyridine-2,3-diamine.
  • a suspension of lithium aluminum hydride (1 M in THF, 112.0 ml_, 111.6 mmol) in tetrahydrofuran (100 mL) was added ⁇ /-(2-amino-5-bromopyridin-3-yl)-2-ethoxyacetamide (10.2 g, 37.2 mmol) dropwise as a solution in tetrahydrofuran (100 mL) cooled in a dry ice/acetone bath.
  • the reaction mixture was then allowed to warm to room temperature and stirred for 30 min.
  • Step 3 Preparation of 7-bromo-1-(2-ethoxyethyl)-1 ,4-dihvdropyridor2,3-blpyrazine-2,3-dione.
  • 5-bromo-N ⁇ 3 ⁇ -(2-ethoxyethyl)pyridine-2,3-diamine 6.5 g, 25.1 mmol
  • ethyl chlorooxoacetate 3.8 mL, 27.6 mmol
  • ⁇ /, ⁇ /-diisopropylethylamine 5.24 mL, 30.1 mmol
  • Step 4 Preparation of 7-bromo-3-chloro-1 -(2-ethoxyethyl)pyridof2.3-biPyrazin-2(1 H)-one
  • Step 5 7-bromo-1 -(2-ethoxyethylV3-r(2-morpholin-4-ylethyl')aminolpyridof2,3-blpyrazin-
  • Step 6 Preparation of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3.2-dioxaborolan-2-yl)pyridine.
  • 5-bromo-2-fluoropyridine 5.0 g, 28.5 mmol
  • Step 7 Preparation of 1-(2-ethoxyethyl)-7-(6-fluoropyridin-3-yl)-3-r(2-morpholin-4- ylethyl)aminolpyridor2.3-blpyrazin-2(1 H)-one
  • Step 1 Preparation of 5-bromo-N ⁇ 3 ⁇ -(tetrahvdro-2H-pyran-4-ylmethyl)pyridine-2,3-diamine
  • 2,3-diamino-5-bromopyridine (10.0g, 53.2 mmol) dissolved in anhydrous tetrahydrofuran (1.0 L) was added 4 A molecular sieves (54 g) and tetrahydropyranyl-4- carboxaldehyde (7.28 g, 63.8 mmol) at room temperature.
  • the reaction mixture was heated to reflux for 3 hours and then stirred at ambient temperature for 16 hours.
  • the mixture was reheated to reflux for 7 hours then filtered through celite.
  • the filter cake was rinsed with diethyl ether then the filtrate was concentrated in vacuo.
  • the semi-solid was dissolved in ethanol (500 ml_) and sodium borohydride was added at -78 0 C. The mixture was warmed to room temperature and stirred for 1 hour. Water (1.0 L) was added to the reaction mixture and then extracted (3X) with methylene chloride. The organic layers were combined and dried over magnesium sulfate, filtered, and concentrated in vacuo.
  • Step 2 Preparation of 7-bromo-3-chloro-1-(tetrahvdro-2H-pyran-4-ylmethyl)pyridof2,3- blpyrazin-2(1 H)-one
  • Step 3 Preparation of 7-bromo-3-r(2-morpholin-4-ylethyl)aminol-1-(tetrahvdro-2H-pyran-4- ylmethyl)pyridor2.3-b1pyrazin-2(1H)-one
  • Step 4 Preparation of 7-(4-fluorophenyl)-3-K2-morpholin-4-ylethyl)aminol-1-(tetrahvdro-2H- Pyran-4-ylmethyl)pyridor2,3-bipyrazin-2(1H)-one
  • the mixture was heated to reflux for 3 hours.
  • the reaction mixture was then cooled to room temperature and the solvent removed in vacuo.
  • the crude material was partitioned between methylene chloride and water and then subsequently the organic layer was washed with brine. The layers were separated and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo.
  • the crude material was dissolved in 1.25 M HCI/ethanol and stirred for 10 min. The solids were filtered and diethyl ether was added to the filtrate.
  • Step 1 Preparation of (2,2.2-trif luoroethoxyiacetic acid
  • Step 3 Preparation of 5-bromo-N ⁇ 3 ⁇ -r2-(2,2,2-trifluoroethoxy)ethv ⁇ pyridine-2,3-diamine
  • ⁇ /-(2-amino-5-bromopyridin-3-yl)-2-ethoxyacetamide (10.2 g, 37.2 mmol) dropwise as a solution in tetrahydrofuran (100 mL) cooled in a dry ice/acetone bath.
  • the reaction mixture warmed to room temperature and stirred for 30 min.
  • Step 4 Preparation of 7-bromo-1 -r2-(2,2,2-trifluoroethoxy)ethyll-1 ,4-dihvdropyridof2,3- bipyrazine-2.3-dione
  • Step 5 Prepartion of 7-bromo-3-r(2-morpholin-4-ylethyl)amino1-1-f2-(2.2.2- trifluoroethoxy)ethvnpyridor2,3-blPyrazin-2(1 H)-one
  • Step 6 Preparation of 7-(6-methoxypyridin-3-yl)-3-r(2-morpholin-4-ylethyl)aminol-1-r2-(2.2.2- trifluoroethoxy)ethyllPyridor2.3-blpyrazin-2(1H)-one
  • Step 2 Preparation of N-(2-amino-5-bromopvridin-3-vlV2-propoxvacetamide.
  • methylene chloride (-2 L) with ⁇ /, ⁇ /-dimethylformamide (7 ml_) chilled in an ice water bath was added dropwise neat oxalyl chloride (665 ml_, 7.6 mol) over -2 hours maintaining an internal temperature ⁇ 5°C.
  • the reaction mixture was then allowed to warm to ambient temperature.
  • Step 3 Preparation of 5-bromo-N ⁇ 3— (2-propoxyethyltoyridine-2,3-diamine.
  • Step 4 Preparation of 7-bromo-1-(2-propoxyethyl)-1.4-dihvdropyridor2,3-blpyrazine-2,3- dione.
  • Step 5 Prepartion of 7-(6-methoxypyridin-3-yl)-1 -(2-propoxyethyl)-1 ,4-dihvdropyridor2,3- blpyrazine-2.3-dione
  • the mixture was heated to reflux overnight then cooled to ambient temperature and concentrated in vacuo.
  • the crude material was redissolved in methanol, filtered through a bed of celite, and reduced in vacuo.
  • the crude residue was dissolved in hot methanol (80 mL) and water (1.5 L) and then partioned with ethyl acetate.
  • the organic layer was back extracted with ethyl acetate, and the combined aqueous layers were acidified to pH 5 with 6 N hydrochloric acid.
  • the resultant solid was removed by filtration, rinsed with water, triterated with diethyl ether, and dried overnight at 50°C to provide 164 g of 7-(6- methoxypyridin-3-yl)-1-(2-propoxyethyl)-1 ,4-dihydropyrido[2,3-b]pyrazine-2,3-dione as a tan solid.
  • Step 6 Prepartion of N ⁇ 2 ⁇ -r7-(6-methoxypyridin-3-yl)-2-oxo-1-(2-propoxyethyl)-1 ,2- dihvdropyridor2.3-blpyrazin-3-yll-N ⁇ 1 ⁇ .N ⁇ 1—dimethylqlvcinamide
  • Example 5 was prepared by a method similar to that described in Example 1 using 1- methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H-pyrazole in place of 2-fluoro-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine in step 7.
  • Example 6 was prepared by a method similar to that described in Example 1 using A- fluorobenzeneboronic acid in place of 2-f luoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine in step 7.
  • 1 H NMR 400 MHz, CD 3 OD
  • HRMS m/z 442.2284 (calculated for M+H, 442.2249).
  • Example 7 was prepared by a method similar to that described in Example 2 using 2- methoxy-5-pyridineboronic acid in place of 4-fluorobenzeneboronic acid in step 4.
  • 1H NMR 400 MHz, METHAN0L-D4 ⁇ ppm 1.52 (m, 3 H) 1.74 (m, 2 H) 2.27 (m, 2 H) 3.24 (m, 2 H) 3.35 (m, 2 H) 3.74 (d, 2 H) 3.93 (m, 4 H) 4.04 (m, 2 H) 4.10 (m, 2 H) 4.20 (s, 3 H) 4.35 (d, 2 H) 7.48 (d, 1 H) 8.54 (d, 1 H) 8.61 (dd, 1 H) 8.66 (d, 1 H) 8.79 (d, 1 H).
  • HRMS m/z 481.2564 (calculated for M+H, 481.2558).
  • Example 8 was prepared by a method similar to that described in Example 2 using 2- fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine in place of A- fluorobenzeneboronic acid in step 4.
  • 1H NMR 400 MHz, CHLOROFORM-D
  • HRMS m/z 469.2357 (calculated for M+H, 469.2358).
  • Example 9 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1.
  • 1H NMR 400 MHz, METHANOL-D4 ⁇ ppm 0.70 (t, 3 H) 1.42 (m, 2 H) 2.56 (s, 4 H) 2.70 (t, 2 H) 3.35 (t, 2 H) 3.70 (m, 6 H) 3.80 ⁇ t, 2 H) 3.95 (s, 3 H) 4.54 (t, 2 H) 6.89 (d, 1 H) 7.99 (dd, 1 H) 8.11 (d, 1 H) 8.44 (d, 2 H).
  • HRMS m/z 469.2576 (calculated for M+H, 469.2558).
  • Example 10 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and pyrimidine-5-boronic acid in place of 2-methoxy-5-pyridineboronic acid in step 6.
  • 1 H NMR 400 MHz, CHLOROFORM-D
  • HRMS m/z 440.2393 (calculated for M+H, 440.2405).
  • Example 11 was prepared by a method similar to that described in Example 3 using propanol in place of (2,2,2-trifluoroethanol in step 1 and 2-methoxypyrimidine-5-boronic acid in place of 2-methoxy-5-pyridineboronic acid in step 6.
  • 1 H NMR 400 MHz, CHLOROFORM- D
  • HRMS m/z 470.2493 (calculated for M+H, 470.2510).
  • Example 12 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and 2-methoxypyrimidine-5-boronic acid in place of 2,4-dimethoxypyrmidine-5-boronic acid in step 6.
  • Example 13 7-(2-methoxypyrimidin-5-yl)-3-f(2-morpholin-4-ylethyl)amino1-1-(2-propoxyethyl)pyridor2,3- blpyrazin-2(1 H)-one
  • Example 13 was obtained from Example 12 by treatment with iodotrimethylsilane in anhydrous acetonitrile.
  • 1 H NMR 400 MHz, METHANOL-D4 ⁇ ppm 0.78 (t, 3 H) 1.46 (m, 2 H) 3.28 (m, 2 H) 3.39 (t, 2 H) 3.62 (t, 2 H) 3.74 (d, 2 H) 3.84 (t, 2 H) 3.90 (d, 2 H) 4.07 (m, 4 H) 4.59 (t, 2 H) 8.05 (s, 1 H) 8.68 (d, 1 H) 8.70 (d, 1 H).
  • HRMS m/z 472.2318 (calculated for M+H, 472.2303).
  • Example 14 was obtained from Example 11 by treatment with iodotrimethylsilane in anhydrous acetonitrile.
  • 1H NMR 400 MHz, DMSO-D6) ⁇ ppm 0.70 (t, 3 H) 1.36 (m, 2 H) 3.10 (s, 2 H) 3.32 (m, 2 H) 3.40 (m, 2 H) 3.67 (m, 4 H) 3.86 (m, 6 H) 4.55 (t, 2 H) 8.56 (d, 1 H) 8.66 (d, 1 H) 8.99 (s, 2 H) 9.47 (t, 1 H) 11.15 (s, 1 H)HRMS m/z 456.2389 (calculated for M+H, 456.2354).
  • Example 15 was prepared by a method similar to that described in Example 3 using 4- fluorobenzeneboronic acid in place of 2-methoxy-5-pyridineboronic acid in step 6.
  • 1 H NMR 400 MHz, METHANOL-D4 ⁇ ppm 2.57 (s, 4 H) 2.71 (t, 2 H) 3.69 (m, 4 H) 3.73 (t, 2 H) 3.91 (q, 2 H) 4.03 (t, 2 H) 4.59 (t, 2 H) 7.20 (m, 2 H) 7.69 (m 2 H) 8.07 (d, 1 H) 8.48 (d, 1 H).
  • HRMS m/z 496.1395 (calculated for M+H, 496.1966).
  • Example 16 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , beta-alanine t-butyl ester hydrochloride in place of 4-(2-aminoethyl)morpholine in step 5, and 2-methoxypyrimidine-5-boronic acid in place of 2,4-dimethoxypyrmidine-5-boronic acid in step 6.
  • Example 17 was obtained from Example 16 by treatment with concentrated hydrochloric acid in dioxane.
  • 1 H NMR 400 MHz, DMSO-D6) ⁇ ppm 0.64 (t, 3 H) 1.31 (m, 2 H) 2.69 (t, 2 H) 3.29 (t, 2 H) 3.71 (m, 4 H) 3.90 (s, 3 H) 4.58 (t, 2 H) 6.99 (d, 1 H) 8.23 (dd, 1 H) 8.62 (d, 2 H) 8.69 (d, 1 H) 9.46 (t, 1 H).
  • HRMS m/z 428.1932 (calculated for M+H, 428.1928).
  • Example 18 was obtained from Example 17 by a method similar to that described in step
  • Example 19 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , beta-alaninamide hydrochloride in place of 4-(2-aminoethyl)morpholine in step 5, and 2-methoxypyrimidine-5-boronic acid in place of 2,4-dimethoxypyrmidine-5-boronic acid in step 6.
  • Example 20 was prepared by a method similar to that described in Example 1 using 4- methyl valeric acid in place of ethoxyacetic acid in step 1. HRMS m/z 455.2572 (calculated for M+H, 455.2565).
  • Example 21
  • Example 21 was prepared by a method similar to that described in Example 1 using 4- methyl valeric acid in place of ethoxyacetic acid in step 1 and 4-fluorobenzeneboronic acid in place of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine in step 7.
  • HRMS m/z 454.2622 (calculated for M+H, 454.2613).
  • Example 22 was prepared by a method similar to that described in Example 1 using 3- tetrahydrofuroic acid in place of ethoxyacetic acid in step 1 and 4-fluorobenzeneboronic acid in place of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine in step 7. Furthermore, the chlorodimidate of step 4 was prepared as a two step one pot synthesis from the diamine of step 2 as in Example 2 step 2. HRMS m/z 454.2262 (calculated for M+H, 454.2249).
  • Example 23 was prepared by a method similar to that described in Example 1 using 4- methyl valeric acid in place of ethoxyacetic acid in step 1 and 2-methoxy-5-pyridineboronic acid in place of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine in step 7.
  • HRMS m/z 467.2783 (calculated for M+H, 467.2765).
  • Example 24 was prepared by a method similar to that described in Example 2 using cyclohexanecarboxaldehyde in place of tetrahydropyranyl-4-carboxadehyde in step 1 with a Dean Stark trap and catalytic glacial acetic acid added in place of the molecular sieves.
  • HRMS m/z 466.2581 (calculated for M+H, 466.2613).
  • Example 25 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and 4-aminomethyltetrahydropyran in place of 4-(2-aminoethyl)morpholine in step 5.
  • Example 26 was prepared by a method similar to that described in Example 3 using glycine tert-butyl ester in place of 4-(2-aminoethyl)morpholine in step 5.
  • HRMS m/z510.1954 (calculated for M+H, 510.1959).
  • Example 27 was prepared by a method similar to that described in Example 3 using 4- aminomethyltetrahydropyran in place of 4-(2-aminoethyl)morpholine in step 5.
  • HRMS m/z 494.2037 (calculated for M+H, 494.2010).
  • Example 28 was prepared by a method similar to that described in Example 4 using propanol in place of 2,2,2-trifluoroethanol in step 1. HRMS m/z 481.1801 (calculated for M+H, 481.1806).
  • Example 29
  • Example 29 was prepared by a method similar to that described in Example 4 using glycinamide in place of N ⁇ 1 ⁇ ,N ⁇ 1 —dimethylglycinamide in step 6.
  • HRMS /r /z413.1919 (calculated for M+H, 413.1932).
  • Example 30 was prepared by a method similar to that described in Example NEW using N ⁇ 1 — methylglycinamide in place of N ⁇ 1 ⁇ ,N ⁇ 1 —dimethylglycinamide in step 6.
  • 1 H NMR 400 MHz, CHLOROFORM-D
  • HRMS m/z 427.2O74 (calculated for M+H, 427.2088).
  • Example 31 was prepared by a method similar to that described in Example 4 using N ⁇ 1 ⁇ ,N ⁇ 1 ⁇ -diethylglycinamide in place of N ⁇ 1 ⁇ ,N ⁇ 1 ⁇ -dimethylglycinamide in step 6.
  • HRMS m/z 469.2517 (calculated for M+H, 469.2558).
  • Example 32 was prepared by a method similar to that described in Example 4 using 2- morpholin-4-yl-2-oxoethylamine in place of N ⁇ 1 ⁇ ,N ⁇ 1 —dimethylglycinamide in step 6.
  • HRMS m/z 483.2355 (calculated for M+H, 483.2350).
  • Example 33 was prepared by a method similar to that described in Example 4 using 1- methylpiperidin-4-amine in place of N ⁇ 1 ⁇ ,N ⁇ 1 —dimethylglycinamide in step 6.
  • HRMS m/z 453.2602 (calculated for M+H, 453.2609).
  • Example 34 was prepared by a method similar to that described in Example 4 using tert- butyl 4-aminopiperidine-1-carboxylate in place of N ⁇ 1 ⁇ ,N ⁇ 1 ⁇ -dimethylglycinamide in step 6.
  • HRMS m/z 539.2947 (calculated for M+H, 539.2976).
  • Example 35 was prepared by a method similar to that described in Example 4 using tert- butyl 2-aminoethylcarbamate in place of N ⁇ 1 ⁇ ,N ⁇ 1 —dimethylglycinamide in step 6.
  • HRMS m/z 499.2656 (calculated for M+H, 499.2663).
  • Example 36 was obtained from Example 17 by the following peptide coupling reaction.
  • N-[7-(6-methoxypyridin-3-yl)-2-oxo-1 -(2-propoxyethyl)-1 ,2-dihydropyrido[2,3-b]pyrazin-3- yl]-beta-alanine 215.0 mg, 0.5 mmol
  • O-(7- azabenzotriazol-1-yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /'-tetramethyluronium hexafluorophosphate 228.0 mg, 0.6 mmol
  • reaction mixture stirred for 10 min and methylamine (2.0 M in tetrahydrofuran, 2.5 mL, 5.0 mmol) was added and subsequently heated to 5O 0 C.
  • the reaction mixture stirred for 1 hour and the solvent was removed in vacuo.
  • Example 37 was prepared by a method similar to that described in Example 36 using morpholine in place of methylamine.
  • 1 H NMR 400 MHz, CD 3 OD
  • HRMS m/z 497.2530 (calculated for M+H, 497.2507).
  • Example 38 was prepared by a method similar to that described in Example 36 using diethylamine in place of methylamine.
  • 1 H NMR 400 MHz, CD 3 OD
  • HRMS m/z 483.2703 (calculated for M+H, 483.2714).
  • Example 39 was prepared by a method similar to that described in Example 36 using isopropylamine in place of methylamine.
  • 1H NMR 400 MHz, METHANOL-D4 ⁇ ppm 0.70 (t,
  • Example 40 was prepared by a method similar to that described in Example 4 using tert- butyl 4-(aminomethyl)piperidine-1-carboxylate in place of N ⁇ 1 ⁇ ,N ⁇ 1 ⁇ -dimethylglycinamide in step 6.
  • 1 H NMR 400 MHz, CHLOROFORM-D
  • Example 41 was obtained from Example 40 by treatment with a 0.3 M solution of 20% trifluoroacetic acid and 80% methylene chloride (v/v).
  • 1H NMR 400 MHz, CHLOROFORM- D
  • HRMS m/z 453.2601 (calculated for M+H, 453.2609).
  • Example 42 was obtained from Example 34 by treatment with a 0.3 M solution of 20% trifluoroacetic acid and 80% methylene chloride (v/v).
  • 1 H NMR 400 MHz, METHANOL-D4 ⁇ ppm 0.70 (t, 3 H) 1.42 (m, 2 H) 1.94 (m, 2 H) 2.32 (m, 2 H) 3.20 (m, 2 H) 3.35 (t, 2 H) 3.50 (m, 2 H) 3.81 (t, 2 H) 3.96 (s, 3 H) 4.37 (m, 1 H) 4.57 (t, 2 H) 6.92 (d, 1 H) 8.02 (dd, 1 H) 8.20 (d, 1 H) 8.46 (d, 1 H) 8.53 (d, 1 H).
  • HRMS m/z 439.2449 (calculated for M+H, 439.2452).
  • Example 43 was obtained from Example 41 by the following acid chloride reaction. To 7-
  • Example 44 was prepared by a method similar to that described in Example 43 using acetyl chloride in place of methanesulfonyl chloride.
  • 1H NMR 400 MHz, METHANOL-D4 ⁇ ppm 0.71 (t, 3 H) 1.27 (m, 2 H) 1.42 (m, 2 H) 1.85 (m, 2 H) 2.08 (s, 3 H) 2.12 (m, 1 H) 2.63 (m, 1 H) 3.10 (m, 1 H) 3.36 (t, 2 H) 3.49 (m, 2 H) 3.81 (t, 2 H) 3.91 (m, 1 H) 3.95 (s, 3 H) 4.51 (m, 1 H) 4.56 (t, 2 H) 6.91 (d, 1 H) 8.01 (dd, 1 H) 8.13 (d, 1 H) 8.45 ⁇ d, 1 H) 8.48 (d, 1 H)HRMS m/z 495.2721 (calculated for M+H, 495.2714).
  • Example 45 was obtained from Example 41 by the following peptide coupling reaction.
  • Example 46 was prepared by a method similar to that described in Example 43 using dimethylcarbamyl chloride in place of methanesulfonyl chloride.
  • 1 H NMR 400 MHz, METHANOL-D4 ⁇ ppm 0.71 (t, 3 H) 1.29 (m, 2 H) 1.42 (m, 2 H) 1.79 (m, 2 H) 2.02 (m, 1 H) 2.75 (m, 2 H) 2.81 (s, 6 H) 3.36 (t, 2 H) 3.50 (d, 2 H) 3.68 (m, 2 H) 3.81 (t, 2 H) 3.95 (s, 3 H) 4.55 (t, 2 H) 6.91 (d, 1 H) 8.00 (dd, 1 H) 8.12 (d, 1 H) 8.44 (d, 1 H) 8.47 (d, 1 H).
  • HRMS m/z 524.2989 (calculated for M+H, 524.2980).
  • Example 47 was obtained from Example 41 by the following reaction. To 7-(6- methoxypyridin-3-yl)-3-[(piperidin-4-ylmethyl)amino]-1-(2-propoxyethyl)pyrido[2,3-b]pyrazin- 2(1H)-one trifluoroacetate (250 mg, 0.4 mmol) in ⁇ /, ⁇ /-dimethylformamide (1.5 mL) was added potassium carbonate (304 mg, 2.2 mmol), and 2-bromoethyl methyl ether (46.0 DL, 0.5 mmol) at room temperature. The reaction mixture was warmed to 5O 0 C for 5 hours and the solvent was removed in vacuo.
  • Example 48 was prepared by a method similar to that described in Example 47 using 2- bromoethanol in place of 2-bromoethyl methyl ether.
  • 1 H NMR 400 MHz, METHANOL-D4 ⁇ ppm 0.69 (t, 3 H) 1.39 (m, 2 H) 1.49 (m, 2 H) 1.89 (d, 2 H) 1.98 (m, 1 H) 2.48 (m, 2 H) 2.81 (t, 2 H) 3.23 (m, 2 H) 3.34 (t, 2 H) 3.50 (d, 2 H) 3.73 (t, 2 H) 3.79 (t, 2 H) 3.94 (s, 3 H) 4.54 (t, 2 H) 6.89 (d, 1 H) 7.99 (dd, 1 H) 8.12 (d, 1 H) 8.43 (d, 1 H) 8.47 (d, 1 H).
  • HRMS m/z 497.2875 (calculated for M+H, 497.2871).
  • Example 49 was obtained from Example 42 by the following isocyanate reaction.
  • Example 50 was prepared by a method similar to that described in Example 47 using 3- bromo-1-propanol in place of 2-bromoethyl methyl ether.
  • 1 H NMR 400 MHz, CD 3 OD
  • HRMS m/z 511.3045 (calculated for M+H, 511.3027).
  • Example 51 was prepared from Example 42 by a method similar to that described in
  • Example 43 using acetyl chloride in place of methanesulfonyl chloride.
  • 1 H NMR 400 MHz, METHANOL-D4 ⁇ ppm 0.70 (t, 3 H) 1.42 (m, 2 H) 1.60 (m, 2 H) 2.11 (m, 5 H) 2.86 (m, 2 H) 3.35 (t, 2 H) 3.80 (t, 2 H) 3.97 (m, 4 H) 4.36 (m, 1 H) 4.54 (m, 3 H) 6.91 (d, 1 H) 8.01 ⁇ dd, 1 H) 8.13 (d, 1 H) 8.45 (d, 1 H) 8.49 (d, 1 H).
  • HRMS m/z 481.2565 (calculated for M+H, 481.2558).
  • Example 52 was prepared from Example 42 by a method similar to that described in
  • Example 43 1 H NMR (400 MHz, CDCI 3 ) ⁇ 0.73 (t, 3 H), 1.45 (m, 2 H), 1.71 (m, 2 H), 2.26 ⁇ m, 2 H), 2.81 (s, 3 H), 2.91 (m, 2 H), 3.34 (t, 2 H), 3.81 (m, 4 H), 3.98 (s, 3 H), 4.37 (m, 1 H), 4.47 (t, 2 H), 6.59 (d, 1 H), 6.85 (d, 1 H), 7.80 (dd, 1 H), 7.96 (d, 1 H), 8.40 (d, 1 H), 8.58 (d, 1 H).
  • HRMS m/z 517.2238 (calculated for M+H, 517.2228).
  • Example 53 was prepared from Example 42 by a method similar to that described in Example 43 using dimethylcarbamyl chloride in place of methanesulfonyl chloride.
  • 1 H NMR 400 MHz, CD 3 OD
  • HRMS m/z 510.2779 (calculated for M+H, 510.2823).
  • Example 54 was prepared from Example 42 by a method similar to that described in Example 49.
  • 1 H NMR 400 MHz, CD 3 OD
  • HRMS m/z 496.2698 (calculated for M+H, 496.2667).
  • Example 55 was prepared from Example 42 by a method similar to that described in
  • Example 45 1 H NMR (400 MHz, CHLOROFORM-D) ⁇ ppm 0.73 (m, 3 H) 1.46 (m, 4 H) 2.24 (dd, 2 H) 2.97 (m, 1 H) 3.19 (m, 1 H) 3.34 (t, 2 H) 3.57 (m, 2 H) 3.80 (m, 2 H) 3.98 (s, 3 H) 4.18 (s, 2 H) 4.47 (m, 2 H) 4.59 (d, 1 H) 6.56 (m, 1 H) 6.85 (d, 1 H) 7.80 (dd, 1 H) 7.97 (s, 1 H) 8.41 (d, 1 H) 8.59 (d, 1 H). HRMS m/z 497.2512 (calculated for M+H, 497.2507).
  • Example 56 1 H NMR (400 MHz, CHLOROFORM-D) ⁇ ppm 0.73 (m, 3 H) 1.46 (m, 4 H) 2.24 (dd, 2 H) 2.97 (m, 1 H) 3.19 (
  • Example 56 was prepared from Example 42 by a method similar to that described in Example 47 using 2-bromoethanol in place of 2-bromoethyl methyl ether.
  • 1 H NMR 400 MHz, CD 3 OD
  • HRMS m/z 483.2748 (calculated for M+H, 483.2714).
  • Example 57 was prepared from Example 42 by a method similar to that described in Example 47 using 3-bromo-1-propanol in place of 2-bromoethyl methyl ether.
  • 1 H NMR 400 MHz, METHAN0L-D4 ⁇ ppm 0.71 (t, 3 H) 1.42 (m, 2 H) 1.75 (m, 4 H) 2.11 (d, 2 H) 2.26 (m, 2 H) 2.54 (m, 2 H) 3.04 (m, 2 H) 3.36 (t, 2 H) 3.63 (t, 2 H) 3.81 (t, 2 H) 3.96 (s, 3 H) 4.18 (m, 1 H) 4.56 (t, 2 H) 6.92 (d, 1 H) 8.01 (dd, 1 H) 8.15 (d, 1 H) 8.45 (d, 1 H) 8.49 (d, 1 H).
  • HRMS m/z 497.2839 (calculated for M+H, 497.2871).
  • Example 58 was prepared from Example 42 by a method similar to that described in Example 47.
  • 1 H NMR 400 MHz, CD 3 OD
  • ⁇ 0.70 ⁇ t, 3 H 1.42 (m, 2 H), 1.72 (m, 2 H), 2.07 (d, 2 H), 2.27 (t, 2 H), 2.62 (t, 2 H), 3.01 (d, 2 H), 3.35 (m, 5 H), 3.55 (t, 2 H), 3.80 (t, 2 H), 3.95 (s, 3 H) 1 4.14 (m, 1 H), 4.55 (t, 2 H), 6.90 (d, 1 H), 8.00 (dd, 1 H), 8.12 (d, 1 H), 8.44 (d, 1 H), 8.47 (d, 1 H).
  • HRMS m/z 497.2861 (calculated for M+H, 497.2871).
  • Example 59 was obtained by a method similar to that described in Example 4 using N 1 N- bis(2-hydroxyethyl)ethylene diamine in place of N ⁇ 1 ⁇ ,N ⁇ 1 ⁇ -dimethylglycinamide in step 6.
  • 1 H NMR 400 MHz, CD 3 OD
  • HRMS m/z 487.2668 (calculated for M+H, 487.2663).
  • Example 60 was prepared from Example 35 by a method similar to that described in Example 41.
  • 1 H NMR 400 MHz, METHANOL-D4 ⁇ ppm 0.72 (t, 3 H) 1.42 (m, 2 H) 3.37 (m, 4 H) 3.85 (t, 2 H) 3.98 (t, 2 H) 4.15 (s, 3 H) 4.67 (t, 2 H) 7.38 (d, 1 H) 8.50 (dd, 1 H) 8.67 (d, 1 H) 8.74 (d, 1 H) 8.78 (d, 1 H).
  • HRMS m/z 399.2142 (calculated for M+H, 399.2139).
  • Example 61 was prepared from Example 60 by a method similar to that described in Example 45.
  • 1H NMR 400 MHz, CHLOROFORM-D
  • HRMS m/z 457.2203 (calculated for M+H, 457.2194).
  • Example 62 was prepared by a method similar to that described in Example 4 using 2-(2- aminoethylamino)ethanol in place of N ⁇ 1 ⁇ ,N ⁇ 1 ⁇ -dimethylglycinamide in step 6.
  • 1 H NMR 400 MHz, METHANOL-D4 ⁇ ppm 0.70 (t, 3 H) 1.42 (m, 2 H) 3.21 (m, 2 H) 3.37 (m, 4 H) 3.81 (m, 4 H) 3.89 (t, 2 H) 3.96 (s, 3 H) 4.54 (t, 2 H) 6.93 (d, 1 H) 8.02 (dd, 1 H) 8.18 (d, 1 H) 8.45 (d, 1 H) 8.53 (d, 1 H).
  • HRMS m/z 443.2383 (calculated for M+H, 443.2401).
  • Example 63 was prepared by a method similar to Example 4 using N-methyl-N- ethylamine in place of N ⁇ 1 ⁇ ,N ⁇ 1 — dimethylglycinamide in step 6.
  • 1 H NMR (CD 3 SOCD 3 ) ⁇ 8.55 (dd, 2H), 8.10 (dd, 1 H), 8.05 (d, 1 H), 6.92 (d, 1 H), 4.45 (t, 2H), 3.87 (bs, 6H), 3.66 (t, 2H), 3.65 (m, 2H),3.29 (m, 2H), 1.32 (m, 2H), 1.18 (t, 3H), 0.66 (t, 3H).
  • HRMS m/z398.2161 (calculated for M+H, 398.2187).
  • Example 64 was prepared by a method similar to that described in Example 4 using isoporpoxyamine in place of of N ⁇ 1 ⁇ ,N ⁇ 1 ⁇ -dimethylglycinamide in step 6.
  • 1 H NMR 400 mHz, (CDg) 2 SO) .510.15 (s, 1H), 8.51 (m, 1H), 8.25 (bs, 1H), 8.05 (dd,1H), 7.89 (s, 1H), 6.90 (d,
  • Example 65 was prepared by a method similar to that described in Example 4 using methoxyamine in place of of N ⁇ 1 ⁇ ,N ⁇ 1— dimethylglycinamide in step 6.
  • 1 H NMR 400 mHz, (CDg) 2 SO) 810.42 (s, 1H), 8.49 (d, 1 H), 8.23 (d, 1 H), 8.03, (dd, 1 H), 7.87 (d, 1H), 6.89 (d,1H), 4.31 (t, 2H), 3.85 (m, 6H), 3.61 (t, 2H), 3.27 (t, 2H), 1.32 (m, 2H), 0.66 (t, 3H).
  • HRMS m/z 386.1841 (calculated for M+H, 386.1823).
  • Example 66 was prepared by a method similar to that described in Example 4 using N 1 O- dimethylhydroxylamine in place of of N ⁇ 1 ⁇ ,N ⁇ 1 ⁇ -dimethylglycinamide in step 6.
  • 1 H NMR 400 mHz, (CDa) 2 SO) ⁇ 8.69 (d, 1H), 8.63 (d, 1H), 8.19 (d, 1H), 8.17 (dd, 1H), 6.95 (d, 1 H), 4.51 (t, 2H), 3.89 (s, 3H), 3.79 (s, 3H), 3.68 (t, 2H), 3.36 (s, 3H), 3.30 (t, 2H), 1.31 (m, 2H), 0.63 (t, 3H).
  • HRMS m/z 400.1979 (calculated for M+H, 400.1979).
  • Example 67 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and isobutylamine in place of 4-(2- aminoethyl)morpholine in step 5.
  • Example 68 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , isobutylamine in place of 4- ⁇ 2- aminoethyl)morpholine in step 5, and 3,5-dimethylisoxazole-4-boronic acid in place of 2- methoxy-5-pyridineboronic acid in step 6.
  • Example 69 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , isobutylamine in place of 4-(2- aminoethyl)morpholine in step 5, and 4-fluorophenylboronic acid in place of 2-methoxy-5- pyridineboronic acid in step 6.
  • Example 70 3-(isopropylam ino)-7-(6-m ethoxypyridin-3-yl)- 1 -(2-propoxyethyl)pyridof2,3-biPyrazin-2( 1 H)- one
  • Example 70 was prepared by a method similar to that described in Example 4 using isoproylamine in place of N ⁇ 1 ⁇ ,N ⁇ 1 ⁇ -dimethylglycinamide in step 6.
  • Example 71 was prepared by a method similar to that described in Example 4 using cyclohexylamine in place of N ⁇ 1 ⁇ ,N ⁇ 1 ⁇ -dimethylglycinamide in step 6.
  • Example 72 was prepared by a method similar to that described in Example 4 using cyclopropylamine in place of N ⁇ 1 ⁇ ,N ⁇ 1 ⁇ -dimethylglycinamide in step 6.
  • HRMS m/z 396.2024, (calculated for M+H, 396.2030).
  • Example 73 was prepared by a method similar to that described in Example 4 using diethylamine in place of N ⁇ 1 ⁇ ,N ⁇ 1 ⁇ -dimethylglycinamide in step 6.
  • Example 74 was prepared by a method similar to that described in Example 4 using aminotetrahydropyran in place of N ⁇ 1 ⁇ ,N ⁇ 1 ⁇ -dimethylglycinamide in step 6.
  • Example 75 was prepared by a method similar to that described in Example 4 using cyclopentylamine in place of N ⁇ 1 ⁇ ,N ⁇ 1 —dimethylglycinamide in step 6.
  • Example 76 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , 1-(3-aminopropyl)pyrrolidin-2-one in place of 4-(2-aminoethyl)morpholine in step 5, and 2-methoxypyrimidin-5-ylboronic acid in place of 2-methoxy-5-pyridineboronic acid in step 6.
  • Example 77 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , 1-(3-aminopropyl)pyrrolidin-2-one in place of 4-(2-aminoethyl)morpholine in step 5, and 4-flouroboronic acid in place of 2-methoxy-5- pyridineboronic acid in step 6.
  • Example 78 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , (5-methylpyrazin-2-yl)methylamine in place of 4-(2-aminoethyl)morpholine in step 5, and 4-flouroboronic acid in place of 2-methoxy- 5-pyridineboronic acid in step 6.
  • Example 79 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1, (5-methylpyrazin-2-yl)methylamine in place of 4-(2-aminoethyl)morpholine in step 5, and 4-3,5-dimethylisoxazol-4-ylboronic acid in place of 2-methoxy-5-pyridineboronic acid in step 6.
  • Example 80 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and (5-methylpyrazin-2-yl)methylamine in place of 4-(2-aminoethyl)morpholine in step 5.
  • Example 81 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , 2-aminomethylpyridine in place of 4-(2- aminoethyl)morpholine in step 5, and 4-flouroboronic acid in place of 2-methoxy-5- pyridineboronic acid in step 6.
  • Example 82 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and 2-aminomethylpyridine in place of 4- (2-aminoethyl)morpholine in step 5.
  • 1 H NMR (CDCI 3 ) ⁇ 8.56-8.58 ⁇ m, 2H), 8.39 (d, 1H), 7.91 (d, 1H), 7.77-7.80 (m, 2H), 7.62-7.67 (m, 1 H), 7.34 (d, 1 H), 7.17-7.20 (m, 1H), 6.83 (d, 1H), 4.94 (d, 2H), 4.46 (t, 2H), 3.96 (s, 3H), 3.78 (t, 2H), 3.31 (t, 2H), 1.63 (s, 2H), 1.41-1.46 (m, 2H), 0.71 (t, 3H).
  • HRMS m/z 447.2160, (calculated for M+H, 447.2139).
  • Example 83 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , 2-aminomethylpyridine in place of 4-(2- aminoethyl)morpholine in step 5, and ,5-dimethylisoxazol-4-ylboronic acid in place of 2- methoxy-5-pyridineboronic acid in step 6.
  • Example 84 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1, pyrazin-2-ylmethylamine in place of 4-(2- aminoethyl)morpholine in step 5, and 4-fluorophenylboronic acid in place of 2-methoxy-5- pyridineboronic acid in step 6.
  • Example 85 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and pyrazin-2-ylmethylamine in place of 4- (2-aminoethyl)morpholine in step 5.
  • Example 86 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , pyrazin-2-ylmethylamine in place of 4-(2- aminoethyl)morpholine in step 5, and 4-3,5-dimethylisoxazol-4-ylboronic acid in place of 2- methoxy-5-pyridineboronic acid in step 6.
  • Example 87 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , 2-isopropoxyethylamine in place of 4-(2- aminoethyl)morpholine in step 5, and 4-fluorophenylboronic acid in place of 2-methoxy-5- pyridineboronic acid in step 6.
  • Example 88 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and 2-isopropoxyethylamine in place of 4- (2-aminoethyl)morpholine in step 5.
  • Example 89 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , 2-isopropoxyethylamine in place of 4-(2- aminoethyl)morpholine in step 5, and 3,5-dimethylisoxazol-4-ylboronic acid in place of 2- methoxy-5-pyridineboronic acid in step 6.
  • Example 90 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , cyclohexanemethylamine in place of 4-(2- aminoethyl)morpholine in step 5, and 4-fluorophenyl boronic acid in place of 2-methoxy-5- pyridineboronic acid in step 6.
  • Example 91 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and cyclohexanemethylamine in place of 4-(2-aminoethyl)morpholine in step 5.
  • Example 92 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , cyclohexanemethylamine in place of 4-(2- aminoethyl)morpholine in step 5, and 3,5-dimethylisoxazol-4-ylboronic acid in place of 2- methoxy-5-pyridineboronic acid in step 6.
  • Example 93 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and ethylamine in place of 4-(2- aminoethyl)morpholine in step 5.
  • 1 H NMR (CDCI 3 ) ⁇ 8.55 (d,1 H), 8.38 (d, 1H), 7.92 (d, 1H), 7.76-7.79 (m, 1 H), 6.82 (d, 1 H), 6.64 (t, 1 H), 4.44 (t, 2H), 3.95 (s, 3H) 1 3.75 (t, 2H), 3.64-3.71 (m, 2H), 3.30 (t, 2H), 1.39-1.46 (m, 2H), 1.30 (t, 3H), 0.71 (t, 3H).
  • HRMS m/z 385.2066, (calculated for M+H, 385.2030).
  • Example 94 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , ethylamine in place of 4-(2- aminoethyl)morpholine in step 5, and 3,5-dimethylisoxazol-4-ylboronic acid in place of 2- methoxy-5-pyridineboronic acid in step 6.
  • Example 95 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , ethylamine in place of 4-(2- aminoethyl)morpholine in step 5, and 4-fluorophenylboronic acid in place of 2-methoxy-5- pyridineboronic acid in step 6.
  • Example 96 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and ammonia in place of 4-(2- aminoethyl)morpholine in step 5.
  • 1 H NMR (CDCI 3 ) ⁇ 8.59 (d, 1 H), 8.39 (m, 1H), 7.93 (d, 1 H), 7.77-7.80 (m, 1H), 6.82-6.84 (m, 1H), 4.64 (t, 2H), 3.97 (s, 3H), 3.78 (t, 2H), 3.32 (t, 2H), 1.41- 1.46 (m, 2H), 0.71 (t, 3H).
  • Example 97 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , ammonia in place of 4-(2- aminoethyl)morpholine in step 5, and 3,5-dimethylisoxazol-4-ylboronic acid in place of 2- methoxy-5-pyridineboronic acid in step 6.
  • 1 H NMR (CDCI 3 ) ⁇ 8.13 (s, 1H), 8.02 ⁇ s, 1H), 4.48 (t, 2H), 3.77 (t, 2H), 3.28 (t, 2H), 2.48 (s, 3H), 2.31 (s, 3H), 1.34-1.40 (m, 2H), 0.66 (t, 3H).
  • Example 98 was prepared by a method similar to that described in Example 4 using 3- hydroxypropylamine in place of N ⁇ 1 ⁇ ,N ⁇ 1 "—dimethylglycinamide in step 6.
  • 1 H NMR (CDCI 3 ) ⁇ 8.55 (d, 1 H), 8.38 (d, 1H), 7.94 ⁇ s, 1H), 7.58-7.78 (m, 1 H), 7.04 (s, 1H), 6.83 (d, 1H), 4.42- 4.46 (m, 2H), 3.96 (s, 3H), 3.76-3.82 (m, 4H), 3.70 (t, 2H), 3.31 (t, 2H), 1.85-1.91 (m, 2H), 1.39-1.48 (m, 2H), 0.71 (t, 3H).
  • HRMS m/z 414.2109, (calculated for M+H, 414.2136).
  • Example 99 was prepared by a method similar to that described in Example 4 using 2- ethoxyethylamine in place of N ⁇ 1 ⁇ ,N ⁇ 1 ⁇ -dimethylglycinarmde in step 6.
  • 1 H NMR (CDCI 3 ) ⁇ 8.54 (d, 1H), 8.38 (d, 1H), 8.02 (d, 1H), 7.64-7.79 (m, .1H), 7.14 (s, 1H), 6.83 (d, 1H), 4.45 (t, 2H), 3.96 (s, 3H), 3.82-3.86 (m, 2H), 3.77 (t, 2H), 3.65 (t, 2H), 3.51 (q, 2H), 3.30 (t, 2H), 1.37- 1.46 (m, 2H), 1.19 (t, 3H), 0.69 (t, 3H).
  • HRMS m/z 428.2274, (calculated for M+H, 428.2292).
  • Example 100 was prepared by a method similar to that described in Example 4 using 3- methylbutylamine in place of N ⁇ 1 ⁇ ,N ⁇ 1 —dimethylglycinamide in step 6.
  • 1 H NMR (CDCI 3 ) ⁇ 8.57 (d, 1H), 8.38 (d, 1H), 8.02 (s, 1H), 7.76-7.79 (m, 1H), 6.83 ⁇ d, 1H), 6.74 (s, 1 H), 4.45 (t, 2H), 3.96 (s, 3H), 3.77 (t, 2H), 3.64-3.69 (m, 2H), 3.31 (t, 2H), 1.65-1.75 (m, 1H), 1.58 (q, 2H), 1.39-1.47 (m, 2H), 0.94 (d, 6H), 0.70 (t, 3H).
  • Example 101 was prepared by a method similar to that described in Example 4 using t- butylamine in place of N ⁇ 1 ⁇ ,N ⁇ 1 ⁇ -dimethylglycinamide in step 6.
  • 1 H NMR (CDCI 3 ) ⁇ 8.56 (d, 1H) 1 8.38 (d, 1 H) 1 7.87 (S 1 1 H), 7.76-7.79 (m, 1H), 6.82 (d, 1 H) 1 6.61 (S 1 1 H), 4.43 (t, 2H), 3.96 (s, 3H), 3.76 (t, 2H), 3.32 (t, 2H), 1.57 ⁇ s, 9H), 1.40-1.48 (m, 2H), 0.73 (t, 3H).
  • HRMS m/z 412.2360, (calculated for M+H, 412.2343).
  • Example 102 was prepared by a method similar to that described in Example 4 using dimethylamine in place of N ⁇ 1 ⁇ ,N ⁇ 1 --dimethylglycinamide in step 6.
  • 1 H NMR (CDCI 3 ) ⁇ 8.49 (d, 1 H), 8.37 (m, 1 H), 7.86 (d, 1H) 1 7.75-7.78 (m, 1 H), 6.80-6.82 (m, 1 H), 4.37 (t, 2H), 3.95 (s, 3H), 3.74 (t, 2H) 1 3.49 (s, 6H), 3.31 (t, 2H) 1 1.39-1.46 (m, 2H), 0.71 (t, 3H).
  • HRMS m/z 384.2080, (calculated for M+H, 384.2030).
  • Example 103 was prepared by a method similar to that described in Example 4 using propylamine in place of N ⁇ 1 ⁇ ,N ⁇ 1 —dimethylglycinamide in step 6.
  • 1 H NMR ⁇ CDCI 3 ⁇ 8.56 (d, 1 H), 8.38 (d, 1 H), 7.98 (s, 1 H), 7.76-7.79 (m, 1H), 6.83 (d, 1 H), 6.77 (s, 1H), 4.45 (t, 2H), 3.96 (s, 3H), 3.77 (t, 2H) 1 3.62 (q, 2H), 3.29-3.33 (m, 2H), 1.67-1.75 (m, 2H), 1.39-1.46 (m, 2H), 0.99 (t, 3H), 0.71 (t, 3H).
  • HRMS m/z 398.2164, (calculated for M+H, 398.2187).
  • Example 104 was prepared by a method similar to that described in Example 4 using ethanolamine in place of N ⁇ 1 ⁇ ,N ⁇ 1 —dimethylglycinamide in step 6.
  • 1 H NMR (CDCI 3 ) ⁇ 8.53 (d, 1 H), 8.38 (d, 1 H), 7.96 (d, 1 H), 7.76-7.79 (m, 1H), 7.15 (t, 1 H), 6.82 (d, 1 H) 1 4.44 (t, 2H) 1 3.96 (s, 3H), 3.91 (t, 2H) 1 3.83 (q, 2H) 1 3.76 (t, 2H) 1 3.32 (t, 2H) 1 1.38-1.46 (m, 2H) 1 0.71 (t, 3H).
  • HRMS m/z 400.1973, (calculated for M+H, 400.1979).
  • Example 105 was prepared by a method similar to that described in Example 4 using methylamine in place of N ⁇ 1 ⁇ ,N ⁇ 1 —dimethylglycinamide in step 6.
  • 1 H NMR (CDCI 3 ) ⁇ 8.56 (d, 1 H) 1 8.38 (d, 1 H), 7.93 (d, 1H), 7.76-7.79 (m, 1 H), 6.82 (d, 1 H) 1 6.69 ⁇ d, 1H) 1 4.44 (t, 2H), 3.96 (s, 3H), 3.76 (t, 2H) 1 3.30 (t, 2H) 1 3.19 (d, 3H) 1 1.38-1.46 (m, 2H) 1 0.70 (t, 3H).
  • HRMS m/z 370.1865, (calculated for M+H, 370.1874).
  • Example 106 was prepared by a method similar to that described in Example 4 using 3,3,3-trifluoropropylamine in place of N ⁇ 1 ⁇ ,N ⁇ 1 ⁇ -dimethylglycinamide in step 6.
  • 1 H NMR (CDCI 3 ) ⁇ 8.57 (d, 1H), 8.38 (d, 1H), 7.93 (d, 1H), 7.77-7.79 (m, 1H), 6.80-6.84 (m, 2H), 4.45 (t, 2H), 3.96 (s, 3H), 3.91 (q, 2H), 3.77 (t, 2H), 3.31 (t, 2H), 2.50-2.61 (m, 2H), 1.38-1.47 (m, 2H), 0.71 (t, 3H).
  • HRMS m/z 452.1927, (calculated for M+H, 452.1904).
  • Example 107 was prepared by a method similar to that described in Example 4 using (S)-(+)-tetrahydrofurfurylamine in place of N ⁇ 1 ⁇ ,N ⁇ 1 — dimethylglycinamide in step 6.
  • 1 H NMR (CDCI 3 ) ⁇ 8.57 (d, 1H), 8.38 (d, 1H), 7.95 (s, 1H), 7.76-7.79 (m, 1H), 7.02 (s, 1H), 6.83 (d, 1H), 4.45 (t, 2H), 4.11-4.19 (m, 1 H), 3.87-3.98 (m, 5H), 3.73-3.78 (m, 3H), 3.52-3.59 (m, 1H), 3.31 (t, 2H), 1.93-2.08 (m, 1H), 1.86-1.93 (m, 2H), 1.57-1.66 (m, 1H), 1.38-1.47 (m, 2H), 0.71 (t, 3H).
  • HRMS m/z 440.2301 (calculated for M+H
  • Example 108 was prepared by a method similar to that described in Example 4 using 1- (3-aminopropyl)-2-pyrrolidinone in place of N ⁇ 1 ⁇ ,N ⁇ 1 —dimethylglycinamide in step 6.
  • 1 H NMR (CDCI 3 ) ⁇ 8.52 (d, 1H), 8.38 (d, 1H), 7.90 (d, 1H), 7.36 (s, 1H), 6.80-6.83 (m, 2H), 4.43 (t, 2H), 3.95 (S, 3H), 3.75 (t, 2H), 3.64 (q, 2H), 3.37-3.40 (m, 4H), 3.30 (t, 2H), 2.38 ⁇ t, 2H), 1.98-2.05(m, 2H), 1.85-1.92 (m, 2H), 1.38-1.46 (m, 2H), 0.71 (t, 3H).
  • HRMS m/z 481.2547, (calculated for M+H, 481.2558).
  • Example 109 was prepared by a method similar to that described in Example 4 using (R)-(-)-tetrahydrofurfurylamine in place of N ⁇ 1 ⁇ ,N ⁇ 1 ⁇ -dimethylglycinamide in step 6.
  • 1 H NMR (CDCI 3 ) ⁇ 8.54 (d, 1 H), 8.38-8.39 (m, 1 H) 1 7.91 (d, 1 H), 7.76-7.79 (m, 1 H), 6.96 (d, 1H), 6.81- 6.83 (m, 1H), 4.45 (t, 2H), 4.13-4.18 (m, 1 H), 3.86-3.96 (m, 5H), 3.73-3.78 (m, 3H), 3.52-3.59 (m, 1 H), 3.31 (t, 2H), 1.99-2.07 (m, 1 H), 1.85-1.93 (m, 2H), 1.58-1.65 (m, 1H), 1.38-1.47 (m, 2H), 0.71 (t, 3H).
  • HRMS m/z
  • Example 110 was prepared by a method similar to that described in Example 4 using 3- methoxypropyl amine in place of N ⁇ 1 ⁇ ,N ⁇ 1 —dimethylglycinamide in step 6.
  • 1 H NMR (CDCI 3 ) ⁇ 8.54 (d, 1 H), 8.37-8.38 (m, 1H), 7.89 (d, 1 H), 7.76-7.79 (m, 1 H), 7.12 (s, 1 H), 6.81-6.83 (m, 1 H), 4.43 (t, 2H), 3.96 (s, 3H), 3.71-3.78 (m, 4H), 3.52 (t, 2H), 3.35 (s, 3H), 3.31 (t, 2H), 1.92- 1.98 (m, 2H), 1.40-1.46 (m, 2H), 0.71 (t, 3H).
  • HRMS m/z 428.2262, (calculated for M+H, 428.2292).
  • Example 111 was prepared by a method similar to that described in Example 4 using 2- methoxyethyl amine in place of N ⁇ 1 ⁇ ,N ⁇ 1 —dimethylglycinamide in step 6.
  • 1 H NMR (CDCI 3 ) ⁇ 8.54 (d, 1 H), 8.38 (d, 1 H), 7.90 (d, 1 H), 7.76-7.79 (m, 1 H), 6.94 (t, 1 H), 6.82 (d, 1H), 4.44 (t, 2H), 3.96 (S, 3H), 3.81-3.85 (m, 2H), 3.76 (t, 2H), 3.62 (t, 2H), 3.36 (s, 3H), 3.32 (t, 2H), 1.40- 1.45 (m, 2H), 0.71 (t, 3H).
  • HRMS m/z 414.2107, (calculated for M+H, 414.2136).
  • Example 112 was prepared by a method similar to that described in Example 4 using 2- (methylamino)ethanol in place of N ⁇ 1 ⁇ ,N ⁇ 1 —dimethylglycinamide in step 6.
  • 1 H NMR (CDCI 3 ) ⁇ 8.52 (d, 1H), 8.38 (d, 1 H), 7.85 (d, 1 H), 7.76-7.78 (m, 1 H), 6.82 (d, 1H), 4.39 (s, 2H), 4.03-4.06 (m, 2H), 3.92-3.97 (m, 5H), 3.75 (t, 2H), 3.45 (s, 3H), 3.31 ⁇ t, 2H), 1.40-1.47 (m, 2H), 0.72 (t, 3H).
  • HRMS m/z 414.2103, (calculated for M+H, 414.2136).
  • Example 113 was prepared by a method similar to that described in Example 4 using 2,2,2-trifluoroethylamine in place of N ⁇ 1 ⁇ ,N ⁇ 1 —dimethylglycinamide in step 6.
  • 1 H NMR (CDCI 3 ) ⁇ 8.61 (d, 1H), 8.40 (d, 1H), 7.98 (d, 1 H), 7.77-7.80 (m, 1H), 6.84 (d, 1 H), 6.79 ⁇ t, 1H), 4.47 (t, 2H), 4.31-4.40 (m, 2H), 3.97 (s, 3H), 3.79(t, 2H), 3.31 (t, 2H), 1.39-1.48 (m, 2H), 0.71 (t, 3H).
  • HRMS m/z 438.1735, (calculated for M+H, 438.1748).
  • Example 114
  • Example 114 was prepared by a method similar to that described in Example 4 using cyclobutylamine in place of N ⁇ 1 ⁇ ,N ⁇ 1 —dimethylglycinamide in step 6.
  • 1 H NMR (CDCI 3 ) ⁇ 8.55 (d, 1H), 8.38 (d, 1 H), 7.87 (d, 1H), 7.76-7.79 (m, 1 H), 6.82 (d, 1 H), 6.74 (d, 1 H), 4.74- 4.84 (m, 1H), 4.43 (t, 2H), 3.96 (s, 3H), 3.75 (t, 2H), 3.30 (t, 2H), 2.45-2.53 (m, 2H), 1.95-2.02 (m, 2H), 1.73-1.81 (m, 2H), 1.39-1.47 (m, 2H), 0.71 (t, 3H).
  • HRMS m/z 410.2181 , (calculated for M+H, 410.2187).
  • Example 115 was prepared from Example 97 by the following reaction.
  • a mixture of 3- amino-7-(6-methoxypyridin-3-yl)-1 -(2-propoxyethyl)pyrido[2,3-b]pyrazin-2(1 H)-one 300 mg, 0.84 mmol
  • acetic anhydride 400 mg, 3.92 mmol
  • triethylamine 500 mg, 4.95 mmol
  • dichloromethane 5.0 mL
  • the solution became homogeneous and was poured into ethyl acetate (25 mL).
  • Example 116 was prepared from Example 97 by the following reaction. To a mixture of 3-amino-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[2,3-b]pyrazin-2(1 H)-one (301 mg, 0.84 mmol) and triethylamine (505 mg, 5.0 mmol) in dichloromethane (5.0 ml_) was added methanesulfonylchloride (300 mg, 2.65 mmol) and the solution stirred at room temperature for 16 hours. An additional aliquot of methanesulfonylchloride (300 mg, 2.65 mmol) added and the reaction stirred for 4 hours.
  • methanesulfonylchloride 300 mg, 2.65 mmol
  • the solution was poured into ethyl acetate (25 ml_) and the solution was extracted with 5% aqueous citric acid ( 2 x 10 ml_), saturated aqueous sodium bicarbonate (2 x 10 ml_), and brine (10 ml_). The solution was dried over sodium sulfate and solvent removed at reduced pressure.
  • Example 117 was prepared by a method similar to that described in Example 1 using 6- methoxypyridin-3-ylboronic acid in place of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)pyridine in step 7.
  • Example 118 was prepared by a method similar to that described in Example 1 using 3,4-difluorophenylboronic acid in place of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)pyridine in step 7.
  • 1 HNMR (CDCI 3 , 400MHz) ⁇ 8.60 (s, 1 H), 7.95 ⁇ s, 1 H), 7.40 (m, 1 H), 7.30 (m, 2 H), 4.50 (t, 2 H) 3.80 (m, 8 H), 3.50 (q, 2 H), 2.60 (m, 6 H), 1.10 (t, 3 H).
  • Example 119 was prepared by a method similar to that described in Example 1 using N,N-dimethylethane-1 ,2-diamine in place of 4-(2-aminoethyl)morpholine in step 5 and 3,4- difluorophenylboronic acid in place of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine in step 7.
  • Example 120 was prepared by a method similar to that described in Example 1 using N,N-dimethylethane-1 ,2-diamine in place of 4-(2-aminoethyl)morpholine in step 5 and 6- methoxypyridin-3-ylboronic acid in place of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)pyridine in step 7.
  • Example 121 was prepared by a method similar to that described in Example 1 using N,N-dimethylethane-1 ,2-diamine in place of 4-(2-aminoethyl)morpholine in step 5 and 3-- chloro-4-fluorophenylboronic acid in place of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridine in step 7.
  • Example 122 was prepared by a method similar to that described in Example 1 using pentanoic acid in place of ethoxyacetic acid in step 1 and L-alanine methyl ester in place of 4-(2-aminoethyl)morpholine in step 5.
  • Example 123 was prepared by a method similar to that described in Example 1 using pentanoic acid in place of ethoxyacetic acid and L-alanine methyl ester in place of 4- ⁇ 2- aminoethyl)morpholine in step 5.
  • the mixture was heated to 100 0 C for 2 hours.
  • the mixture was cooled to room temperature, acidified with 2N HCI, extracted into dichloromethane, dried over sodium sulfate, filtered, and concentrated in vacuo.
  • the crude material was chromatographed eluting in a gradient of 100% DCM to 95/5/0.5 DCM/MeOH/AcOH to afford 26 mg of the cross coupled acid as a pale yellow solid.
  • Example 124 was prepared by a method similar to that described in Example 1 using 2- pyrrolidin-1-ylethanamine in place of 4-(2-aminoethyl)morpholine in step 5 and 6- methoxypyridin-3-ylboronic acid in place of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ) 3,2-dioxaborolan- 2-yl)pyridine in step 7.
  • Example 125 was prepared by a method similar to that described in Example 1 6- methylpyridin-3-ylboronic acid in place of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine in step 7.
  • 1 HNMR (CDCI 3 , 400MHz) ⁇ 8.80 (s, 1 H), 8.60 (s, 1 H), 8.00 ⁇ s, 1 H), 7.80 (d, 1 H), 7.30 (s, 1 H), 4.50 (t, 2 H), 3.80 (m, 8 H), 3.50 (t, 2 H), 2.70 (m, 3 H), 2.60 ⁇ s, 3 H), 2.50 (m, 3 H), 1.10 (t, 3 H).
  • Example 126 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and 4-fluorophenylboronic acid in place of 2-methoxy-5-pyridineboronic acid in step 6.
  • 1 H NMR 400 MHz, CHLOROFORM-D
  • HRMS m/z 456.2390 (calculated for M+H, 446.2405).
  • the IC 50 of test compounds can be measured using an in vitro assay using PDE5 enzyme isolated from human platelets.
  • the IC 50 is the concentration of test compound required to inhibit the hydrolysis of cGMP to GMP by the PDE5 enzyme by 50% relative to the activity of uninhibited controls.
  • the PDE5 enzyme for use in the assay can be obtained from human platelets by appropriate modification of the method of Thompson, WJ etal.; Biochemistry 18(23), 5228-5237, 1979, as described by Ballard SA et al.; J. Urology 159(6), 2164-2171 , 1998.
  • the PDE5 enzyme so obtained can be used to catalyze the hydrolysis of [ 3 H]CGMP (Amersham Biosciences) to 5' nucleotide [ 3 H]GMP.
  • the [ 3 H]GMP binds to yttrium silicate SPA beads (Amersham Biosciences) and is detected by scintillation counting. More specifically, the effect of the test compound at different concentrations can be evaluated in the assay by contacting the compound with a fixed amount of PDE5 enzyme in the presence of substrate (cGMP or cAMP in a 3:1 ratio unlabelled to [ 3 H]-labeled). Scintillation counting can be used as described above to determine relative PDE5 enzyme activity. The inhibition of PDE5 enzyme activity is then calculated relative to total PDE5 enzyme activity of uninhibited controls.
  • Buffer A 20 mM Tris-HCI, 5 mM MgCI 2 , pH 7.4
  • Buffer B 2 mg/ml BSA in Buffer A (enzyme buffer)
  • cGMP substrate Final concentration of 500 nM in assay The amount of 3 H-labeled substrate added depends upon the specific activity of [ 3 H]cGMP, and the cGMP substrate is diluted with a 10 mM stock of cold cGMP in Buffer A for a final substrate concentration of 500 nM in the assay.
  • PDE enzyme Prepared in Buffer B. The dilution factor is determined by enzyme activity.
  • SPA beads 20 mg/ml suspension prepared in dH2O. Positive Control Negative Control Standard/Test compound
  • Stocks of standard and test compounds are prepared at 5 mM in 100% DMSO.
  • the compound is serially diluted in a dilution plate using a 10-point Vz log dilution format. 2 ⁇ l of the compound dilution is added in duplicate to the wells of the assay plate. 2 ⁇ l of 100%
  • DMSO dimethyl methoxysulfoxide
  • 25 ⁇ l of Buffer A are added to all wells.
  • 25 ⁇ l of Buffer B are added to the negative control wells.
  • 25 ⁇ l of enzyme are added to the remaining wells.
  • 50 ⁇ l of substrate are added to each well. Plates are sealed and incubated for 60 minutes on a plate shaker at 30 C. 50 ⁇ l of SPA beads are added to stop the reaction. The plates are again sealed and shaken for 15 minutes to allow the beads to bind the GMP product. The beads are allowed to settle for 30 minutes and then read on a NXT TopCount scintillation counter. Data are analyzed with a curve fitting application for plate-based screening. Percent inhibition in this assay is calculated as follows:
  • Inhibition (%) [(mean maximum - compound value/ (mean maximum - mean minimum)] x 100.
  • the IC 50 value is determined from sigmoid dose-response curves of enzyme activity versus compound concentration.
  • Method 2 Alternative Human Platelet PDE5 Enzyme Inhibition Scintillation Proximity Assay The IC 50 of test compounds also can be measured in an alternative in vitro assay that varies from Method 1 as described below:
  • Buffer A 20 mM Tris-HCI, 5 mM MgCI 2, pH 7.4
  • Buffer B 2 mg/ml BSA in Buffer A (enzyme buffer)
  • cGMP substrate Final concentration of 50 nM in assay
  • the amount of 3 H-labeled substrate added depends upon the specific activity of [ 3 H]cGMP, and it is diluted in Buffer A.
  • PDE enzyme Prepared in Buffer B. The dilution factor is determined by enzyme activity.
  • SPA beads 4 mg/ml suspension prepared in dH 2 O.

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Abstract

Compounds of Formula (I), wherein R2, Y6, R6A, R6, and R8 are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, synthetic methods, and intermediates are also disclosed.

Description

PYRIDINE [2,3-b] PYRAZINONES
Cross Reference to Related Applications
This application claims priority from U. S. Provisional Application Serial Number 60/684,130 filed May 24, 2005, the disclosure of which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The present invention comprises a class of pyridine pyrazinone compounds having a structure of Formula I and pharmaceutical compositions comprising a compound of Formula I. The present invention also comprises methods of treating a subject by administering a therapeutically effective amount of a compound of Formula I to the subject. In general, these compounds inhibit, in whole or in part, the enzyme: cyclic guanylate monophosphate-specific phosphodiesterase type 5 (PDE-5).
BACKGROUND OF THE INVENTION
The prevalence of hypertension in developed countries is about 20% of the adult population, rising to about 60-70% of those aged 60 or more. Hypertension is associated with an increased risk of stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease and renal impairment. Despite the large number of anti-hypertensive drugs available in various pharmacological categories, additional agents useful for the treatment of hypertension are still needed.
Vascular endothelial cells secrete nitric oxide (NO). This acts on vascular smooth muscle cells and leads to the activation of guanylate cyclase and the accumulation of cyclic guanosine monophosphate (cGMP). The accumulation of cGMP causes the muscles to relax and the blood vessels to dilate, leading to a reduction in blood pressure. The cGMP is inactivated by hydrolysis to guanosine 5'-monophosphate (GMP) by a cGMP-specific phosphodiesterase. One cGMP-phosphodiesterase is Phosphodiesterase type 5 (PDE5). Inhibitors of PDE5 decrease the rate of hydrolysis of cGMP and potentiate the actions of nitric oxide. Improved drug therapies for the treatment of subjects suffering from or susceptible to a cardiovascular condition are desirable. PDE-5 inhibitors for treating cGMP-mediated conditions and corresponding drug therapies are desirable.
SUMMARY OF THE INVENTION In one embodiment, the invention comprises compounds of Formula I:
Figure imgf000004_0001
wherein R2, Y6, R6, R6A and R8 are as defined in the detailed description of the invention.
In another embodiment, the invention comprises a pharmaceutical composition comprising a compound of Formula I. In another embodiment, the invention comprises methods of treating a condition in a subject by administering a therapeutically effective amount of a compound of Formula I to the subject.
In another embodiment, the invention comprises a method for inhibiting PDE-5, and methods for treating a condition in a subject mediated by PDE-5 activity by administering a compound of Formula I to the subject.
In another embodiment, the invention comprises intermediates useful in the synthesis of compounds having the structure of Formula I.
DETAILED DESCRIPTION OF THE INVENTION This detailed description of embodiments is intended only to acquaint others skilled in the art with the inventions, the principles, and the practical applications so that others skilled in the art may adapt and apply the inventions in their numerous forms, as they may be best suited to the requirements of a particular use. These inventions, therefore, are not limited to the embodiments described in this specification, and may be modified. A. Abbreviations and Definitions
Figure imgf000004_0002
Figure imgf000005_0001
The term "alkyl" (alone or in combination with other term(s)) refers to a linear or branched-chain saturated hydrocarbyl substituent (i.e., a substituent 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. Examples of such 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.
The term "alkenyl" (alone or in combination with other term(s)) 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. Examples of alkenyl radicals include ethenyl, allyl, propenyl, butenyl and 3-methylbutenyl. The terms "alkenyl", and "lower alkenyl", embrace radicals having "cis" and "trans" orientations, or alternatively, "Z" and "E" orientations.
The term "alkynyl" (alone or in combination with other term(s)) 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. Examples of aikynyl radicals include 1-propynyl, 2-propynyl, 1-butyne, 2-butynyl and 1-pentynyl.
The term "amino", alone or in combination with another term(s), refers to -NH2 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.
The term "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. Examples of aryl moieties include phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl.
The term "carbocyclyl", alone or in combination with another term(s), refers to a saturated cyclic (i.e., "cycloalkyl"), partially saturated cyclic (i.e., "cycloalkenyl"), or completely unsaturated (i.e., "aryl") hydrocarbyl substituent containing from 3 to 14 carbon ring atoms ("ring atoms" are the atoms bound together to form the ring or rings of a cyclic substituent). A carbocyclyl may be a single ring, which typically contains from 3 to 6 ring atoms. Examples of such single-ring carbocyclyls include cyclopropanyl, cyclobutanyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl. A carbocyclyl alternatively may be 2 or 3 rings fused together, such as naphthalenyl, tetrahydronaphthalenyl (also known as "tetralinyl"), indenyl, isoindenyl, indanyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl (also known as "phenalenyl"), fluoreneyl, decalinyl, and norpinanyl.
The term "carbonyl", alone or in combination with another term(s), means
-C(O)-, which also may be depicted as:
Figure imgf000006_0001
The term "carboxy", alone or in combination with another term(s), refers to a radical of the formula -C(O)OH.
The term "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.
The term "composition" refers to an article of manufacture which results from the mixing or combining of more than one element or ingredient.
The term "compound" refers to a material made up of two or more elements and includes tautomers and pharmaceutically acceptable salts of the compound.
The term "cyano", alone or in combination with another term(s), means -CN, which also
may be depicted:
Figure imgf000006_0002
The term "cycloalkyl", alone or in combination with another term(s), refers to saturated carbocyclic radicals having three to about twelve carbon atoms. In another embodiment, cycloalkyl radicals are "lower cycloalkyl" radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "cycloalkylalkyl", alone or in combination with another term(s), refers to alkyl substituted with cycloalkyl. Examples of such substituents include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.
The term "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.
The term "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). In another embodiment, the halogen is a fluorine or chlorine radical. In another embodiment, the halogen is a fluorine radical. When used in combination with another term(s), the prefix "halo" indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen radicals. For example, haloalkyl refers to an alkyl substituent wherein at least one hydrogen radical is replaced with a halogen radical. Where there are more than one hydrogen replaced with halogens, the halogens may be the same or different. Examples of haloalkyls include chloromethyl, dichloromethyl, difluorochloromethyl, dichlorofluoromethyl, trichloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoroethyl, pentafluoroethyl, difluoropropyl, dichloropropyl, and heptafluoropropyl. Illustrating further, "haloalkoxy" means an alkoxy substituent wherein at least one hydrogen radical is replaced by a halogen radical. Examples of 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).
The term "heterocyclyl", alone or in combination with another term(s), means a saturated (i.e., "heterocycloalkyl"), partially saturated (i.e., "heterocycloalkenyl"), or completely unsaturated (i.e., "heteroaryl") 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, phosphorous, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, phosphorous, and sulfur.
The term "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, phosphorous, 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. Examples of single-ring heterocyclyls include furanyl, dihydrofurnayl, tetradydrofurnayl, thiophenyl (also known as "thiofuranyl"), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl (including oxadiazolyl, 1 ,2,4-oxadiazolyl (also known as "azoximyl"), 1 ,2,5-oxadiazolyl (also known as "furazanyl"), or 1 ,3,4-oxadiazolyl), oxatriazolyl (including 1 ,2,3,4-oxatriazolyl or 1,2,3,5-oxatriazolyl), dioxazolyl (including 1 ,2,3-dioxazolyl, 1 ,2,4-dioxazolyl, 1 ,3,2-dioxazolyl, or 1 ,3,4-dioxazolyl), oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl (including 1 ,2-pyranyl or 1 ,4-pyranyl), dihydropyranyl, pyridinyl (also known as
"azinyl"), piperidinyi, diazinyl (including pyridazinyl (also known as "1 ,2-diazinyl"), pyrimidinyl (also known as "1 ,3-diazinyl" or "pyrimidyl"), or pyrazinyl (also known as "1 ,4-diazinyl")), piperazinyl, triazinyl (including s-triazinyl (also known as "1 ,3,5-triazinyl"), as-triazinyl (also known 1,2,4-triazinyl), and v-triazinyl (also known as "1 ,2,3-triazinyl")), oxazinyl (including 1 ,2,3-oxazinyl, 1 ,3,2-oxazinyl, 1 ,3,6-oxazinyl (also known as "pentoxazolyl"), 1 ,2,6-oxazinyl, or 1 ,4-oxazinyl), isoxazinyl (including o-isoxazinyl or p-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including 1 ,2,5-oxathiazinyl or 1 ,2,6-oxathiazinyl), oxadiazinyl (including 1 ,4,2-oxadiazinyl or 1 ,3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl. 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). Examples of 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, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, and tetrahydroisoquinolinyl. Other examples of 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"), benzothiopyranyl (also known as "thiochromanyl"), 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.
The term "heteroaryl", alone or in combination with another term(s), 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. In one embodiment, heteroaryl radicals are 5- or 6-membered heteroaryl, containing one, two, or three heteroatoms selected from sulphur, nitrogen, phosphorous, and oxygen, selected from thienyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl and pyrazinyl. Examples of heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as 1 ,3,5-, 1 ,2,4- or 1 ,2,3-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-benzopyronyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1 ,4-benzoxazinyl. Other 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, 1 H-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-b]pyridazinyl]; unsaturated 3 to 6-membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, isoxazolyl, oxadiazolyl [e.g., 1 ,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1 ,2,5-oxadiazolyl]; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. 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, 1 ,3,4-thiadiazolyl, 1 ,2,5-thiadiazolyl]; unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like.
The term "heterocyclylalkyl", alone or in combination with another term(s), refers to alkyl substituted with a heterocyclyl.
The term "hydroxy", alone or in combination with another term(s), refers to -OH.
The term "mercapto" or "thiol" refers to a sulfhydryl substituent, which also may depicted as -SH. The term "nitro", alone or in combination with another term(s), refers to -NO2.
The term "sulfonyl", alone or in combination with another term(s), refers to -S(O)2-, which
Figure imgf000010_0001
also may be depicted as:
Thus, for example, "alkyl-sulfonyl-alkyP refers to alkyl-S(O)2-alkyl. Examples of typically preferred alkylsulfonyl substituents include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.
The term "sulfoxyl" , alone or in combination with another term(s), refers to -S(O) -, which
Figure imgf000010_0002
also may be depicted as:
The term "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.
If a substituent is described as being "optionally substituted", the 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. This specification uses the terms "substituent" and "radical" interchangeably.
The term "hypertensive subject" refers to a subject having hypertension, suffering from the effects of hypertension or susceptible to a hypertensive condition if not treated to prevent or control such hypertension.
The term "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.
The terms "prevent," "prevention" or "preventing" refer 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. The term "therapeutically 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.
The term "treatment" (and corresponding terms "treat" and "treating") includes palliative, restorative, and preventative treatment of a subject. The term "palliative treatment" refers to treatment that eases or reduces the effect or intensity of a condition in a subject without curing the condition. The term "preventative treatment" (and the corresponding term "prophylactic treatment") refers to treatment that prevents the occurrence of a condition in a subject. The term "restorative treatment" refers to treatment that halts the progression of, reduces the pathologic manifestations of, or entirely eliminates a condition in a subject. B. Compounds
The present invention comprises, in part, a novel class of pyridine pyrazinone compounds. These compounds are useful as inhibitors of PDE5. For convenience in drafting, Formula I describes ring numbering that is not reflective of standard chemical nomenclature. Compounds of 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:
Figure imgf000011_0001
wherein: R2 is selected from the group consisting of aryl and 3 to 10 membered ring heterocyclyl,
R2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, -OR100, - C(O)R100, -OC(O)R100, -C(O)OR100, -NR100R101, -N(R100)C(O)R101, -C(O)NR100R101, - C(O)NR100C(O)R101, -SR100 -S(O)R100 and -S(O)2R100, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl wherein (a) the alkyl, alkenyl, alkylnyl and cycloalkyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OR102, and -C(O)OR102; and (b) the aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl substituents are optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy and alkoxy;
R100, R101 and R102 are independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, alkoxy, - C(O)OH and -C(O)NH2; Y6 represents a bond or is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl, Y6 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cyano, OXO, cycloalkyl, -OR103, -C(O)R103, -C(O)OR103, -OC(O)R103, -NR103R104, -N(R103)C(O)R104, and -C(O)NR103R104;
R103 and R104 are independently selected from the group consisting of hydrogen and alkyl, wherein the alkyl is 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;
R6 is selected from the group consisting of hydrogen, halogen, oxo, hydroxy, amino, aminoalkyl, alkyl, alkynyl, alkoxy, alkylamino, cycloalkyl, aryl, aryl-C(O)-, heterocyclyl, heteroaryl, mercapto, sulfonyl, aryl-C(O)-NR105-, heterocyclyl-C(O)-, and heterocyclyl-C(O)- NR105- , R6 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, mercapto, oxo, alkyl, alkenyl, alkynyl, alkoxy, aminoalkyl, haloalkyl, hydroxyalkyl, hydroxyalkoxy, carboxyalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR106, -C(O)R106, -C(O)OR106, -OC(O)R106, NR106R107, -N(R106)C(O)R107, -C(O)NR106R107, -C(O)NR106C(O)R107, -SR105, -S(O)R106, - S(O)2R106, -N(R106)S(O)2R107, and -S(O)2NR106R107; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy; R105 is independently selected from the group consisting of hydrogen and alkyl;
R106 and R107 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and cycloalkyl wherein (a) the R106 and R107 alkyl and alkenyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy, and (b) the R106 and R107 alkynyl and cycloalkyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy;
R6A is selected from the group consisting of hydrogen, alkyl, and aminoalkyl, R6A is optionally substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, oxo, hydroxy, alkyl, and alkoxy;
R8 is alkyl; R8 is optionally substituted with one or more R8 substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, alkynyl, cycloalkyl, heterocyclyl, -OR108, -C(O)R108, -C(O)OR108, -OC(O)R108, -NR108R109, -N(R108)C(O)R109, - C(O)NR108R109, -SR108, -S(O)R108, and -S(O)2R108, wherein the alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkyl, and alkoxy; and
R108 and R109 are independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl, wherein (a) when the alkyl is methyl, the methyl is optionally substituted with 1 , 2, or 3 fluoro substituents, (b) when the alkyl comprises at least two carbon atoms, the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy, and (c) the R108 and R109 alkynyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy.
R8 is alkyl, R8 is optionally substituted with one or more R8 substituents independently selected from the group consisting of alkoxy, cycloalkyl, and heterocyclyl, said R8 substituents are optional substituted with halogen. In another embodiment of Formula I, R2 is selected from the group consisting of aryl and
3 to 10 membered ring heterocycyl wherein R2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, -OR100, -C(O)R100, -OC(O)R100, -C(O)OR100, -NR100R101, - N(R100)C(O)R101, -C(O)NR100R101, -C(O)NR100C(O)R101, and -S(O)mR100, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl wherein (a) the alkyl, alkenyl, alkylnyl and cycloalkyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OR102, and - C(O)OR102; and (b) the aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl substituents are optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy and alkoxy;
R100, R101 and R102 are independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, alkoxy, - C(O)OH and -C(O)NH2; R6A is selected from the group consisting of hydrogen and alkyl wherein the R6A alkyl substituent is optionally substituted with one or more substituents selected from the group consisting of chloro, fluoro, alkoxy and hydroxy;
Y6 represents a bond or is selected from the group consisting of alkyl, alkenyl and alkynyl, wherein (a) the Y6 alkyl, alkenyl and alkynyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, cycloalkyl, -OR103, -C(O)R103, -C(O)OR103, -OC(O)R103, -NR103R104, - N(R103)C(O)R104, and -C(O)NR103R104;
R103 and R104 are independently selected from the group consisting of hydrogen and alkyl, wherein the alkyl is 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;
R6 is selected from the group consisting of aryl, aryl-C(O)-, heterocyclyl, aryl-C(O)-NR105- , heterocyclyl-C(O)-, and heterocyclyl-C(O)-NR105- wherein R6 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -OR106, -C(O)R106, -C(O)OR106, - OC(O)R106, -NR106R107, -N(R106)C(O)R107, -C(O)NR106R107, -C(O)NR106C(O)R107, -SR106, - S(O)R106, -S(O)2R106, -N(R106)S(O)2R107, and -S(O)2NR106R107; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy;
R105 is independently selected from the group consisting of hydrogen and alkyl; R106 and R107 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl, wherein (a) the R106 and R107 alkyl and alkenyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy, and (b) the R106 and R107 alkynyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy;
R8 is alkyl; wherein R8 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, alkynyl, -OR108, -C(O)R108, -C(O)OR108, -OC(O)R108, -NR108R109, -N(R108)C(O)R109, - C(O)NR108R109, and -C(O)NR108C(O)R109, wherein the alkynyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkyl, and alkoxy; and
R108 and R109 are independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl, wherein (a) when the alkyl is methyl, the methyl is optionally substituted with 1 , 2, or 3 fluoro substituents, (b) when the alkyl comprises at least two carbon atoms, the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy, and (c) the R108 and R109 alkynyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy.
In another embodiment of Formula I, R2 is selected from the group consisting of aryl and 3 to 10 membered ring heterocycyl wherein R2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, -OR100, -C(O)R100, -OC(O)R100, -C(O)OR100, -NR100R101, - N(R100)C(O)R101, -C(O)NR100R101, -C(O)NR100C(O)R101, -SR100 -S(O)R100 and -S(O)2R100, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl wherein (a) the alkyl, alkenyl, alkylnyl and cycloalkyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OR102, and -C(O)OR102; and (b) the aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl substituents are optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy and alkoxy; R100, R101 and R102 are independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, alkoxy, -C(O)OH and - C(O)NH2;
R6A is selected from the group consisting of hydrogen and alkyl wherein the R6A alkyl substituent is optionally substituted with one or more substituents selected from the group consisting of chloro, fluoro, alkoxy and hydroxy; Y6 represents a bond or is selected from the group consisting of alkyl, alkenyl and alkynyl, wherein (a) the Y6 alkyl, alkenyl and alkynyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, cycloalkyl, -OR103, -C(O)R103, -C(O)OR103, -OC(O)R103, -NR103R104, - N(R103)C(O)R104, and -C(O)NR103R104; R103 and R104 are independently selected from the group consisting of hydrogen and alkyl, wherein the alkyl is 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; R6 is selected from the group consisting of hydrogen, halogen, oxo, hydroxy, amino, aminoalkyl, alkyl, alkynyl, alkoxy, alkylamino, and cycloalkyl wherein (a) the R6 alkyl, alkylamino, alkynyl and cycloalkyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, -OR106, -C(O)R106, -C(O)OR106, -OC(O)R106, -NR105R107, -N(R106)C(O)R107, -N(R106)C(O)COR107, - C(O)NR106R107, -C(O)NR106C(O)R107, -SR10, -S(O)R106, -S(O)2R106, - N(R106)S(O)2R107, and - S(O)2NR106R107, (b) the R6 amino and aminoalkyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, -OR106, -C(O)R106, -C(O)OR106, -OC(O)R106, -NR106R107, -N(R106)C(O)R107, - C(O)NR106R107, -C(O)NR106C(O)R107, -SR106, -S(O)R106, -S(O)2R106, -N(R106)S(O)2R107, and - S(O)2NR106R107,
R106 and R107 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and cycloalkyl wherein (a) the R106 and R107 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy, and (b) the R106 and R107 alkynyl and cycloalkyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy;
R8 is alkyl; wherein the R8 substituent are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkynyl, - OR108, -C(O)R108, -C(O)OR108, -OC(O)R108, -NR108R109, -N(R108)C(O)R109, -C(O)NR108R109, - C(O)NR108C(O)R109, -SR108, -S(O)R108, and -S(O)2R108, wherein the alkynyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkyl, and alkoxy; and R108 and R109 are independently selected from the group consisting of hydrogen, alkyl, and alkynyl, wherein (a) when the alkyl is methyl, the methyl is optionally substituted with 1 , 2, or 3 fluoro substituents, (b) when the alkyl comprises at least two carbon atoms, the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy, and (c) the R108 and
R109 alkynyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy.
In another embodiment of Formula I, R2 is selected from the group consisting of aryl and heterocyclyl, R2 is optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, alkenyl, alkyl, alkynyl, cyano, cycloalkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, nitro, and oxo;
Y6 represents a bond or is selected from the group consisting of alkenyl, alkyl, alkynyl, cycloalkyl, and heterocyclyl, Y6 is optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, alkyl, alkenyl, alkynyl, cyano, cycloalkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, nitro, and oxo;
R6 is selected from the group consisting of alkylamino, alkoxy, alkoxyalkyl, alkyl, alkenyl, alkynl, amino, aminoalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxy, hydroxyalkyl, mercapto, oxo, and sulfonyl; R6 is optionally substituted with one or more R6 substituents independently selected from the group consisting of alkyl, akylamino, alkoxy, aminoalkyl, aryl, cycloalkyl, halogen, heterocyclyl, heteroaryl, hydroxy, hydroxyalkyl, mercapto, oxo, and sulfonyl; said R6 substituents is optionally substituted with one or more substituents independently selected from alkyl, alkylaminocarbonyl, alkylcarbonyl, alkoxy, halogen, oxo and -S(O)2RT, Rτ is independently selected from the group consisting of hydrogen and alkyl;
R6A is selected from the group consisting of alkyl, aminoalkyl, and hydrogen, R6A is optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, alkyl, hydroxy, and oxo; and
R8 is alkyl, R8 is optionally substituted with one or more R8 substituents independently selected from the group consisting of alkoxy, cycloalkyl, and heterocyclyl, said R8 substituents may optional be substituted with halogen.
Selected subclasses of compounds that fall within the scope of the compounds of Formula I are shown in Table A, wherein R2, Y6, R6, R6A , R8, R9, R10, R11, R12, R13 and other substituents can be as defined for compounds of Formula I and as defined in the various embodiments described throughout this specification. Illustrative embodiments of these subclasses of compounds are described later in the specification.
TABLE A
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
R2 SUBSTITUENT I Inn oonnee eemmbbooddiment of Formula I, R2 is a 5 to 7 membered ring aryl that is optionally substituted as provided in Formula I.
In another embodiment of Formula I, R is phenyl that is optionally substituted as provided in Formula I.
In another embodiment of Formula I, R2 is substituted with one or more halogens. In another embodiment, R2 is substituted with one or more fluoro. In another embodiment, R2 is substituted with one or more fluoro and one or more chloro.
In another embodiment of Formula I, R2 is selected from the group consisting of
Figure imgf000019_0002
In another embodiment of Formula I, R2 is a 3 to 10 membered ring heteroaryl that is optionally substituted as provided in Formula I. In another embodiment, R2 is a 5 to 7 membered ring heteroaryl that is optionally substituted as provided Formula I. In another embodiment, R2 is a 5 to 6 membered ring heteroaryl that is optionally substituted as provided in Formula I. In another embodiment of Formula I, R2 is a 5 to 6 membered ring heteroaryl that comprises 1, 2, or 3 ring heteroatoms selected from the group consisting of oxygen and nitrogen.
In another embodiment of Formula I, R2 is selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, tetrahydrofuryl, dihydrofuryl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, pyridazinyl, and morpholinyl, said R2 is optionally substituted as provided in Formula I. In another embodiment of Formula I, R2 is selected from the group consisting of pyrazolyl, isoxazolyl, pyridinyl, and pyrimidinyl, R2 is optionally substituted as provided in Formula I. In another embodiment of Formula I, R2 is selected from the group consisting of
Figure imgf000020_0001
each optionally substituted as provided in Formula I.
In another embodiment of Formula I, R2 is optionally substituted with one or more substituents independently selected from the group consisting of chloro, bromo, fluoro, methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluoromethyl, hydroxy, methoxy, trifluoromethoxy, ethoxy, propoxy, butoxy, amino, methylamino, dimethylamino, ethylamino, diethylamino, methylsulfonyl, and ethylsulfonyl. In another embodiment, R2 is optionally substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, hydroxy, methoxy, and methyl.
In another embodiment of Formula I, R2 is substituted with one or two halogens. In another embodiment, R2 is substituted with one chloro and one fluoro. In another embodiment, R2 is substituted with one methoxy.
In another embodiment of Formula I, R2 is selected from the group consisting of
Figure imgf000021_0001
wherein R9, R10, R11 , R12 and R13 are independently selected from the group consisting of hydrogen, halogen, oxo, alkyl, -OR100, -C(O)R100, -OC(O)R100, -C(O)OR100, -NR100R101 and - C(O)NR100R101, wherein the alkyl substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OR102, and - C(O)OR102; and
R100, R101, and R102 are independently selected from the group consisting of hydrogen and C1 to C4 alkyl.
In another embodiment, R9, R10, R11, R12 and R13 are independently selected from the group consisting of hydrogen, cyano, oxo, halogen, hydroxy, alkyl, C3-C6-cycloalkyl, phenyl, alkoxy, alkylamino, alkylthio and alkylsulfonyl. In another embodiment, the R10 and R12 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. In another embodiment, the R9, R11 and R13 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. In another embodiment, the R11 and R13 substituents are independently selected from the group consisting of hydrogen, fluoro, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, amino, methylamino and dimethylamino. In another embodiment, the R11 and R13 substituents are independently selected from the group consisting of hydrogen, fluoro, methyl, methoxy, ethyl and hydroxy. In another embodiment, the R11 substituent is methoxy.
In another embodiment of Formula I, R2 is selected from the group consisting of
Figure imgf000022_0001
wherein R9, R10, R11, R12 and R13 are independently selected from the group consisting of hydrogen, fluoro, methyl, trifluoromethyl, and methoxy.
In another embodiment of Formula I, R2 is substituted at the para position with a substituent as described in Formula I. In another embodiment, R2 has one or more substituents independently selected from the group consisting of fluoro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, amino, methylamino, and dimethylamino. In another embodiment of Formula I, R2 is substituted at a para position with a substituent as defined herein. In another embodiment, R2 is substituted at a para position with a substituent selected from the group consisting of fluoro, methyl, trifluoromethyl, methoxy, and trifluoromethoxy.
In another embodiment, R2 is selected from the group consisting of 3-pyridinyl and 4- pyridinyl, described in Formulas H-A and H-G:
Figure imgf000022_0002
(H-G) wherein:
R9, R10, R11, R12 and R13 are independently selected from the group consisting of hydrogen, halogen, cyano, oxo, alkyl, cycloalkyl, phenyl, 5-7 membered ring heterocyclyl, - ORA, -C(O)RA, -OC(O)RA, -C(O)ORA, -NRARB, -N(RB)C(O) Rc, -C(O)NRARB, - C(O)NRAC(O)RB, -SRA, -S(O)RA, -S(O)2RA, -N(RA)S(O)2RB, and -S(O)2NRARB, wherein (a) the alkyl substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, -ORC, -C(O)OR0, and - C(O)NRCRD, and (b) the cycloalkyl, phenyl, and 5-7 membered ring heterocyclyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, -ORC, -C(O)OR0, and -C(O)NR0R0; wherein RA and RB 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 is optionally substituted with 1 , 2, or 3 halogen substituents, (b) when the alkyl comprises at least two carbon atoms, the alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, cycloalkyl, -0RE, -C(O)ORE, and-C(O)NRERF, and (c) the cycloalkyl, phenyl, and 5-7 membered ring heterocyclyl substituents are optionally substituted with one or more substituents independently selected from halogen, cyano, oxo, alkyl, -ORE, -C(O)ORE, and -C(O)NRERF; and R°, RD, RE and RFare independently selected from the group consisting of hydrogen and alkyl.
In another embodiment, R2 is pyrimidinyl, as described in Formula U-L:
Figure imgf000023_0001
(H-D wherein:
R9, R11 and R13 are independently selected from the group consisting of hydrogen, halogen, cyano, oxo, alkyl, cycloalkyl, phenyl, 5-7 membered ring heterocyclyl, -ORA, - C(O)RA, -OC(O)RA, -C(O)ORA, -NRARB, -N(RB)C(O) R°, -C(O)NRARB, -C(O)NRAC(O)RB, - SRA, -S(O)RA, -S(O)2RA, -N(RA)S(O)2RB, and -S(O)2NRARB, wherein (a) the alkyl substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, -OR0, -C(O)OR0, and -C(O)NR0R0, and (b) the cycloalkyl, phenyl, and 5-7 membered ring heterocyclyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, alkyl, -OR0, -C(O)OR0, and -C(O)NR0R0; wherein RA and RB 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 is optionally substituted with 1 , 2, or 3 halogen substituents, (b) when the alkyl comprises at least two carbon atoms, the alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, cycloalkyl, -0RE, -C(0)0RE, and-C(O)NRERF, and (c) the cycloalkyl, phenyl, and 5- 7 membered ring heterocyclyl substituents are optionally substituted with one or more substituents independently selected from halogen, cyano, oxo, alkyl, -0RE, -C(O)ORE, and - C(O)NRERF; and wherein R0, R°, RE and RFare independently selected from the group consisting of hydrogen and alkyl. Y6 SUBSTITUENT In one embodiment of Formula I1 Y6 represents a bond or is a selected from the group consisting of alkyl, cycloalkyl, and heterocycle, each optionally substituted as provided in Formula I.
In another embodiment of Formula I, Y6 represents a bond. In another embodiment of Formula I, Y6 is C-i to C6-alkyl that is optionally substituted as provided in Formula I.
In another embodiment of Formula I, Y6 is a 5 to 6 membered heterocycle with one or more heteroatoms independently selected from the group consisting of nitrogen and oxygen, said Y6 is optionally substituted as provided in Formula I. In another embodiment of Formula I, Y6 represents a bond or is selected from the group consisting of alkyl and hydroxyalkyl, optionally substituted as described in Formula I. In another embodiment of Formula I, Y6 represents a bond or is selected from the group consisting of methyl, ethyl, propyl, butyl, tert-butyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, dihydroxyethyl,
Figure imgf000024_0001
In another embodiment of Formula I, Y6 is selected from the group consisting of -CH2-, - CH2CH2-, -CH2CH2CH2-, -CH2(CH3)-, -CH2CH2(CH3)-, -CH2(CH3)CH2-, ■C(O)CH2CH2 -, - C(O)CH2-, -C(O)-, -C(O)CH(CH3)-, -CH2C(CHa)2CH-, -C(CH3) 2CH-, -CH2C(CH3)-, - C(O)C(CHg) 2-, -C(O)CH(CH3)CH-, -CH2CH2CH2CH2-,
Figure imgf000024_0002
In one embodiment of Formula I, R6A is selected from the group consisting of alkyl, alkylaminoalkyl, alkoxyalkyl, alkoxycarbonylalkyl, hydrogen, and hydroxycarbonylalkyl that are optionally substituted as set forth in Formula I.
In another embodiment of Formula I, R6A is selected from the group consisting of hydrogen, C1 to C4 alkyl, wherein said C1 to C4 alkyl is optionally substituted with one or more substituents selected from the group consisting of C1 to C4 alkoxy and hydroxy.
In another embodiment of Formula I, R6A is selected from the group consisting of hydrogen, methyl, ethyl, methylaminomethyl, ethylaminoethyl, diethylaminoethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, and hydroxycarbonylmethyl.
In another embodiment of Formula I, R6A is selected from the group consisting of hydrogen and ethyl. R6 SUBSTITUENT In one embodiment of Formula I, R6 is selected from the group consisting of hydrogen, halogen, oxo, hydroxy, amino, aminoalkyl, alkyl, alkynyl, alkoxy, alkylamino, and cycloalkyl, wherein (a) the alkyl, alkynyl, alkoxy, aminoalkyl and alkylamino substituents are optionally substituted with one or more substituents independently selected from the group consisting of -OR105, -C(O)R105, -C(O)OR105, -NR105R106, -N(R105)C(O)R106, -N(R105)C(O)COR106, - N(R105)C(O)OR106, -C(O)NR105R106, -NHC(O)NR105R106, -N(R105JS(O)2R106; and (b) the cycloalkyl substituent is optionally substituted with one or more -OR105, wherein R105 and R106 are independently selected from the group consisting of hydrogen and alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy. In one embodiment of Formula I, R6 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, tert-butyl, and cyclohexyl, wherein (a) the methyl R6 substituent is optionally substituted with one or more substituents independently selected from the group consisting of -OH, -OCH3, -OCH2CH3, -OCH2(CH3)CH31 -C(O)CH2CH2OH, -C(O)OH, - C(O)OCH2(CH3)(CH3)(CH3), -NH2, -NH(CH2CH3), -N(CH3)(CH3), -N(CH2CH3)CH2CH3, - N(H)CH2(CH3)CH3, -N(H)CH2CH2CH2OH, -N(H)CH2C(O)CH3, -NH(CH2CH2OH), - N(H)C(O)OCH3, -N(H)C(O)CH2(CH3)(CH3)(CH3), -NHC(O)OCH2(CH3)(CH3)(CH3), - NHC(O)COCH3, -NHC(O)NHCOCH3, -NCH3C(O)CH3, -NCH3(O)C(O)CH3, N(CH(O)CH3)C(O)CH3, -C(O)NH2, -C(O)NH(CH3), -C(O)NCH3(CH3), - C(O)NHCH2(CH3)(CH3)(CH3), -C(O)NHR106, -N(H)S(O)2CH3, -N(H)S(O)2CHF3, wherein R106 is independently selected from the group consisting of cyclopentyl and cyclohexyl, and
-.106 wherein the R cyclohexyl substituent is optionally substituted with hydroxy; and wherein (b) the cyclohexyl R6 substituent is optionally substituted with hydroxy.
In one embodiment of Formula I, R6 is selected from the group consisting of phenyl, phenyl-C(O)NH-, phenyl -C(O)-, 5 to 6 membered ring fully saturated heterocyclyl, 5 to 6 membered ring fully saturated heterocyclyl-C(O)-, and 5 to 6 membered ring fully saturated heterocyclyl-C(O)-NH, optionally substituted with one or more substituents independently selected from the group consisting of alkyl, -OR105, and -C(O)R105, wherein R105 is selected from the group consisting of hydrogen, methyl, and ethyl.
In one embodiment of Formula I, R6 is selected from the group consisting of phenyl- C(O)NH-,
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000026_0002
Figure imgf000026_0003
Figure imgf000026_0004
Figure imgf000026_0005
In one embodiment of Formula I, R6 is selected from the group consisting of alkylamino, alkylaminoalkyl, alkoxy, alkoxyalkyl, alkyl, alkylsulfonyl, amino, aryl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydroxy, said R6 is optionally substituted as provided in Formula I.
In another embodiment of Formula I, R6 is optionally substituted with one or more substituents independently selected from aryl, cyano, cycloalkyl, halogen, heterocyclyl, oxo, - C(O)RT, -C(O)ORT, -C(O)NRTRU, -ORT, -OC(O)RT, -NRTRU, -N(RT)CORU, -N(RT)S(O)2RU , -SRT, -S(O)RT, and -S(O)2R1, Rτ and Ru are independently selected from the group consisting of hydrogen and alkyl.
In another embodiment of Formula I, R6 is selected from the group consisting of methylamino, ethylamino, propylamino, /so-propylamino, butylamino, fert-butylamino,
Figure imgf000027_0001
In another embodiment of Formula I, R is selected from the group consisting of aminocarbonyl,
Figure imgf000027_0002
, said R6 is optionally substituted as provided in Formula I
In another embodiment of Formula I, R6 is selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butyloxy, and ferf-butyloxy.
I Inn aannootthheerr eemmbbooddiimmeenntt ooff I Formula I, R6 is selected from the group consisting of tert- butylcarboxy and methoxyethyl. In another embodiment of Formula I, R6 is selected from the group consisting of methylsulfonyl and ethylsulfonyl.
In another embodiment of Formula I, R6 is a 5 to 7 membered ring aryl that is optionally substituted as provided in Formula I.
In another embodiment of Formula I, R6 is selected from the group consisting of
Figure imgf000027_0003
In another embodiment of Formula I1 R6 is -NH2.
In another embodiment of Formula I, R6 is selected from the group consisting of cyclopropanyl, cyclobutanyl, cyclopentanyl, and cyclohexanyl, said R6 is optionally substituted as provided in Formula I. In another embodiment of Formula I, R6 is selected from the group consisting of fluoromethyl, difluoromethyl, and trifluoromethyl.
In another embodiment of Formula I, R6 is a 5 to 7 ring membered heterocycle that is optionally substituted as provided in Formula I.
In another embodiment of Formula I, R6 is a 5 to 7 ring membered heteroaryl that is optionally substituted as provided in Formula I.
In another embodiment of Formula I, R6 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 said R6 substituent is optionally substituted as provided in Formula I. In another embodiment of Formula I, R6 is selected from the group consisting of morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, and pyrrolidinyl, said R6 is optionally substituted as provided in Formula I.
In another embodiment of Formula I, R6 is selected from the group consisting of pyrazinyl and pyridinyl, said R6 is optionally substituted as provided in Formula I.
In another embodiment of Formula I, R6 is selected from the group consisting of
Figure imgf000028_0001
In another embodiment of Formula I, R6 is selected from the group consisting of
Figure imgf000028_0002
N S ^^ N^
1^ , and 1^ .
In another embodiment of Formula I, R6 is selected from the group consisting of
Figure imgf000028_0003
In another embodiment of Formula I R6 is selected from the group consisting of
Figure imgf000029_0001
In another embodiment of Formula I, R6 is selected from the group consisting of
Figure imgf000029_0002
In another embodiment of Formula I, R6 is selected from the group consisting of
Figure imgf000029_0003
In another embodiment of Formula I, R6 is selected from the group consisting of
Figure imgf000029_0004
In another embodiment of Formula I, R6 is -OH.
R8 SUBSTITUENT
In one embodiment of Formula I, R8 is C1 to CiO-alkyl, wherein said R8 Ci to C10-alkyl is optionally substituted as provided in Formula I. In another embodiment, R8 is C1 to C6-alkyl, wherein said R8 C1 to C6-alkyl is optionally substituted as provided in Formula I. In another embodiment, R8 is C1 to C4-alkyl, wherein said R8 C1 to C4-alkyl is optionally substituted as provided in Formula I.
In another embodiment of Formula I, R8 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, thiolalkyl, alkylthiol, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy.
In another embodiment of Formula I, R8 alkoxyalkyl optionally substituted as described in Formula I.
In another embodiment of Formula I, R8 is selected from the group consisting of dimethylbutyl, ethoxyethyl, ethoxypropyl, trifluoroethoxyethyl, isopropoxyethyl, and propoxyethyl.
MULTIPLE SUBSTITUENTS In one embodiment of Formula I,
R2 is selected from the group consisting of phenyl and pyridinyl, optionally substituted as described in claim 1 ; Y6 represents a bond or is selected from the group consisting of methyl, ethyl, and propyl;
R6A is selected from the group consisting of hydrogen, C1 to C4 alkyl, wherein said C1 to C4 alkyl is optionally substituted with one or more substituents selected from the group consisting of C1 to C4 alkoxy and hydroxy;
R6 is as described in Formula I, and
R8 is selected from the group consisting of ethoxyethyl and propoxyethyl. In one embodiment of Formula I,
R2 is selected from the group consisting of
Figure imgf000030_0001
and ; R9, R10, R11, R12 and R13 are independently selected from the group consisting of hydrogen, fluoro, methyl, trifluorom ethyl, and methoxy;
Y6 represents a bond or is selected from the group consisting of methyl, ethyl, and propyl;
R6A is as described in Formula I; R8 is selected from the group consisting of propoxyethyl and ethoxyethyl; and
R6 is selected from the group consisting of is selected from the group consisting of phenyl, phenyl- C(O)NH-, phenyl -C(O)-, 5 to 6 membered ring fully saturated heterocyclyl, 5 to 6 membered ring fully saturated heterocyclyl-C(O)-, and 5 to 6 membered ring fully saturated heterocyciyl-C(O)-NH, optionally substituted with one or more substituents independently selected from the group consisting of alkyl, -OR105, and -C(O)R105, wherein R105 is selected from the group consisting of hydrogen, methyl, and ethyl. In one embodiment of Formula I,
R2 is selected from the group consisting of phenyl and pyridinyl, optionally substituted as described in claim 1 ; R6A is hydrogen;
Y6 represents a bond or is selected from the group consisting of methyl, ethyl, propyl, butyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, dihydroxyethyl,
Figure imgf000030_0002
R6 is as described in Formula I, and R8 is selected from the group consisting of ethoxyethyl and propoxyethyl.
In one embodiment of Formula I, R is selected from the group consisting of
Figure imgf000031_0001
and ; R9, R10, R11, R12 and R13 are independently selected from the group consisting of hydrogen, fluoro, methyl, trifluoromethyl, and methoxy; < R6A is hydrogen; Y6 represents a bond;
R8 is selected from the group consisting of ethoxyethyl and propoxyethyl; and R6 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, and cyclohexyl, optionally substituted with one or more substituents independently selected from the group consisting of -OR105, -C(O)R105, -C(O)OR105, -NR105R106, -N(R105)C(O)R106, - N(R105)C(O)OR106, -C(O)NR105R106, -NHC(O)NR105R106, -N(R105)S(O)2R106, wherein R105 and R106 are independently selected from the group consisting of hydrogen, methyl, ethyl, butyl, cyclopentyl, cyclohexyl, optionally substituted with one or more substituent selected from the group consisting of halogen, oxo, hydroxy, and methyl.
In one embodiment of Formula I,
Figure imgf000031_0002
R2 is ;
R11 is selected from the group consisting of hydrogen, chloro, fluoro, methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluoromethyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, amino, methylamino, dimethylamino, ethylamino, and diethylamino; R6A is hydrogen;
Y6 is selected from the group consisting of methyl and ethyl;
R8 is selected from the group consisting of ethoxyethyl and propoxyethyl; and R6 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, and cyclohexyl, optionally substituted with one or more substituents independently selected from the group consisting of -OR105, -C(O)R105, -C(O)OR105, -NR105R106, -N(R105)C(O)R106, -
N(R105)C(O)OR106, -C(O)NR105R106, -NHC(O)NR105R106, -N(R105)S(O)2R106, wherein R105 and R106 are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, cyclopentyl, cyclohexyl, optionally substituted with one or more substituent selected from the group consisting of halogen, oxo, hydroxy, and methyl. In one embodiment of Formula I, Rzis methoxypyridinyl. In another embodiment, R2 is
Figure imgf000031_0003
In another embodiment of Formula I, R2 is methoxypyridinyl and Y6 is -C(O)CH2-. In another embodiment of Formula I, R2 is methoxypyridinyl and R8 is selected from the group consisting of ethoxyethyl, isopropoxyethyl and propoxyethyl.
In another embodiment of Formula I, R2 is methoxypyridinyl and R6A is hydrogen. In another embodiment, the compound has a formula:
Figure imgf000032_0001
wherein R6 is as defined in Formula I.
In another embodiment of Formula I-X, R6 is selected from the group consisting of alkoxy, alkylamino, amino, heterocyclyl, and hydroxy. In another embodiment of Formula I-X, R6 is selected from the group consisting of methoxy, ethoxy, isopropoxy, propoxy, butoxy, ferf-butoxy, methylamino, ethylamino, dimethylamino, diethylamino, morpholinyl, and hydroxy.
C. Isomers
When an asymmetric center is present in a compound of Formula (I) through (IV), the compound will exist in the form of enantiomers. In one embodiment, the present invention comprises optical isomers and mixtures, including racemic mixtures of the compounds of Formula (I) through (IV). In another embodiment, the present invention comprises diastereomeric forms (individual diastereomers and mixtures thereof) of compounds of Formula (I) through (IV). When a compound of Formula (I) through (IV) contains an alkenyl group or moiety, geometric isomers may arise.
D. Tautomeric Forms
The present invention comprises the tautomeric forms of compounds of Formula (I) through (IV). For instance, a tautomeric form of the following compound:
Figure imgf000032_0002
may be represented by:
Figure imgf000032_0003
The various ratios of the tautomers in solid and liquid form is dependent on the various substituents on the molecule as well as the particular crystallization technique used to isolate a 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 temperature and humidity, 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. The term "pharmaceutically acceptable salt" refers to a salt prepared by combining a compound of Formula (I) - (I-CC) with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption. Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound. For use in medicine, the salts of the compounds of this 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.
Specific examples of 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, β-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate, and undecanoate. In another embodiment, examples of suitable addition salts formed include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsyate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihidrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.
In another embodiment, representative salts include benzenesulfonate, hydrobromide and hydrochloride. Furthermore, where the compounds of the invention carry an acidic moiety, 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.
In another embodiment, 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. Basic nitrogen-containing groups may be quatemized with agents such as lower alkyl (C1 to C6) 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. In one embodiment, salts of the compounds of this invention include hydrochloric acid
(HCI) salts, trifluoroacetate (CF3COOH or 'TFA") salts, mesylate salts, and tosylate salts.
Pharmaceutically acceptable salts of compounds of Formula (I) to (IV) may be prepared by one or more of three methods:
(i) by reacting the compound of any one of Formula (I)- (IV) with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of any one of Formula (I)- (IV) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; and (iii) by converting one salt of the a compound of Formula (I) through (IV) to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. All three reactions are typically carried out in solution. 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. F. Methods of Treatment The present invention further comprises methods for treating a condition in a subject having or susceptible to having such a condition, by administering to the subject a therapeutically-effective amount of one or more compounds of Formula (I) through (IV) as described above. In one embodiment, the treatment is preventative treatment.
In another embodiment, the treatment is palliative treatment.
In another embodiment, 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. Conditions
The conditions that can be treated in accordance with the present invention are PDE-5 mediated conditions. Such conditions include cardiovascular diseases, metabolic diseases, central nervous system diseases, pulmonary diseases, sexual dysfunction, and renal dysfunction.
In one embodiment, the condition is a cardiovascular disease, particularly a cardiovascular disease selected from the group consisting of hypertension (such as essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, hypertension associated with diabetes, hypertension associated with atherosclerosis, and renovascular hypertension) ; complications associated with hypertension (such as vascular organ damage, congestive heart failure, angina, stroke, glaucoma and impaired renal function); valvular insufficiency; stable, unstable and variant (Prinzmetal) angina; peripheral vascular disease; myocardial infarct; stroke; thromboembolic disease; restenosis; arteriosclerosis; atherosclerosis; pulmonary arterial hypertension; angiostenosis after bypass; angioplasty (such as percutaneous transluminal angioplasty, or percutaneous transluminal coronary angioplasty); hyperlipidemia; hypoxic vasoconstriction; vasculitis, such as Kawasaki's syndrome; heart failure (such as congestive, decompensated, systolic, diastolic, left ventricular heart failure, right ventricular heart failure, left ventricular hypertrophy); Raynaud's disease; preeclampsia; pregnancy-induced high blood pressure; cardiomyopathy; and arterial occlusive disorders.
In another embodiment, the condition is hypertension. In another embodiment, the condition is pulmonary arterial hypertension. In another embodiment, the condition is heart failure. In another embodiment, the condition is diastolic heart failure. In another embodiment, the condition is systolic heart failure. In another embodiment, the condition is angina. In another embodiment, the condition is thrombosis. In another embodiment, the condition is stroke.
In another embodiment, the condition is a metabolic disease, particularly a metabolic disease selected from the group consisting of Syndrome X; insulin resistance or impaired glucose tolerance; diabetes (such as type I and type Il diabetes); syndromes of insulin resistance (such as insulin receptor disorders, Rabson-Mendenhall syndrome, leprechaunism, Kobberiing-Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Cushing syndrome, acromegaly, pheochomocytoma, glucagonoma, primary aldosteronism, somatostatinoma, Lipoatrophic diabetes, β-cell toxin induced diabetes, Grave's disease, Hashimoto's thyroiditis and idiopathic Addison's disease); diabetic complications (such as diabetic gangrene, diabetic arthropathy, diabetic nephropathy, diabetic glomerulosclerosis, diabetic deramatopathy, diabetic neuropathy, peripheral diabetic neuropathy, diabetic cataract, and diabetic retinopathy); hyperglycemia; and obesity.
In another embodiment, the condition is insulin resistance. In another embodiment, the condition is nephropathy.
In another embodiment, the condition is a disease of the central nervous system, particularly a disease of the central nervous system selected from the group consisting of vascular dementia; craniocerebral trauma; cerebral infarcts; dementia; concentration disorders; Alzheimer's disease; Parkinson's disease; amyolateral sclerosis (ALS); Huntington's disease; multiple sclerosis; Creutzfeld-Jacob; anxiety; depression; sleep disorders; and migraine. In one embodiment, the condition is Alzheimer's disease. In another embodiment, the condition is Parkinson's disease. In one embodiment, the condition is ALS. In another embodiment, the condition is a concentration disorder.
In one embodiment, the condition is a pulmonary disease, particularly a pulmonary disease selected from the group consiting of asthma; acute respiratory distress; cystic fibrosis; chronic obstructive pulmonary disease (COPD); bronchitis; and chronic reversible pulmonary obstruction.
In one embodiment, the condition is sexual dysfunction, particularly sexual dysfunction selected from the group consiting of impotence (organic or psychic); male erectile dysfunction; clitoral dysfunction; sexual dysfunction after spinal cord injury; female sexual arousal disorder; female sexual orgasmic dysfunction; female sexual pain disorder; and female hypoactive sexual desire disorder. In another embodiment, the condition is erectile dysfunction.
In another embodiment, the condition is renal dysfunction, particularly a renal dysfunction selected from the group consisting of acute or chronic renal failure; nephropathy (such as diabetic nephropathy); glomerulopathy; and nephritis.
In another embodiment, the condition is pain. In another embodiment, the condition is acute pain. Examples of acute pain include acute pain associated with injury or surgery. In another embodiment, the condition is chronic pain. Examples of chronic pain include 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 such as bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (including postchemotherapy syndrome, chronic postsurgical pain syndrome, post radiation syndrome, pain associated with immunotherapy, or pain associated with hormonal therapy), arthritic pain (including osteoarthritis and rheumatoid arthritis pain), chronic post-surgical pain, post herpetic neuralgia, trigeminal neuralgia, HIV neuropathy, phantom 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. In another embodiment, the condition is nociceptive pain (including pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain). In another embodiment, the condition is pain associated with inflammation (including arthritic pain (such as osteoarthritis and rheumatoid disease pain), ankylosing spondylitis, visceral pain (including inflammatory bowel disease, functional bowei disorder, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, functional abdominal pain syndrome, Crohn's disease, ileitis, ulcerative colitis, dysmenorrhea!, cystitis, pancreatitis and pelvic pain). In another embodiment, the condition is pain resulting from musculoskeletal disorders (including myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenosis, polymyositis and pyomyositis). In another embodiment, 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). In another embodiment, the condition is selected from the group consisting of head pain (including migraine such as migraine with aura and migraine without aura), cluster headache, tension- type headache mixed headache and headache associated with vascular disorders; orofacial pain, including dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain).
In another embodiment, the condition is a urologic condition selected from the group consisting of bladder outlet obstruction; incontinence and benign prostatic hyperplasia. In another embodiment, the condition is an ophthalmic condition selected from retinal disease; macular degeneration and glaucoma.
In another embodiment, the condition is selected from the group consisting of tubulointerstitial disorders; anal fissure; baldness; cancerous cachexia; cerebral apoplexy; disorders of gut motility; enteromotility disorders; dysmenorrhoea (primary and secondary); glaucoma; macular degeneration; antiplatelet; haemorrhoids; incontinence; irritable bowel syndrome (IBS); tumor metastasis; multiple sclerosis; neoplasia; nitrate intolerance; nutcracker oesophagus; osteoporosis; infertility; premature labor; psoriasis; retinal disease; skin necrosis; and urticaria. In another embodiment, the condition is osteoporosis. In another embodiment, the condition is associated with endothelial dysfunction, particularly 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 methods and compositions of the present invention are suitable for use with, for example, mammalian subjects such as humans, other primates (e.g., monkeys, chimpanzees), companion animals (e.g., dogs, cats, horses), farm animals (e.g., goats, sheep, pigs, cattle), laboratory animals (e.g., mice, rats), and wild and zoo animals (e.g., wolves, bears, deer). In another embodiment, the subject is a human.
Hypothesized Mechanism Without being held to a particular theory, it is hypothesized that compounds of Formula
(I) through (IV) 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. A condition in which, for instance, insufficient cGMP is a major component, and whose production or action is modulated in response to PDE-5, would therefore be considered a_disorder mediated by cGMP. Thus, compounds of Formula (I) through (IV) would be therapeutically useful in methods for treating hypertension by administering to a hypertensive subject a therapeutically-effective amount of a compound of Forumulae (I) through (IV). Other examples of circulatory-related disorders which can be treated by compounds of the invention include congestive heart failure, renal failure, angina, and glaucoma. Co-administration
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.
For instance, in one embodiment, one or more compounds of Formulae (I) through (IV) may be administered with aspirin.
In one embodiment, one or more compounds of Formulae (I) through (IV) may be coadministered with one or more angiotensin converting enzyme (ACE) inhibitors. Examples of the one or more ACE inhibitors for use with the one or morecompound of Formulae (I) - (IV) include quinapril (such as ACCUPRIL™), perindopril (such as ACEON™), captopril (such as CAPOTEN™), enalapril (such as VASOTEC™), ENALAPRILAT™, ramipril (such as
ALT ACE™), cilazapril, delapril, fosenopril (such as MONOPRIL™), zofenopril, indolapril, benazepril (such as LOTENSIN™), lisinopril (such as PRINIVIL™ or ZESTRIL™), spirapril, trandolapril (such as MAVIK™), perindep, pentopril, moexipril (such as UNIVASC™) or pivopril. In another embodiment, one or more compounds of Formulae (I) through (IV) may be coadministered with one or more alpha blockers such as dozazosin (such as CARDURA™), phenoxybenzamine (such as DIBENZYLINE™), or terazosin (such as HYTRIN™), CDRI- 93/478 and CR-2991. In another embodiment, one or more compounds of Formulae (I) through (IV) may be coadministered with one or more alpha-beta blockers such as labetalol (such as NORMODYNE™ or TRANDATE™).
In another embodiment, one or more compounds of Formulae (I) through (IV) may be coadministered with one or more angiotensin Il receptor blockers such as candesartan (such as ATACAND™), eprosartan (such as TEVETEN™), irbesartan (such as AVEPRO™), losartan (such as COZAAR™), olmesartan, olmesartan medoxomil (such as BENICAR™), tasosartan, telmisartan (such as MICARDIS™), valsartan (such as DIOVAN™) or zolasartan, FI-6828K, RNH-6270, UR-7198, Way-126227, KRH-594, TAK-536, BRA-657, and TA-606.
In another embodiment, one or more compounds of Formulae (I) through (IV) may be co- administered with one or more alpha-2-delta ligands such as gabapentin, pregabalin (such as LYRICA™), [(1 R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1- aminomethyl-cyclohexylmethyl)-4H-[1 ,2,4]oxadiazol-5-one, C-[1 -(1 H-tetrazol-5-ylmethyl)- cycloheptyl]-methylamine, (3S,4S)-(1 -aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (1 α,3α,5α)-(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5- methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl- nonanoic acid and (3S,5R)-3-amino-5-methyl-octanoic acid), (2S,4S)-4-(3- Chlorophenoxy)praline, or (2S,4S)-4-(3-Fluorobenzyl)praline.
In another embodiment, one or more compounds of Formulae (I) through (IV) may be coadministered with one or more beta blockers such as timolol (such as BLOCARDEN™), carteolol (such as CARTROL™), carvedilol (such as COREG™), nadolol (such as
CORGARD™), propranolol (such as INNOPRAN XL™), betaxolol (such as KERLONE™), penbutolol (such as LEVATOL™), metoprolol (such as LOPRESSOR™ or TOPROL-XL™), atenolol (such as TENORMIN™), or pindolol (such as VISKEN™), and bisoprolol.
In another embodiment, one or more compounds of Formulae (I) through (IV) may be co- administered with one or more calcium channel blockers such as nifedipine {such as
ADALAT™, ADALAT CC™ or PROCARDIA™), verapamil (such as CALAN™, COVERA- HS™, ISOPTIN SR™ or VERELAN™), diltiazem (such as CARDIZEM™ CARDIZEM CD™, CARDIZEM LA™, CARDIZEM SR™, DILACOR™, TIAMATE™ or TIAZAC™), isradipine (such as DYNACIRC™ or DYNACIRC CR™), amlodipine (such as NORVASC™), felodipine (such as PLENDIL™), nisoldipine (such as SULAR™), or bepridil (such as VASCOR™), vatanidipine, clevidipine, lercanidipine, dilitiazem, and NNC-55-0396.
In another embodiment, one or more compounds Formulae (I) through (IV) may be coadministered with one or more central antiadrenergics such as methyldopa (such as ALDOMET™), clonidine (such as CATAPRES™ or CATAPRES-TTS™), guanfacine (such as TENEX™), or guanabenz (such as WYTENSIN™).
In another embodiment, one or more compounds of Formulae (I) through (IV) may be coadministered with one or more diruretics such as hydroclorothiazide (such as M1CROZIDE™ or ORETIC™), hydroflumethiazide (such as SALURON™), bemetanide (such as BUMEX™), torsemide (such as DEMADEX™), metolazone (such as ZAROXOLYN™), chlorothiazide (such as DIURIL™, ES1DRIX™ or HYDRODIURIL™), triamterene (such as DYRENIUM™), ethacrynic acid (such as EDECRIN™), chlorthalidone (such as HYGROTON™), furosemide (such as LASIX™), indapamide (such as LOZOL™), or amiloride (such as M1DAMOR™ or MODURETIC™).
In another embodiment, one or more compounds of Formulae (1) through (IV) may be coadministered with one or more glycosides / inotropic agents such as digoxin (such as LANOXIN™).
In another embodiment, one or more compounds of Formulae (I) through (IV) 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 (IV) 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. In another embodiment, one or more compounds of Formulae (I) through (IV) may be coadministered with one or more human B-type natriuretic peptides <hBNP) such as nesiritide (such as NATRECOR™).
In another embodiment, one or more compounds of Formulae (I) through (IV) may be coadministered with one or more renin inhibitors such as Aliskiren (SPP 100), SPP-500/600 and YS-004-39.
In another embodiment, one or more compounds of Formulae (I) through (IV) may be coadministered with one or more soluble guanylate cyclase activator ("sGCa"). An example of a suitable soluble guanylate cyclase activator is BAY-41-8543. in another embodiment, one or more compounds of Formulae (I) through (IV) may be co- administered with one or more neutral endopeptidase (NEP) inhibitors, such as, for example, omapatrilat, fasidotril, mixanpril, sampatrilat, Z13752A ,
Figure imgf000041_0001
Figure imgf000041_0002
In another embodiment, one or more compounds of Formulae (I) through (IV) may be coadministered with one or more aldosterone receptor antagonists such as eplerenone (such as INSPRA™) or spironolactone (such as ALDACTONE™).
In another embodiment, one or more compounds of Formulae (I) through (IV) may be coadministered with one or more bradykinin agonists.
In another embodiment, one or more compounds of Formulae (I) through (IV) may be coadministered with one or more endothelian antagonists. Examples of suitable endothelin antagonists include ambrisentan, darusentan, J-104132, SPP-301 , TBC-3711 , YM-62899, YM-91746, and BMS-193884.
In another embodiment, one or more compounds of Formulae (I) through (IV) may be coadministered with niacin or one or more nicotinic acid derivatives, such as NIACOR™, NIASPAN™, NICOLAR™, or SLO-NIACIN™. In another embodiment, one or more compounds of Formulae (I) through (IV) may be coadministered with one or more fibric acid derivatives, such as clofibrate (such as ATROMID- S™), gemfibrozil (such as LOPID™), or fenofibrate (such as TRICOR™).
In another embodiment, one or more compounds of Formulae (I) through {IV) may be coadministered with one or more cholesteryl ester transport protein inhibitors (CETPi), such as torcetrapib.
In another embodiment, one or more compounds of Formulae (I) through (IV) may be coadministered with one or more bile acid sequestants, such as colestipol (such as COLESTID™), cholestyramine (such as LOCHOLEST™, PREVALITE™, QUESTRAN™, or QUESTRAN LIGHT™), colesevelam (such as WELCHOL™). In another embodiment, one or more compounds of Formulae (I) through (IV) may be coadministered with an apical sodium-dependent bile acid cotransporter inhibitors, such as SD- 5613, AZD7806 or 264W94. In another embodiment, one or more compounds of Formulae (I) through (IV) may be coadministered with one or more cholesterol absorbtion inhibitors, such as ezetimibe (such as ZETIA™).
In another embodiment, one or more compounds of Formulae (I) through (IV) may be co- administered with one or more 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) such as fluvastatin (such as LESCOL™), atorvastatin (such as LIPITOR™), lovastatin (such as ALTOCOR™ or MEVACOR™), pravastatin (such as PRAVACHOL™), rosuvastatin (such as CRESTOR™), or simvastatin (such as ZOCOR™).
In another embodiment, one or more compounds of Formulae (I) through (IV) may be co- administered with one or more alpha glucosidase inhibitors, such as miglitol (such as GLYSET™), or acarbose (such as PRECOSE™).
In another embodiment, one or more compounds of Formulae (I) through (IV) may be coadministered with one or more biguanides, such as roseiglitazone (such as AVANDAMET™), or metformin (such as GLUCOPHAGE™ or GLUCOPHAGE XR™). In another embodiment, one or more compounds of Formulae (I) through (IV) may be coadministered with one or more insulins, such as HUMALOG™, HUMALOG 50/50™, HUMALOG 75/25™, HUMULIN 50/50™, HUMALIN 75/25™, HUMALIN L™, HUMALIN N™, HUMALIN R™, HUMALIN R U-500™, HUMALIN U™, ILETIN Il LENTE™, ILETIN Il NPH™, ILETIN Il REGULAR™, LANTUS™, NOVOLIN 70/30™, NOVILIN N™, NOVILIN R™, NOVOLOG™, or VELOSULIN BR™, and EXUBERA™.
In another embodiment, one or more compounds of Formulae (I) through (IV) may be coadministered with one or more meglitnides, such as repaglinide (such as PRANDIN™) or nateglinide (such as STARLIX™).
In another embodiment, one or more compounds of Formulae (I) through (IV) may be co- administered with one or more sulfonylureas, such as glimepiride (such as AMARYL™), glyburide (such as DIABETA™, GLYNASE PRESTAB™ or M1CRONASE™), or glipizide (such as GLUCOTROL™, or GLUCOTROL XL™).
In another embodiment, one or more compounds of Formulae (I) through (IV) may be coadministered with one or more thiazolidinediones, such as pioglitazone (such as ACTOS™) or rosiglitazone (such as AVANDIA™).
Administration and Dosing
Typically, a compound described in this specification is administered in an amount effective to inhibit PDE-5. The compounds of the present invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. 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. In one embodiment, the total daily dose of a compound of Formula (I) through (IV) (administered in single or divided doses) is typically from about 0. 01 to about 100 mg/kg. In another embodiment, total daily dose of the compound of Formula (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 Formula (I) through (IV) per kg body weight). In one embodiment, dosing is from 0.01 to 10 mg/kg/day. In another embodiment, dosing is from 0.1 to 1.0 mg/kg/day. Dosage unit compositions may contain such amounts or submultiples thereof to make up the daily dose. In many instances, the administration of the 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.
For oral administration, 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 1 mg to about 100 mg of active ingredient. Intravenously, doses may range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.
The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.
These dosages are based on an average human subject having a weight of about 60kg to about 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
For the avoidance of doubt, references herein to "treatment" include references to curative, palliative, preventative, and prophylactic treatment. G. Use in the Preparation of a Medicament
In one embodiment, the present invention comprises methods for the preparation of a pharmaceutical composition (or "medicament) comprising the compounds of Formula (I) through (IV) in combination with one or more pharmaceutically-acceptable carriers and/or other active ingredients for use in treating a cGMP-mediated condition.
In another embodiment, the invention comprises the use of one or more compounds of Formula (I) through (IV) in the preparation of a medicament for the treatment of hypertension.
In another embodiment, the invention comprises the use of one or more compounds of Formula (I) through (IV) in the preparation of a medicament for the treatment of angina. In another embodiment, the invention comprises the use of one or more compounds of Formula (I) through (IV) in the preparation of a medicament for the treatment of congestive heart failure.
In another embodiment, the invention comprises the use of one or more compounds of Formula (I) through (IV) 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 Formula (I) through (IV) in the preparation of a medicament for the treatment of erectile dysfunction.
H. Pharmaceutical Compositions For the treatment of the conditions referred to above, the compounds of Formula (I) through (IV) can be administered as compound perse. Alternatively, pharmaceutically acceptable salts are suitable for medical applications because of their greater aqueous solubility relative to the parent compound.
In another embodiment, the present invention comprises pharmaceutical compositions. Such pharmaceutical compositions comprise compounds of Formula (I) through (IV) presented with a pharmaceutically-acceptable carrier. The carrier can be a solid, a liquid, or both, and may be formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compounds.
Compounds of Formula (I) through (IV) 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, for example, 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. In another embodiment, the oral administration may be in a powder or granule form. In another embodiment, the oral dose form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of Formula (I) through <IV) are ordinarily combined with one or more adjuvants. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.
In another embodiment, 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.
In another embodiment, 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) may be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents.
In another embodiment, the present invention comprises a topical dose form. "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. When the compounds of this invention are administered by a transdermal device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. 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. For intranasal administration or administration by inhalation, 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.
In another embodiment, the present invention comprises a rectal dose form. Such 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, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, et al., Eds., Pharmaceutical Dosage Forms. Marcel Decker, New York, N.Y., 1980; and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999. I. Kits
The present invention further comprises kits that are suitable for use in performing the methods of treatment or prevention described above. In one embodiment, 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.
In another embodiment, the kit of the present invention comprises one or more compounds of Formula (I) through (IV) and an ACE inhibitor.
In another embodiment, the kit of the present invention comprises one or more compounds of Formula (I) through (IV) and an angiotensin Il receptor antagonist. In another embodiment, the kit of the present invention comprises one or more compounds of Formula (I) through (IV) and an aldosterone receptor antagonist.
In another embodiment, the kit of the present invention comprises one or more compounds of Formula (I) through (IV) and a NO donor. J. Compound Preparations Schemes
The starting materials used herein are commercially available or may prepared by routine methods (such as those methods disclosed in reference books such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wiley- lnterscience)).
The compounds of the present invention may be prepared using the methods illustrated in the general synthetic schemes and experimental procedures detailed below. The general synthetic schemes are presented for purposes of illustration and are not intended to be limiting. The substituted pyrido[2,3-b]pyrazin-2(1 H)-ones VII are prepared through two routes which diverge from a common intermediate as described in Scheme 1 and Scheme 2. The first intermediate preparation commences with the reaction of commercially available 5- bromopyridine-2,3-diamine I with activated esters such as an acid chloride or acid derivatives prepared under peptide coupling conditions utilizing peptide coupling reagents such as 1-[3- (dimethyl-aminopropy]-3-ethylcarbodiimide methiodide , 1.S-dicyclohexylcarbodiimide, or 0-(7- azabenzotriazol-1-yl)-1 ,1,3,3-tetramethyluromium hexafluorophosphate in the presence of an organic base such as triethylamine, N, Λ/-diisopropylethylamine, or 4-methylmorpholine in a solvent such as dichloromethane, tetrahydrofuran, Λ/,Λ/-dimethylformamide, or dioxane to provide the desired N-(2-amino-5-bromopyridin-3-yl)alkylsubstitutedamide II. Reduction of the amide using hydride reagents such as lithium aluminum hydride, borane, or diisobutylaluminum hydride in ethereal solvents such as tetrahydrofuran or diethyl ether provides the corresponding 5-bromo-N~3~alkylsubstituted-pyridine-2,3-diamine III. Conversion of the diamine III to the cyclic dione IV could be achieved by addition of ethyl chlorooxoacetate or oxalyl chloride to diamine III in an organic solvent such as toluene, dichloromethane, or tetrahydrofuran with organic bases such as triethylamine, 4- methylmorpholine, or Λ/,Λ/-diisopropylethylamine present at O0C followed by warming to room temp or the reflux temperature of the solvent. The 7-bromo-1-alkylsubstituted-1 ,4- dihydropyrido-[2,3-b]pyrazine-2,3-dione IV is the common intermediate for the preparation of the substituted pyrido[2,3-b]pyrazin-3(4H)-ones VII. Scheme 1
Figure imgf000047_0001
1 Il
LiAIH4 THF
Figure imgf000047_0002
IV
III
An alternate route to 5-bromo-N~3~alkylsubstitutedpyridine-2,3-diamine 111 is illustrated in Scheme 2. Under reductive amination conditions, commercially available 5-bromopyridine- 2,3-diamine I is condensed with suitable aldehydes in solvents such as anhydrous tetrahydrofuran at the reflux temperature of the solvent in the presence of a water scavenger such as 4A molecular sieves or a Dean-Stark trap to provide the intermediate imine. Subsequent treatment of the desired iminie with reducing agents such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride in protic solvents such as ethanol at -780C to room temperature affords the 5-bromo- N~3~alkylsubstitutedpyridine-2,3-diamine III. Conversion of the diamine III to the cyclic dione IV could be achieved by addition of ethyl chlorooxoacetate or oxalyl chloride to a solution of diamine III in an organic solvent such as toluene, dichloromethane, or tetrahydrofuran with organic bases such as triethylamine, 4-methylmorpholine, or Λ/,Λ/-diisopropylethylamine present at O0C followed by warming to room temp or the reflux temperature of the solvent.
Scheme 2
Figure imgf000047_0003
I III IV
One route to the substituted pyrido[2,3-b]pyrazin-2(1H)-ones VII as described in Scheme 3 starts with the preparation of the 7-bromo-3-chloro-1-alkylsubstituted-pyrido[2,3-b]pyrazin- 2(1H)-one V by treatment of the dihydropyrido[2,3-b]pyrazine-2,3- dione IV with agents for conversion of the amide to the chloropyrazine. One such preparation treats dione IV with phosphorous oxychloride in the presence of phase transfer catalysts such as tetraethylammonium chloride under reflux in solvents such as propionitrile or acetonitrile. An alternate procedure prepares the chloroimidate V by dissolving dione IV in solvents such as dichloromethane, tetrahydrofuran, or dioxane and treating with oxalyl chloride in the presence of a catalytic amount of dimethylformamide. The desired pyrazinone Vl is prepared by displacement of the 3-chloro in 7-bromo-3-chloro-1-alkylsubstituted-pyrido[2,3-b]pyrazin- 2(1H)-one V with suitable primary or secondary amines in solvents such dichloromethane, tetrahydrofuran, or dioxane with organic bases such as triethylamine, 4-methylmorpholine, or Λ/,Λ/-diisopropylethylamine. Palladium catalyzed Suzuki coupling between the bromide of pyrazinone Vl and substituted phenyl or heterocylic boronic acids in solvents such as aqueous ethylene glycol dimethyl ether, aqueous ethers, or aqueous toluene utilizing typical palladium coupling reagents such as palladium(ll) acetate or tetrakis(triphenylphosphine)palladium with a base such as sodium carbonate or potassium carbonate affords the desired substituted pyrido[2,3-b]pyrazin-2(1 H)-ones VII.
Scheme 3
Figure imgf000048_0001
IV
R1NH2
Figure imgf000048_0002
X = Halogen, alkyl, OR, OH, etc.
A second route as described in Scheme 4 to substituted pyrido[2,3-b]pyrazin-2(1 H)-ones VlI commences with a palladium catalyzed Suzuki coupling between the bromide of the pyrazinedione IV and substituted phenyl or heterocylic boronic acids in solvents such as aqueous ethylene glycol dimethyl ether, aqueous ethers, or aqueous toluene utilizing typical palladium coupling reagents such as palladium(ll) acetate or tetrakis(triphenylphosphine)palladium with a base such as sodium carbonate or potassium carbonate. Conversion of the amide to the chloropyrazine IX utilizes chlorination reagents such as phosphorous oxychloride in the presence of tetraethylammonium chloride or oxalyl chloride in solvents such as acetonitrile, propionitrile, dichloromethane, or toluene at room temperature to reflux. Displacement of the chloro group in the chloroimidate IX with suitable primary or secondary amines in solvents such dichloromethane, tetrahydrofuran, or dioxane with organic bases such as triethylamine, 4-methylmorpholine, or Λ/,Λ/-diisopropylethylamine gives the desired substituted pyrido[2,3-b]pyrazin-3(4H)-ones VII.
Scheme 4
Figure imgf000049_0001
The preparation of substituted amine analogs in the C(6) position similar to compounds XII, XIII, XIV, and XV are shown in Schemes 6-9. The starting amines X are prepared by utilizing mono-protected diamines in the second step of Scheme 3 or the final step of Scheme 4. The protecting groups used are typically carbamates that are removed using conditions to afford the free amine Xl (Scheme 5).
Scheme 5
Figure imgf000049_0002
Xl
Amide derivatives XII could be prepared by treatment of the amine Xl with activated esters such as acid chlorides or acid derivatives prepared from acids utilizing peptide coupling reagents such as 1-[3-(dimethylamino-propy]-3-ethylcarbo-diimide methiodide, 1 ,3- dicyclohexylcarbodiimide, or 0-(7-Azabenzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluromium hexafluorophosphate in the presence of an organic base such as triethylamine, N, N- diisopropylethyiamine, 4-methylmorpholine in a solvent such as dichloromethane, tetrahydrofuran, or dioxane as outlined in Scheme 6.
Scheme 6
Figure imgf000050_0001
Xl XII
As outlined in Scheme 7, exposing the amine Xl as a solution in solvents such as tetrahydrofuran, dichloromethane, or dioxane to an aldehyde in the presence of a catalytic amount of acids such as hydrochloric or acetic acid to a reducing agent such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxy-borohydride leads to the desired amine derivatives XIII. Furthermore, substituted amines XIII can be prepared by the treatment of amine Xl with alkyl halides in solvents such as Λ/,Λ/-dimethylformamide or tetrahydrofuran with a base such as sodium hydride, potassium carbonate, or cesium carbonate.
Scheme 7
Figure imgf000050_0002
Formation of sulfonamides XIV could be prepared through treatment of the the amine VII with sulfonyl chlorides in organic solvents such as tetrahydrofuran, dichloromethane, or dioxanes and organic bases such as triethylamine, N-methylmorpholines, or N, N- diisopropylethylamine as outlined in Scheme 8.
Scheme 8
Figure imgf000050_0003
Xl XIV Formation of ureas XV could be prepared through treatment of the the amine VII with carbamyl chlorides in organic solvents such as tetrahydrofuran, dichloromethane, or dioxanes and organic bases such as triethylamine, N-methylmorpholines, or Λ/,Λ/-diisopropylethylamine as outlined in Scheme 9. Additionally, ureas XV can be prepared by treating amine VII with isocyanates in solvents such as dichloromethane, tetrahydrofuran, or dioxanes with organic bases such as triethylamine, N-methylmorpholines, or Λ/,/V-diisopropylethylamine as outlined in Scheme 9.
Scheme 9
Figure imgf000051_0001
Xl base XV
Acylation of the 3-amine in the pyrido[2,3-b]pyrazin-3(4H)-ones VII could be accomplished by treatment of VII with activated esters such as an acid chloride or acid derivatives prepared under peptide coupling conditions utilizing peptide coupling reagents such as 1-[3-(dimethylaminopropy]-3-ethylcarbodiimide methiodide , 1 ,3- dicyclohexylcarbodiimide, or 0-(7-azabenzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluromium hexafluorophosphate in the presence of an organic base such as triethylamine, N, N- diisopropylethylamine, or 4-methylmorpholine in a solvent such as dichloromethane, tetrahydrofuran, Λ/,Λ/-dimethylformamide, or dioxane to provide the desired acetamide XVI as outlined in Scheme 10.
Scheme 10
Figure imgf000051_0002
XVI
Formation of sulfonamides XVII could be prepared through treatment of the pyrido[2,3- b]pyrazin-3(4H)-ones VII with sulfonyl chlorides in organic solvents such as tetrahydrofuran, dichloromethane, or dioxanes and organic bases such as triethyl amine, N- methylmorpholines, or N, Λ/-diisopropylethylamine as outlined in Scheme 11. Scheme 11
Figure imgf000052_0001
XVII
The following illustrate the synthesis of various compounds. Other compounds of this invention may be prepared using the methods illustrated in these Examples, either alone or in combination with techniques generally known in the art.
Example 1
1-(2-ethoxyethyl)-7-(6-fluoropyridin-3-yl)-3-f(2-morpholin-4-ylethyl)aminolpyrido[2,3-blpyrazin-
Figure imgf000052_0002
The 2,3-diamino-5-bromopyridine (30.0 g, 159.5 mmol), ethoxyacetic acid (15.12 mL, 159.5 mmol), triethylamine (33.4 mL, 239.3 mmol) and O-(7-azabenzotriazol-1-yl)-/V,/V,Λ/',Λ/'- tetramethyluronium hexafluorophosphate (60.84 g, 159.5 mmol) were mixed in N, N- dimethylformamide (500 mL) at room temperature. The mixture was warmed to 50°C and stirred 16 hours. The solvent was removed in vacuo. Water (500 mL) was added to the brown oil and extracted with ethyl acetate (400 mL). The organic layer was separated then dried over magnesium sulfate, filtered, and the solvent removed in vacuo. The crude brown oil was purified via flash column chromatography (eluent = 1:1 hexanes/ethyl acetate (8 L) to 2:1 ethyl acetate/hexanes (3 L) to 4:1 ethyl acetate/hexanes (3 L)). Removal of the solvent afforded 37.0 g of Λ/-(2-amino-5-bromopyridin-3-yl)-2-ethoxyacetamide as a brown oil. LRMS ES+ 274/276 [M+H]+.
Figure imgf000053_0001
Step 2: Preparation of 5-bromo-N~3~-(2-ethoxyethvhpyridine-2,3-diamine. To a suspension of lithium aluminum hydride (1 M in THF, 112.0 ml_, 111.6 mmol) in tetrahydrofuran (100 mL) was added Λ/-(2-amino-5-bromopyridin-3-yl)-2-ethoxyacetamide (10.2 g, 37.2 mmol) dropwise as a solution in tetrahydrofuran (100 mL) cooled in a dry ice/acetone bath. The reaction mixture was then allowed to warm to room temperature and stirred for 30 min. The mixture was heated to 5O0C for 1.5 hours then cooled to room temperature and stirred for 16 hours. The reaction vessel was then cooled in a dry ice/acetone bath and water (10 mL) was slowly added, followed by 2.5 N sodium hydroxide solution (10 mL), and subsequent water addition (30 mL). The mixture was stirred for 5 min then filtered through celite while being rinsed with methylene chloride. The solvent was removed in vacuo, ethyl Aacetate was added, and the solution was dried over magnesium sulfate. The dried material was filtered and concentrated in vacuo to afford 6.60 g of 5- bromo-N~3~-(2-ethoxyethyl)pyridine-2,3-diamine as a brown liquid. HRMS m/z 260.0399/262.0390(calculated for M+H, 260.0393/262.0373).
Figure imgf000053_0002
Step 3: Preparation of 7-bromo-1-(2-ethoxyethyl)-1 ,4-dihvdropyridor2,3-blpyrazine-2,3-dione. To 5-bromo-N~3~-(2-ethoxyethyl)pyridine-2,3-diamine (6.5 g, 25.1 mmol) in toluene (300 mL) was added ethyl chlorooxoacetate (3.8 mL, 27.6 mmol) and Λ/,Λ/-diisopropylethylamine (5.24 mL, 30.1 mmol) at -78°C. The dry ice/acetone -bath was removed and the reaction temperature was warmed to room temperature, stirred for 2 hours, then heated at 90°C for 2 hours. The solvent was then removed in vacuo and the crude material was purified via flash column chromatography (eluent = methylene chloride (1L) to 1% methanol/methylene chloride (1.5 L). The desired material was collected and concentrated in vacuo to afford 4.16 g of 7-bromo-1-(2-ethoxyethyl)-1 ,4-dihydropyrido[2,3-b]pyrazine-2,3-dione as a brown oil. HRMS m/z314.0150/316.0130(cafculated for M+H, 314.0135/316.0115).
Figure imgf000054_0001
Step 4: Preparation of 7-bromo-3-chloro-1 -(2-ethoxyethyl)pyridof2.3-biPyrazin-2(1 H)-one
To 7-bromo-1-(2-ethoxyethyl)-1 ,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (3.94 g, 12.6 mmol) in propionitrile (63 ml_) was added tetraethylammonium chloride monohydrate (6.3 g, 37.8 mmol) and phosphorous oxychloride (17.3 mL, 189.0 mmol). The mixture was heated to reflux for 1 hour. The solvent was removed in vacuo and the resultant residue was partitioned between methylene chloride and a minimal amount of water. The organic layer was washed with brine, separated, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3.35 g of 7-bromo-3-chloro-1-(2-ethoxyethyl)pyrido[2,3-b]pyrazin-2(1 H)-one as a brown oil. LCMS ES+ 332/334 [M+H]+.
Figure imgf000054_0002
Step 5: 7-bromo-1 -(2-ethoxyethylV3-r(2-morpholin-4-ylethyl')aminolpyridof2,3-blpyrazin-
2(i m-one
To 7-bromo-3-chloro-1-(2-ethoxyethyl)pyrido[2,3-b]pyrazin-2(1 H)-one (1.0 g, 3.0 mmol) in tetrahydrofuran (6 mL) was added triethylamine (0.84 mL, 6.0 mmol) and 4-(2- aminoethyl)morpholine (0.44 mL, 3.3 mmol) at room temperature and stirred for 16 hours.
The solvent was removed in vacuo and the resultant residue partitioned between methylene chloride and water followed by the organic layer being washed with brine. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated in vacuoXo afford 0.98 g of 7-bromo-1-(2-ethoxyethyl)-3-[(2-morpholin-4-ylethyl)amino]pyrido[2,3-b]pyrazin-
2(1H)-one as a brown semi-solid. HRMS m/z 426.1109/428.1074(calculated for M+H,
426.1135/428.1117).
Figure imgf000054_0003
Step 6: Preparation of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3.2-dioxaborolan-2-yl)pyridine. To a solution of 5-bromo-2-fluoropyridine (5.0 g, 28.5 mmol) in Λ/,Λ/-dimethylformamide
(100 mL) was added bis(pinacoloato)diborane (8.0 g, 31.5 mmol) and potassium acetate (8.4 g, 85.6 mmol). After 5 min [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (725 mg, 0.89 mmol) was added and the reaction mixture heated to 800C. After 3 hr HPLC indicated complete conversion and the reaction mixture was left to stir at room temperature over night. The solvent was removed in vacuo and the resultant residue taken up in diethyl ether then extracted with 1 N sodium hydroxide solution. The aqueous extract was neutralized to pH 6 with 3N hydrochloric acid then extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate, filtered then reduced in vacuo to yield the desired boronic ester as a brown oil which partially crystallized upon standing. LCMS ES+ 142 [M+H]+.
Figure imgf000055_0001
Step 7: Preparation of 1-(2-ethoxyethyl)-7-(6-fluoropyridin-3-yl)-3-r(2-morpholin-4- ylethyl)aminolpyridor2.3-blpyrazin-2(1 H)-one
To a solution of 7-bromo-1-(2-ethoxyethyl)-3-[(2-morpholin-4-ylethyl)amino]pyrido[2,3- b]pyrazin-2(1 H)-one in ethylene glycol dimethyl ether/water (3 mL = 2 mL gylme/1 mL water) was added of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine from step 6 (190 mg, 0.85 mmol), sodium carbonate (166.0 mg, 1.6 mmol), and tetrakis(triphenylphosphine)- palladium (0) (82.0 mg, 0.07 mmol) at room temperature. The mixture was heated to reflux for 2 hours and another 0.5 equivalent (79 mg, 0.4 mmol) of the boronic ester and more solvent (3 mL) was added. After refluxed for an additional 3 hours, the mixture was cooled to room temperature and stirred for 16 hours. The solvent was removed in vacuo and the crude material was partitioned between methylene chloride and water. The organic layer was then washed brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Ethyl acetate was added to the resultant oil and immediately a solid started forming. Heating the solid in ethyl acetate followed by addition of a small amount of hexanes afforded 166 mg of 1- (2-ethoxyethyl)-7-(6-fluoropyridin-3-yl)-3-[(2-morpholin-4-ylethyl)amino]pyrido[2,3-b]pyrazin- 2(1H)-one as a tan solid. 1H NMR (400 MHz, CD3OD) δ 8.52 (m, 2 H), 8.27 (m, 1 H)1 8.18 (m, 1 H), 7.20 (m, 1 H), 4.55 (t, 2 H), 3.81 (t, 2 H), 3.73 (t, 2 H), 3.69 (m, 4 H), 3.47 (q, 2 H), 2.70 (t, 2 H), 2.57 (m, 4 H), 1.04 (t, 3 H). HRMS m/z 443.2208 (calculated for M+H, 443.2201).
Example 2 7-(4-fluorophenyl)-3-r(2-morpholin-4-ylethvflaminol-1-(tetrahvdro-2H-pyran-4- ylmethyl)pyridor2,3-biPyrazin-2(1HVone
Figure imgf000056_0001
Step 1: Preparation of 5-bromo-N~3~-(tetrahvdro-2H-pyran-4-ylmethyl)pyridine-2,3-diamine To 2,3-diamino-5-bromopyridine (10.0g, 53.2 mmol) dissolved in anhydrous tetrahydrofuran (1.0 L) was added 4 A molecular sieves (54 g) and tetrahydropyranyl-4- carboxaldehyde (7.28 g, 63.8 mmol) at room temperature. The reaction mixture was heated to reflux for 3 hours and then stirred at ambient temperature for 16 hours. The mixture was reheated to reflux for 7 hours then filtered through celite. The filter cake was rinsed with diethyl ether then the filtrate was concentrated in vacuo. The semi-solid was dissolved in ethanol (500 ml_) and sodium borohydride was added at -78 0C. The mixture was warmed to room temperature and stirred for 1 hour. Water (1.0 L) was added to the reaction mixture and then extracted (3X) with methylene chloride. The organic layers were combined and dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude brown foam was purified via flash column chromatography (eluent = 1 :1 hexanes/ethyl acetate to 5:1 hexanes/ethyl acetate (6 L total) to methanol (2 L) to afford 6.58 g of 5-bromo-N~3~- (tetrahydro-2H-pyran-4-ylmethyl)pyridine-2,3-diamine as a brown solid. HRMS m/z 286.05489/288.0531 (calculated for M+H, 286.0549/288.0530).
Figure imgf000056_0002
Step 2: Preparation of 7-bromo-3-chloro-1-(tetrahvdro-2H-pyran-4-ylmethyl)pyridof2,3- blpyrazin-2(1 H)-one
To 5-bromo-N~3~-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2,3-diamine (5.9 g, 20.6 mmol) in methylene chloride (200 mL) with Λ/,Λ/-dimethylformamide (10 mL) was added triethylamine (6.3 mL, 45.2 mmol) followed by oxalyl chloride (2.0 mL, 22.6 mmol) slowly at - 78 0C. The reaction mixture stirred for 1 hour and then warmed to room temperature where it stirred for 30 min. Oxalyl chloride (3.6 mL, 41.1 mmol) was added dropwise to the reaction mixture at room temperature and stirred 16 hours. The mixture was then concentrated in vacuo, dissolved in ethyl acetate, and washed with water followed by brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuoXo afford 3.37 g of 7- bromo-3-chloro-1-(tetrahydro-2H-pyran-4-ylmethyl)pyrido[2,3-b]pyrazin-2(1H)-one as a brown solid. No further purification was attempted. LCMS ES+ 358/360 [M+H]+.
Figure imgf000057_0001
Step 3: Preparation of 7-bromo-3-r(2-morpholin-4-ylethyl)aminol-1-(tetrahvdro-2H-pyran-4- ylmethyl)pyridor2.3-b1pyrazin-2(1H)-one
To 7-bromo-3-chloro-1 -(tetrahydro-2H-pyran-4-ylmethyl)pyrido[2,3-b]pyrazin-2(1 H)-one (2.0 g, 5.7 mmol) in tetrahydrofuran (15 ml.) was added triethylamine (1.6 ml_, 11.4 mmol) and 4-(2-aminoethyl)morpholine (817 DL, 6.2 mmol) at room temperature. The reaction mixture was stirred for 1.5 hours then concentrated in vacuo. The resultant residue was dissolved in methylene chloride, washed with water then brine, dried over magnesium sulfate, filtered, and concentrated In vacuo to afford 2.3 g of 7-bromo-3-[(2-morpholin-4- ylethyl)amino]-1-(tetrahydro-2H-pyran-4-ylmethyl)pyrido[2,3-b]pyrazin-2(1 H)-one as a tan solid. HRMS m/z 452.1313/454.1283(calculated for M+H, 452.1292/454.1274).
Figure imgf000057_0002
Step 4: Preparation of 7-(4-fluorophenyl)-3-K2-morpholin-4-ylethyl)aminol-1-(tetrahvdro-2H- Pyran-4-ylmethyl)pyridor2,3-bipyrazin-2(1H)-one
To a solution of 7-bromo-3-[(2-morpholin-4-ylethyl)amino]-1-(tetrahydro-2H-pyran-4- ylmethyl)pyrido[2,3-b]pyrazin-2(1H)-one (250.0 mg, 0.6 mmol) in ethylene glycol dimethyl ether/water (1.8 mL = 1.3 mL gylme/0.5 mL water) was added 4-fluorobenzeneboronic acid (92.0 mg, 0.7 mmol), sodium carbonate (128.0 mg, 1.3 mmol), and tetrakis(triphenylphosphine)palladium (0) (64.0 mg, 0.06 mmol) at room temperature. The mixture was heated to reflux for 3 hours. The reaction mixture was then cooled to room temperature and the solvent removed in vacuo. The crude material was partitioned between methylene chloride and water and then subsequently the organic layer was washed with brine. The layers were separated and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was dissolved in 1.25 M HCI/ethanol and stirred for 10 min. The solids were filtered and diethyl ether was added to the filtrate. The newly formed precipitate was filtered and rinsed with acetonitrile which resulted in 88 mg of 7- (4-fluorophenyl)-3-ft2-moφholin-4-ylethyl)amino]-1-(tetrahydro-2H-pyran-4- ylmethyl)pyrido[2,3-b]pyrazin-2(1H)-one as a brown solid. 1H NMR (400 MHz, METHANOL- D4) δ ppm 1.51 (m, 3 H) 1.73 (m, 2 H) 2.24 (m, 2 H) 3.19 (m, 2 H) 3.35 (m, 2 H) 3.57 (m, 2 H) 3.73 (m, 2 H) 3.94 (m, 4 H) 4.08 (m, 2 H) 4.35 (d, 2 H) 7.31 (t, 2 H) 7.83 (m, 2 H) 8.46 (d, 1 H) 8.55 (d, 1 H). HRMS m/z 468.2413 (calculated for M+H, 468.2405).
Example 3
7-(6-methoxypyridin-3-ylV3-r(2-morpholin-4-ylethyl)aminol-1-r2-(2.2.2- trifluoroethoxy)ethyllPyridoF2,3-bipyrazin-2(1H')-one
Figure imgf000058_0001
Step 1 : Preparation of (2,2.2-trif luoroethoxyiacetic acid
To sodium chloroacetate (10.0 g, 85.9 mmol) in 2,2,2-trifluoroethanol (31.0 ml_, 429.5 mmol) was added solid sodium hydroxide (4.1 g, 103.0 mmol) at room temperature and heated to 60 0C for 72 hours. The solvent was removed in vacuo keeping the temperature on the water bath below 44 °C. The crude material was dissolved in ethyl acetate and washed with water and the layers were separated. The organic layer was washed with brine and set aside. To the aqueous layer, concentrated sulfuric acid (30.0 g) was added at 0 0C and then extracted with ethyl acetate. The organic layer was separated and washed with brine. Both organic layers were combined and taken directly on to the next step. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 3.96 (q, 2 H) 4.26 (s, 2 H).
Figure imgf000058_0002
Step 2: Preparation of N-(2-amino-5-bromopyridin-3-yl)-2-(2,2,2-trifluoroethoxy)acetamide
To a solution of 2,3-diamino-5-bromopyridine (16.1 g, 85.9 mmol), (2,2,2- trifluoroethoxy)acetic acid (13.6 g, 85.9 mmol) in Λ/,Λ/-dimethylformamide (285 mL) was added triethylamine (18.0 mL, 128.9 mmol) and O-(7-azabenzotriazol-1-yl)-Λ/,/V,/V',Λ/'- tetramethyluronium hexafluorophosphate (32.64 g, 85.9 mmol) at room temperature. The mixture was warmed to 50°C and stirred 16 hours. The solvent was removed in vacuo. The resultant residue was partitioned between water (250 mL) and ethyl acetate (200 ml_). The organic layer was separated, washed an additional time with water, dried over magnesium sulfate, filtered, and the solvent removed in vacuo. The crude brown oil was applied to a flash column chromatography (eluent = 2.5% methanol/methylene chloride (5 L). Removal of the solvent afforded 22.94 g of N-(2-amino-5-bromopyridin-3-yl)-2-ethoxyacetamide as a brown solid. HRMS m/z 327.9922/329.9903 (calculated for M+H, 327.9903/329.9883).
Figure imgf000059_0001
Step 3: Preparation of 5-bromo-N~3~-r2-(2,2,2-trifluoroethoxy)ethvπpyridine-2,3-diamine To a suspension of lithium aluminum hydride (1 M in THF, 112.0 mL, 111.6 mmol) in tetrahydrofuran (100 mL) was added Λ/-(2-amino-5-bromopyridin-3-yl)-2-ethoxyacetamide (10.2 g, 37.2 mmol) dropwise as a solution in tetrahydrofuran (100 mL) cooled in a dry ice/acetone bath. The reaction mixture warmed to room temperature and stirred for 30 min. The reaction mixture was heated to 50°C for 1 hour and then cooled in a dry ice/acetone bath. Water (5 mL) was slowly added, followed by 2.5 N sodium hydroxide solution (10 mL), and subsequent water addition (15 mL). The mixture was stirred for 5 min and wad then filtered through celite while being rinsed with methylene chloride. The solvent was removed in vacuo and the crude material purified via Biotage column chromatography (eluent = 2.5% methanol/methylene chloride (2 L) to afford 5.94 g of 5-bromo-N~3~-[2-(2,2,2- trifluoroethoxy)ethyl]pyridine-2,3-diamine as a brown solid. LCMS ES+ 314/316 [M+H]\
Figure imgf000059_0002
Step 4: Preparation of 7-bromo-1 -r2-(2,2,2-trifluoroethoxy)ethyll-1 ,4-dihvdropyridof2,3- bipyrazine-2.3-dione
To 5-bromo-N~3~-[2-(2,2,2-trifluoroethoxy)ethyl]pyridine-2,3-diamine (5.8 g, 18.6 mmol) and triethylamine (5.7 mL, 40.9 mmol) in methylene chloride (200 mL) was added oxalyl chloride (1.92 mL, 20.5 mmol) slowly at -78 0C. The reaction mixture was stirred for 2 hours and then warmed to room temperature where the solvent was removed in vacuo. The material was partitioned between ethyl acetate and water. The organic layer was washed with brine then concentrated in vacuo. Precipitation occurred when diethyl ether was added to the residue. Filtration of the solid resulted in 5.43 g of 7-bromo-1-[2-(2,2,2- trifluoroethoxy)ethyl]-1 ,4-dihydropyrido[2,3-b]pyrazine-2,3-dione as a tan solid. HRMS m/z 367.9870/369.9840 (calculated for M+H, 367.9582/369.9833).
Figure imgf000060_0001
Step 5: Prepartion of 7-bromo-3-r(2-morpholin-4-ylethyl)amino1-1-f2-(2.2.2- trifluoroethoxy)ethvnpyridor2,3-blPyrazin-2(1 H)-one
To 7-bromo-1 -[2-(2,2,2-trif luoroethoxy)ethyl]-1 ,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (1.0 g, 2.7 mmol) in Λ/,Λ/-dimethylformamide (20 DL) and methylene chloride (27 ml_) was added oxalyl chloride (475.0 DL) at room temperature and stirred for 16 hours. The solvent was removed in vacuo and the intermediate residue dissolved in tetrahydrofuran (5.4 mL). To this mixture was added triethylamine (758.0 DL, 5.4 mmol) and 4-(2-aminoethyl)morpholine (393.0 DL, 3.0 mmol) at room temperature. The reaction mixture was stirred for 1.5 hours and the solvent was removed in vacuo. The crude material was dissolved in methylene chloride, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo Xo afford 1.14 g of 7-bromo-3-[(2-morpholin-4-ylethyl)amino]-1-[2- (2,2,2-trifluoroethoxy)ethyl]pyrido[2,3-b]pyrazin-2(1 H)-one as a brown semi-solid. HRMS m/z 480.0847/482.0823 (calculated for M+H, 480.0853/482.0834).
Figure imgf000060_0002
Step 6: Preparation of 7-(6-methoxypyridin-3-yl)-3-r(2-morpholin-4-ylethyl)aminol-1-r2-(2.2.2- trifluoroethoxy)ethyllPyridor2.3-blpyrazin-2(1H)-one
To a solution of 7-bromo-3-[(2-morpholin-4-ylethyl)amino]-1-[2-(2,2,2- trifluoroethoxy)ethyl]pyrido[2,3-b]pyrazin-2(1H)-one (305.0 mg, 0.6 mmol) in ethylene glycol dimethyl ether/water (2.1 mL = 1.5 mL gylme/0.6 mL water) was added 2-methoxy-5- pyridineboronic acid (117 mg, 0.8 mmol), sodium carbonate (149.0 mg, 1.4 mmol), and tetrakis(triphenylphosphine)palladium (0) (74.0 mg, 0.06 mmol) at room temperature. The mixture was heated to reflux for 1.5 hours then cooled to ambient temperature and concentrated in vacuo. The crude material was partitioned between methylene chloride and water. The organic layer washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified via Biotage column chromatography (eluent = 2.5% methanol/methylene chloride (5 L) which resulted in 214 mg of 7-(6- methoxypyridin-3-yl)-3-[(2-morpholin-4-ylethyl)amino]-1-[2-(2,2,2- trifluoroethoxy)ethyl]pyrido[2,3-b]pyrazin-2(1 H)-one as a tan solid. 1 H NMR (400 MHz, METHANOL-D4) δ ppm 2.57 (s, 4 H) 2.70 (t, 2 H) 3.69 (m, 4 H) 3.72 (t, 2 H) 3.91 (m, 2 H) 3.95 (s, 3 H) 4.02 (t, 2 H) 4.59 (t, 2 H) 6.90 (d, 1 H) 7.99 (dd, 1 H) 8.06 (d, 1 H) 8.43 (d, 1 H) 8.47 (d, 1 H). HRMS m/z 509.2096 (calculated for M+H, 509.2119). Example 4
N~2~-[7-(6-methoxypyridin-3-yl)-2-oxo-1-(2-propoxyethyl)-1 ,2-dihvdropyridor2,3-blpyrazin-3- vi1-N~1 ~,N~1 — dimethvlqlvcinamide
Figure imgf000061_0001
O ' \^~v^ -QH
Step 1 : Preparation of propoxyacetic acid
To sodium chloroacetate (843 g, 7.2 mol) in propanol (2.15 kg, 35.8 mol) was added solid sodium hydroxide (357 g, 8.9 mol) at room temperature and heated to 50 0C for -17 hours. Excess propanol was removed in vacuo and the residual solids dissolved water (2.2 L) and cooled in an ice water bath. Concentrated sulfuric acid (483 g) was added in portions over -15 min. The lower aqueous layer was back extracted with ethyl acetate. The combined organic layers were washed with water then brine and reduced in vacuo. The crude acid was taken forward "as is". H NMR (400 MHz, CHLOROFORM-D) δ ppm 10.8 (bs, 1 H), 4.1 (s, 2H), 3.5 (t, 2H), 1.6 (m, 2H), 0.9 (t, 3H).
Figure imgf000061_0002
Step 2: Preparation of N-(2-amino-5-bromopvridin-3-vlV2-propoxvacetamide. To a solution of propoxyacetic acid (810 g, 6.7 mol) in methylene chloride (-2 L) with Λ/,Λ/-dimethylformamide (7 ml_) chilled in an ice water bath was added dropwise neat oxalyl chloride (665 ml_, 7.6 mol) over -2 hours maintaining an internal temperature < 5°C. The reaction mixture was then allowed to warm to ambient temperature. After -17 hours the reaction mixture was reduced in vacuo with the temperature maintained < 200C and vacuum > 50 torr to provide 966 g of the crude acid chloride (-87% pure by 1HNMR). The acid chloride (615 g, 4.5 mol) was dissolved in anhydrous tetrahydrofuran (2 L) and added over -2 hours to a solution of 2,3-diamino-5-bromopyridine (736 g, 3.9 mmol) and triethylamine (455 g, 4.5 mol) in anhydrous tetrahydrofuran (14 L) maintaining a temperature <5°C. Additional acid chloride (66 g, 0.5 mol) was added until the reaction was determined to be complete by HPLC. The reaction mixture was filtered, the cake washed with ethyl acetate, and the filtrate concentrated in vacuo. The solvent was removed in vacuo. The crude material was purified by via Biotage column chromatography (eluent = 40% ethyl acetate/hexane to 100% ethyl acetate). Similar fractions were combined, concentrated in vacuo, and the resultant solid triterated with a mixture of ethyl acetate (-200 mL) and hexane (-2 L) to afford 822 g of N-(2- amino-5-bromopyridin-3-yl)-2-propoxyacetamide. H NMR (400 MHz, CHLOROFORM-D) δ ppm 8.10 (bs, 1 H), 8.00 (s, 1 H), 7.80 (s, 1 H), 4.70 (bs, 2H), 4.05 (s, 2H), 3.55 (t, 2H), 1.65 (m, 2H), 0.95 (t, 3H).
Figure imgf000062_0001
Step 3: Preparation of 5-bromo-N~3— (2-propoxyethyltoyridine-2,3-diamine.
To a suspension of lithium aluminum hydride (1 M in THF, 6.3 L, 6.3 mol) in anhydrous tetrahydrofuran (6 L) was added N-(2-amino-5-bromopyridin-3-yl)-2-propoxyacetamide (858 g, 3.0 mol) as a solution in tetrahydrofuran (6L) at a rate to maintain an internal temperature < 5°C. The reaction mixture warmed to room temperature and stirred overnight. The reaction mixture was cooled each of the following added at a rate to maintain a temperature <5°C: water (350 mL 2.5 N sodium hydroxide solution (700 mL), and water (1050 mL). The mixture was allowed to warm to 15°C then filtered through a bed of celite while being rinsed with methylene chloride. The solvent was removed in vacuo, the crude material dissolved in toluene then filtered, and reconcentrated in vacuo to afford 755 g of 5-bromo-N~3— (2- propoxyethyl)pyridine-2,3-diamine. LCMS ES+ 274/276 [M+H]+.
Figure imgf000063_0001
Step 4: Preparation of 7-bromo-1-(2-propoxyethyl)-1.4-dihvdropyridor2,3-blpyrazine-2,3- dione.
To methylene chloride (4 L) at room temperature was simultaneously added a solution of 5-bromo-N~3~-(2-propoxyethyl)pyridine-2,3-diamine (685 g, 2.5 mol) and triethylamine (532 g, 5.3 mol) in methylene chloride (-300 ml_) and oxalyl chloride (582 g, 4.9 mol) in methylene chloride (~4 L) while maintaining an internal temperature of ~20°C with ice water bath cooling. Upon complete addition (-3.5 hours) LCMS indicated complete consumption of starting material. The reaction mixture was quenched by addition to cold water (6L) and the solids removed by filtration. All collected solids were redissolved in warm methylene chloride, and the solution filtered through celite and concentrated in vacuo. The resultant solid was azeotroped with toluene, triterated with diethyl ether, and filtered to provide 743 g of 7-bromo- 1 -(2-propoxyethyl)-1 ,4-dihydropyrido[2,3-b]pyrazine-2,3-dione as a tan solid. LCMS ES+ 328/330 [MH-H]+.
Figure imgf000063_0002
Step 5: Prepartion of 7-(6-methoxypyridin-3-yl)-1 -(2-propoxyethyl)-1 ,4-dihvdropyridor2,3- blpyrazine-2.3-dione
To a solution of 7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-1 ,4-dihydropyrido[2,3- b]pyrazine-2,3-dione (169 g, 0.5 mol), 2-methoxy-5-pyridineboronic acid (89.7 g, 0.6 mol, triphenylphosphine (2.2 g, 0.0084 mol), and palladium (II) acetate (0.7 g, 0.003 mol) in n- propanol (1.4 L) at room temperature was added a solution of sodium carbonate (106 g, 1.0 mol) in water (-500 mL). The mixture was heated to reflux overnight then cooled to ambient temperature and concentrated in vacuo. The crude material was redissolved in methanol, filtered through a bed of celite, and reduced in vacuo. The crude residue was dissolved in hot methanol (80 mL) and water (1.5 L) and then partioned with ethyl acetate. The organic layer was back extracted with ethyl acetate, and the combined aqueous layers were acidified to pH 5 with 6 N hydrochloric acid. The resultant solid was removed by filtration, rinsed with water, triterated with diethyl ether, and dried overnight at 50°C to provide 164 g of 7-(6- methoxypyridin-3-yl)-1-(2-propoxyethyl)-1 ,4-dihydropyrido[2,3-b]pyrazine-2,3-dione as a tan solid. 1H NMR (400 MHz1 DMS0-D6) δ ppm 12.50 (s, 1H), 8.55 (s, 1H), 8.40 (s, 1H), 8.05 (m, 2H), 6.90 (d, 1 H), 4.35 (t, 2H), 3.85 (s, 3H), 3.65 (t, 2H), 3.30 (t, 2H), 1.35 (m, 2H), 0.65 (t, 3H). HRMS m/z 357.1542 (calculated for M+H, 357.1557).
Figure imgf000064_0001
Step 6: Prepartion of N~2~-r7-(6-methoxypyridin-3-yl)-2-oxo-1-(2-propoxyethyl)-1 ,2- dihvdropyridor2.3-blpyrazin-3-yll-N~1 ~.N~1—dimethylqlvcinamide
To 7-(6-methoxypyridin-3-yl)-1 -(2-propoxyethyl)-1 ,4-dihydropyrido[2,3-b]pyrazine-2,3- dione (3.5 g, 9.8 mmol) in Λ/,/V-dimethylformamide (76 DL, 1.0 mmol) and methylene chloride (98 ml_) was added oxalyl chloride (2.4 mL, 24.5 mmol) at room temperature and stirred for 1 hour. The solvent was removed in vacuo and the intermediate residue mixed with tetrahydrofuran (20 mL), triethylamine (6.8 mL, 48.8 mmol) and N~1 ~,N~1~- dimethylglycinamide (1.8 g, 10.8 mmol) at room temperature. The reaction mixture was stirred for 1 hour and the solvent was removed in vacuo. The crude material was partitioned between methylene chloride and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified via Biotage column choromatography (gradient eluant of 2% methanol/methylene chloride to 5% methanol/methylene chloride) to afford 3.0 g of N~2~-[7-(6-methoxypyridin-3-yl)-2-oxo-1-(2- propoxyethyl)-1 ,2-dihydropyrido[2,3-b]pyrazin-3-yl]-N~1 ~,N~1 —dimethylglycinamide as a white solid. 1 H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.72 (t, 3 H) 1.44 (m, 2 H) 3.03 (s, 3 H) 3.06 (s, 3 H) 3.32 (t, 2 H) 3.79 (t, 2 H) 3.98 (s, 3 H) 4.39 (d, 2 H) 4.47 (t, 2 H) 6.84 (d, 1 H) 7.63 (t, 1 H) 7.80 (dd, 1 H) 7.93 (d, 1 H) 8.40 (d, 1 H) 8.55 (d, 1 H). HRMS m/z 441.2231 (calculated for M+H, 441.2245). Example 5
1 -(2-ethoxyethyl)-7-(1 -methyl-1 H-pyrazol-4-yl)-3-r(2-morpholin-4-ylethyl)aminoipyridor2.3- blpyrazin-2(1 H)-one
Figure imgf000064_0002
Example 5 was prepared by a method similar to that described in Example 1 using 1- methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H-pyrazole in place of 2-fluoro-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine in step 7.
1H NMR (400 MHz, CD3OD) (free base) δ 8.46 (m, 1 H), 8.08 (s, 1 H), 8.03 (m, 1 H), 7.91 (s, 1 H), 4.52 (t, 2 H), 3.94 (s, 3 H), 3.80 (t, 2 H), 3.70 (m, 6 H), 3.47 (q, 2 H), 2.69 (t, 2 H), 2.56 (m, 4 H), 1.05 (t, 3 H). HRMS m/z 428.2442 (calculated for M+H, 428.2405).
Example 6
1-(2-ethoxyethyl)-7-(4-fluorophenyl)-3-r(2-morpholin-4-ylethyl)aminolPyridor2.3-bipyrazin-
2(1 HV-one
Figure imgf000065_0001
Example 6 was prepared by a method similar to that described in Example 1 using A- fluorobenzeneboronic acid in place of 2-f luoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine in step 7. 1H NMR (400 MHz, CD3OD) δ 8.73 (s, 1 H), 8.57 (s, 1 H), 7.83 <m, 2 H), 7.31 (t, 2 H), 4.63 (m, 2 H), 4.06 (m, 4 H), 3.88 (m, 4 H), 3.72 (m, 2 H), 3.58 (m, 2 H), 3.47 (m, 2 H), 3.24 (m, 2 H), 1.04 (t, 3 H). HRMS m/z 442.2284 (calculated for M+H, 442.2249).
Example 7
7-(6-methoxypyridin-3-yl)-3-r(2-morpholin-4-ylethyl)aminol-1-(tetrahvdro-2H-pyran-4- ylmethyl)pyridor2,3-blpyrazin-2(1 H)-one
Figure imgf000065_0002
Example 7 was prepared by a method similar to that described in Example 2 using 2- methoxy-5-pyridineboronic acid in place of 4-fluorobenzeneboronic acid in step 4. 1H NMR (400 MHz, METHAN0L-D4) δ ppm 1.52 (m, 3 H) 1.74 (m, 2 H) 2.27 (m, 2 H) 3.24 (m, 2 H) 3.35 (m, 2 H) 3.74 (d, 2 H) 3.93 (m, 4 H) 4.04 (m, 2 H) 4.10 (m, 2 H) 4.20 (s, 3 H) 4.35 (d, 2 H) 7.48 (d, 1 H) 8.54 (d, 1 H) 8.61 (dd, 1 H) 8.66 (d, 1 H) 8.79 (d, 1 H). HRMS m/z 481.2564 (calculated for M+H, 481.2558).
Example 8
7-(6-fluoropyridin-3-yl)-3-r(2-morpholin-4-ylethyl)amino1-1-(tetrahydro-2H-pyran-4- ylmethvl)pvridor2.3-biPvrazin-2(1 H)-one
Figure imgf000066_0001
Example 8 was prepared by a method similar to that described in Example 2 using 2- fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine in place of A- fluorobenzeneboronic acid in step 4. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.57 (m, 5 H) 2.16 (s, 2 H) 2.63 (m, 6 H) 3.31 (m, 2 H) 3.78 (s, 4 H) 3.97 (d, 2 H) 4.21 (d, 2 H) 7.08 (dd, 1 H) 7.56 (d, 1 H) 7.99 (m, 1 H) 8.43 (d, 1 H) 8.58 (d, 1 H). HRMS m/z 469.2357 (calculated for M+H, 469.2358).
Example 9
7-(6-methoxypyridin-3-yl)-3-f(2-morpholin-4-ylethyl)aminol-1-(2-propoxyethyl)pyridor2.3- bipyrazin-2(1 HVone
Figure imgf000066_0002
Example 9 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1. 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.70 (t, 3 H) 1.42 (m, 2 H) 2.56 (s, 4 H) 2.70 (t, 2 H) 3.35 (t, 2 H) 3.70 (m, 6 H) 3.80<t, 2 H) 3.95 (s, 3 H) 4.54 (t, 2 H) 6.89 (d, 1 H) 7.99 (dd, 1 H) 8.11 (d, 1 H) 8.44 (d, 2 H). HRMS m/z 469.2576 (calculated for M+H, 469.2558).
Example 10
3-r(2-morpholin-4-ylethyl)amino1-1-(2-propoxyethyl)-7-pyrimidin-5-ylpyridof2,3-blpyrazin-
2(im-one
Figure imgf000066_0003
Example 10 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and pyrimidine-5-boronic acid in place of 2-methoxy-5-pyridineboronic acid in step 6. 1 H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.72 (t, 3 H) 1.45 (m, 2 H) 2.51 (m, 4 H) 2.68 (t, 2 H) 3.33 (t, 2 H) 3.74 (m, 6 H) 3.82 (t, 2 H) 4.48 (t, 2 H) 8.03 (d, 1 H) 8.62 (d, 1 H) 8.99 (s, 2 H) 9.24 (s, 1 H). HRMS m/z 440.2393 (calculated for M+H, 440.2405).
Example 11
7-(2-methoxypyrimidin-5-yl)-3-rf2-morpholin-4-ylethyl)aminol-1-(2-propoxyetriyl)pyridor2,3- biPvrazin-2(1 H)-one
Figure imgf000067_0001
Example 11 was prepared by a method similar to that described in Example 3 using propanol in place of (2,2,2-trifluoroethanol in step 1 and 2-methoxypyrimidine-5-boronic acid in place of 2-methoxy-5-pyridineboronic acid in step 6. 1 H NMR (400 MHz, CHLOROFORM- D) δ ppm 0.73 (t, 3 H) 1.45 (m, 2 H) 2.51 (m, 4 H) 2.67 (t, 2 H) 3.33 (t, 2 H) 3.74 (m, 6 H) 3.81 (t, 2 H) 4.07 (s, 3 H) 4.47 (t, 2 H) 7.18 (m, 1 H) 7.94 (d, 1 H) 8.56 (d, 1 H) 8.75 (s, 2 H). HRMS m/z 470.2493 (calculated for M+H, 470.2510).
Example 12 7-(2.4-dimethoxypyrimidin-5-yl)-3-r(2-morpholin-4-ylethyl)amino1-1-(2-propoxyethyl)pyridof2,3- bipyrazin-2(1 HVone
Figure imgf000067_0002
Example 12 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and 2-methoxypyrimidine-5-boronic acid in place of 2,4-dimethoxypyrmidine-5-boronic acid in step 6. 1H NMR (400 MHz,
CHLOROFORM-D) δ ppm 0.75 (t, 3 H) 1.46 (m, 2 H) 2.51 (m, 4 H) 2.67 (t, 2 H) 3.34 (t, 2 H) 3.75 (m, 8 H) 4.03 (s, 3 H) 4.04 (s, 3 H) 4.44 (t, 2 H) 7.13 (t, 1 H) 7.88 (d, 1 H) 8.31 (s, 1 H) 8.52 (d, 1 H). HRMS m/z 500.2613 (calculated for M+H, 500.2616).
Example 13 7-(2-methoxypyrimidin-5-yl)-3-f(2-morpholin-4-ylethyl)amino1-1-(2-propoxyethyl)pyridor2,3- blpyrazin-2(1 H)-one
Figure imgf000068_0001
Example 13 was obtained from Example 12 by treatment with iodotrimethylsilane in anhydrous acetonitrile. 1 H NMR (400 MHz, METHANOL-D4) δ ppm 0.78 (t, 3 H) 1.46 (m, 2 H) 3.28 (m, 2 H) 3.39 (t, 2 H) 3.62 (t, 2 H) 3.74 (d, 2 H) 3.84 (t, 2 H) 3.90 (d, 2 H) 4.07 (m, 4 H) 4.59 (t, 2 H) 8.05 (s, 1 H) 8.68 (d, 1 H) 8.70 (d, 1 H). HRMS m/z 472.2318 (calculated for M+H, 472.2303).
Example 14
7-(2-hvdroxypyrimidin-5-yl)-3-f(2-morpholin-4-ylethyl)aminol-1-(2-propoxyethyl)pyridor2,3- blpyrazin-2(1 H)-one
Figure imgf000068_0002
Example 14 was obtained from Example 11 by treatment with iodotrimethylsilane in anhydrous acetonitrile. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.70 (t, 3 H) 1.36 (m, 2 H) 3.10 (s, 2 H) 3.32 (m, 2 H) 3.40 (m, 2 H) 3.67 (m, 4 H) 3.86 (m, 6 H) 4.55 (t, 2 H) 8.56 (d, 1 H) 8.66 (d, 1 H) 8.99 (s, 2 H) 9.47 (t, 1 H) 11.15 (s, 1 H)HRMS m/z 456.2389 (calculated for M+H, 456.2354).
Example 15
7-(4-fluorophenvh-3-K2-morpholin-4-ylethyl)aminol-1-J2-(2.2.2-trifluoroethoxy)ethvnpyridof2,3- blpyrazin-2(1 H)-one
Figure imgf000068_0003
Example 15 was prepared by a method similar to that described in Example 3 using 4- fluorobenzeneboronic acid in place of 2-methoxy-5-pyridineboronic acid in step 6. 1 H NMR (400 MHz, METHANOL-D4) δ ppm 2.57 (s, 4 H) 2.71 (t, 2 H) 3.69 (m, 4 H) 3.73 (t, 2 H) 3.91 (q, 2 H) 4.03 (t, 2 H) 4.59 (t, 2 H) 7.20 (m, 2 H) 7.69 (m 2 H) 8.07 (d, 1 H) 8.48 (d, 1 H). HRMS m/z 496.1395 (calculated for M+H, 496.1966).
Example 16 tert-butyl N-f7-(6-methoxypyridin-3-yl)-2-oxo-1 -(2-propoxyethyl)-1 ,2-dihydropyridof2,3- blPvrazin-3-vll-beta-alaninate
Figure imgf000069_0001
Example 16 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , beta-alanine t-butyl ester hydrochloride in place of 4-(2-aminoethyl)morpholine in step 5, and 2-methoxypyrimidine-5-boronic acid in place of 2,4-dimethoxypyrmidine-5-boronic acid in step 6. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.73 (t, 3 H) 1.43 (m, 2 H) 1.45 (s, 9 H) 2.64 (t, 2 H) 3.33 (t, 2 H) 3.78 (t, 2 H) 3.90 (m, 2 H) 3.97 (s, 3 H) 4.45 (t, 2 H) 6.84 (d, 1 H) 7.05 (t, 1 H) 7.80 (dd, 1 H) 7.90 (d, 1 H) 8.40 (d, 1 H) 8.56 (d, 1 H). HRMS m/z 484.2533 (calculated for M+H, 484.2554).
Example 17
N-f7-(6-methoxypyridin-3-yl)-2-oxo-1-(2-propoxyethyl)-1 ,2-dihvdropyridor2.3-bipyrazin-3-vπ- beta-alanine
Figure imgf000069_0002
Example 17 was obtained from Example 16 by treatment with concentrated hydrochloric acid in dioxane. 1 H NMR (400 MHz, DMSO-D6) δ ppm 0.64 (t, 3 H) 1.31 (m, 2 H) 2.69 (t, 2 H) 3.29 (t, 2 H) 3.71 (m, 4 H) 3.90 (s, 3 H) 4.58 (t, 2 H) 6.99 (d, 1 H) 8.23 (dd, 1 H) 8.62 (d, 2 H) 8.69 (d, 1 H) 9.46 (t, 1 H). HRMS m/z 428.1932 (calculated for M+H, 428.1928).
Example 18 N~3~-r7-(6-methoxypyridin-3-yl)-2-oxo-1-(2-propoxyethyl)-1.2-dihvdropyridor2.3-biPyrazin-3- yl1-N~1 ~,N~1 —dimethyl-beta-alaninamide
Figure imgf000070_0001
Example 18 was obtained from Example 17 by a method similar to that described in step
1 of Example 3. 1 H NMR (400 MHz, METHANOL-D4) δ ppm 0.71 (t, 3 H) 1.42 (m, 2 H) 2.82 (t, 2 H) 2.94 (m, 3 H) 3.06 (s, 3 H) 3.35 (t, 2 H) 3.80 (t, 2 H) 3.85 <t, 2 H) 3.95 (S1 3 H) 4.55 (t,
2 H) 6.91 (d, 1 H) 8.01 (dd, 1 H) 8.14 (d, 1 H) 8.45 (d, 1 H) 8.49 (d, 1 H). HRMS m/z 455.2418 (calculated for M+H, 455.2401).
Example 19
N~3~-f7-(6-methoxypyridin-3-yl)-2-oxo-1-(2-propoxyethyl)-1 ,2-dihvdropyridor2,3-blpyrazin-3- yli-beta-alaninamide
Figure imgf000070_0002
Example 19 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , beta-alaninamide hydrochloride in place of 4-(2-aminoethyl)morpholine in step 5, and 2-methoxypyrimidine-5-boronic acid in place of 2,4-dimethoxypyrmidine-5-boronic acid in step 6. 1 H NMR (400 MHz, DMS0-D6) δ ppm 0.63 (t, 3 H) 1.31 (m, 2 H) 2.42 (m, 2 H) 3.36 (m, 1 H) 3.44 (m, 1 H) 3.60 (m, 2 H) 3.66 (t, 2 H) 3.86 (S, 3 H) 4.49 (m, 2 H) 6.85 (s, 1 H) 6.91 (d, 1 H) 7.36 (s, 1 H) 7.93 (t, 1 H) 8.07 (d, 1 H) 8.10 (dd, 1 H) 8.55 (d, 1 H) 8.57 (d, 1 H). HRMS m/z 427.2098 (calculated for M+H, 427.2208).
Example 20
7-(6-fluoropyridin-3-yl)-1-(4-methylpentyl)-3-r(2-morpholin-4-ylethyl)aminolPyridor2,3- b1pyrazin-2(1 H)-one
Figure imgf000070_0003
Example 20 was prepared by a method similar to that described in Example 1 using 4- methyl valeric acid in place of ethoxyacetic acid in step 1. HRMS m/z 455.2572 (calculated for M+H, 455.2565). Example 21
7-(4-fluorophenyl)-1-(4-methylpentyl)-3-r(2-morpholin-4-ylethvπaminolpyridor2.3-blpyrazin-
2(1 H)-one
Figure imgf000071_0001
Example 21 was prepared by a method similar to that described in Example 1 using 4- methyl valeric acid in place of ethoxyacetic acid in step 1 and 4-fluorobenzeneboronic acid in place of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine in step 7. HRMS m/z 454.2622 (calculated for M+H, 454.2613).
Example 22
7-(4-fluorophenyl)-3-f(2-morpholin-4-ylethyl)aminol-1-(tetrahvdrofuran-3-ylmethyl)pyridof2,3- bipyrazin-2(1 H)-one
Figure imgf000071_0002
Example 22 was prepared by a method similar to that described in Example 1 using 3- tetrahydrofuroic acid in place of ethoxyacetic acid in step 1 and 4-fluorobenzeneboronic acid in place of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine in step 7. Furthermore, the chlorodimidate of step 4 was prepared as a two step one pot synthesis from the diamine of step 2 as in Example 2 step 2. HRMS m/z 454.2262 (calculated for M+H, 454.2249).
Example 23
7-(6-methoxypyridin-3-yl)-1-(4-methylpentyl)-3-f(2-morpholin-4-ylethyl)aminolPyrido[2,3- blpyrazin-2(1 H)-one
Figure imgf000071_0003
Example 23 was prepared by a method similar to that described in Example 1 using 4- methyl valeric acid in place of ethoxyacetic acid in step 1 and 2-methoxy-5-pyridineboronic acid in place of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine in step 7. HRMS m/z 467.2783 (calculated for M+H, 467.2765).
Example 24
1-(cvclohexylmethyl)-7-(4-fluorophenylV3-l(2-morpholin-4-ylethyl)aminolpyridor2.3-bipyrazin- 2(1H)-one
Figure imgf000072_0001
Example 24 was prepared by a method similar to that described in Example 2 using cyclohexanecarboxaldehyde in place of tetrahydropyranyl-4-carboxadehyde in step 1 with a Dean Stark trap and catalytic glacial acetic acid added in place of the molecular sieves. HRMS m/z 466.2581 (calculated for M+H, 466.2613).
Example 25
7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-r(tetrahvdro-2H-pyran-4- ylmethyl)aminolpvridoJ2,3-bipvrazin-2(1 H)-one
Figure imgf000072_0002
Example 25 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and 4-aminomethyltetrahydropyran in place of 4-(2-aminoethyl)morpholine in step 5. 1 H NMR (400 MHz, METHANOL-D4) δ ppm 0.69 (t, 3 H) 1.37 (m, 4 H) 1.69 (m, 2 H) 2.06 (m, 1 H) 3.37 (m, 4 H) 3.46 (d, 2 H) 3.78 (t, 2 H) 3.93 (m, 5 H) 4.53 (t, 2 H) 6.89 (d, 1 H) 7.98 (dd, 1 H) 8.10{d, 1 H) 8.42 (d, 1 H) 8.46 (d, 1 H). HRMS /77/z 454.2458 (calculated for M+H, 454.2449).
Example 26 tert-butyl N-(7-(6-methoxypyridin-3-ylV2-oxo-1 -12-(2.2.2-trif luoroethoxytethylH ,2- dihvdropvridor2.3-blpvrazin-3-vl)qlycinate
Figure imgf000073_0001
Example 26 was prepared by a method similar to that described in Example 3 using glycine tert-butyl ester in place of 4-(2-aminoethyl)morpholine in step 5. HRMS m/z510.1954 (calculated for M+H, 510.1959).
Example 27
7-(6-methoxypyridin-3-yl)-3-r(tetrahvdro-2H-pyran-4-ylmethyl)amino1-1-r2-(2.2,2- trifluoroethoxy)ethyllpyridor2,3-blPyrazin-2(1H)-one
Figure imgf000073_0002
Example 27 was prepared by a method similar to that described in Example 3 using 4- aminomethyltetrahydropyran in place of 4-(2-aminoethyl)morpholine in step 5. HRMS m/z 494.2037 (calculated for M+H, 494.2010).
Example 28 N~2~-(7-(6-methoxypyridin-3-yl)-2-oxo-1-f2-(2.2,2-trifluoroethoxy)ethvn-1 ,2-dihydropyridor2.3- blpyrazin-3-yl>-N~1 ~.N~1 —dimethylglycinamide
Figure imgf000073_0003
Example 28 was prepared by a method similar to that described in Example 4 using propanol in place of 2,2,2-trifluoroethanol in step 1. HRMS m/z 481.1801 (calculated for M+H, 481.1806). Example 29
N~2~-f7-(6-methoxyPyridin-3-yl)-2-oxo-1-(2-propoxyethylV1,2-dihydropyridor2.3-biDyrazin-3- yliglvcinamide
Figure imgf000074_0001
Example 29 was prepared by a method similar to that described in Example 4 using glycinamide in place of N~1~,N~1 —dimethylglycinamide in step 6. HRMS /r»/z413.1919 (calculated for M+H, 413.1932).
Example 30
N~2~-f7-(6-methoxypyridin-3-yl)-2-oxo-1-(2-propoxyethvπ-1 ,2-dihvdropyridof2,3-bipyrazin-3- yll-N~1 —methylqlycinamide
Figure imgf000074_0002
Example 30 was prepared by a method similar to that described in Example NEW using N~1 — methylglycinamide in place of N~1 ~,N~1 —dimethylglycinamide in step 6. 1 H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.73 (t, 3 H) 1.45 (m, 2 H) 2.85 (d, 3 H) 3.33 <t, 2 H) 3.80 (t, 2 H) 3.99 (s, 3 H) 4.31 (d, 2 H) 4.47 (t, 2 H) 6.38 (s, 1 H) 6.85 (d, 1 H) 7.28 <m, 1 H) 7.80 (dd, 1 H) 7.97 (d, 1 H) 8.41 (d, 1 H) 8.57 (d, 1 H). HRMS m/z 427.2O74 (calculated for M+H, 427.2088).
Example 31
N~1 ~,N~1 ~-diethyl-N~2~-f7-(6-methoxypyridin-3-yl)-2-oxo-1 -(2-propoxyethyl)-1.2- dihvdropyrido[2,3-biPvrazin-3-vπαlvcinamide
Figure imgf000075_0001
Example 31 was prepared by a method similar to that described in Example 4 using N~1 ~,N~1~-diethylglycinamide in place of N~1 ~,N~1 ~-dimethylglycinamide in step 6. HRMS m/z 469.2517 (calculated for M+H, 469.2558).
Example 32
3-(2-morpholino-2-oxoethylamino)-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[2,3- b1pyrazin-2(1 HVone
Figure imgf000075_0002
Example 32 was prepared by a method similar to that described in Example 4 using 2- morpholin-4-yl-2-oxoethylamine in place of N~1 ~,N~1 —dimethylglycinamide in step 6. HRMS m/z 483.2355 (calculated for M+H, 483.2350).
Example 33
7-(6-methoxypyridin-3-yl)-3-r(1-methylpiperidin-4-yl)amino1-1-(2-propoxyethyl)pyridor2.3- blpyrazin-2(1 H)-one
Figure imgf000075_0003
Example 33 was prepared by a method similar to that described in Example 4 using 1- methylpiperidin-4-amine in place of N~1 ~,N~1 —dimethylglycinamide in step 6. HRMS m/z 453.2602 (calculated for M+H, 453.2609).
Example 34 tert-butyl 4-f l7-(6-methoxyPyridin-3-yl)-2-oxo-1 -(2-propoxyethyl)-1 ,2-dihvdropyridof2,3- biPvrazin-3-vl]amino)piperidine-1-carhoxvlate
Figure imgf000076_0001
Example 34 was prepared by a method similar to that described in Example 4 using tert- butyl 4-aminopiperidine-1-carboxylate in place of N~1 ~,N~1 ~-dimethylglycinamide in step 6. HRMS m/z 539.2947 (calculated for M+H, 539.2976).
Example 35 tert-butyl 2-f r7-(6-methoxypyridin-3-yl)-2-oxo-1 -(2-propoxyethylH ,2-dihydropyridof2,3- blpyrazin-3-vriamino)ethvlcarbamate
Figure imgf000076_0002
Example 35 was prepared by a method similar to that described in Example 4 using tert- butyl 2-aminoethylcarbamate in place of N~1 ~,N~1 —dimethylglycinamide in step 6. HRMS m/z 499.2656 (calculated for M+H, 499.2663).
Example 36
N~3~-f7-(6-methoxypyridin-3-yl')-2-oxo-1-(2-propoxyethvπ-1.2-dihvdropyridof2,3-bipyrazin-3- vIl-N-i —methyl-beta-alaninamide
Figure imgf000076_0003
Example 36 was obtained from Example 17 by the following peptide coupling reaction. To N-[7-(6-methoxypyridin-3-yl)-2-oxo-1 -(2-propoxyethyl)-1 ,2-dihydropyrido[2,3-b]pyrazin-3- yl]-beta-alanine (215.0 mg, 0.5 mmol) in Λ/,Λ/-dimethylformamide (1.7 ml.) was added O-(7- azabenzotriazol-1-yl)-Λ/,Λ/,Λ/',Λ/'-tetramethyluronium hexafluorophosphate (228.0 mg, 0.6 mmol) at room temperature. The reaction mixture stirred for 10 min and methylamine (2.0 M in tetrahydrofuran, 2.5 mL, 5.0 mmol) was added and subsequently heated to 5O0C. The reaction mixture stirred for 1 hour and the solvent was removed in vacuo. The crude material was purified via Biotage column chromatography (eluent = 3% methanol/methylene chloride to 5% methanol/methylene chloride (1.3 L, linear gradient) which resulted in 75 mg N~3~-[7- (6-methoxypyridin-3-yl)-2-oxo-1-(2-propoxyethyl)-1,2-dihydropyrido[2,3-b]pyrazin-3-yl]-N~1~- methyl-beta-alaninamide as a white solid. 1H NMR (400 MHz, CD3OD) δ 0.70 (t, 3 H), 1.42 (m, 2 H), 2.61 (t, 2 H), 2.72 (s, 3 H)1 3.35 (t, 2 H), 3.80 (m, 4 H), 3.95 <s, 3 H), 4.54 (t, 2 H), 6.91 (d, 1 H)1 8.01 (dd, 1 H), 8.14 (d, 1 H), 8.45 (d, 1 H), 8.49 (d, 1 H). HRMS m/z 441.2242 (calculated for M+H, 441.2245).
Example 37
3-(3-morpholino-3-oxopropylaminoV7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyltoyridof2,3- blpyrazin-2(1H)-one
Figure imgf000077_0001
Example 37 was prepared by a method similar to that described in Example 36 using morpholine in place of methylamine. 1H NMR (400 MHz, CD3OD) δ 0.70 (t, 3 H), 1.41 (m, 2 H), 2.83 (t, 2 H), 3.34 (t, 2 H), 3.55 (m, 4 H), 3.63 (m, 4 H), 3.79 (t, 2 H), 3.84 (t, 2 H), 3.95 <s, 3 H), 4.53 (t, 2 H), 6.89 (d, 1 H), 7.99 (dd, 1 H), 8.11 (d, 1 H), 8.43 (d, 1 H), 8.47 <d, 1 H). HRMS m/z 497.2530 (calculated for M+H, 497.2507).
Example 38
N~3~-ri-(2-ethoxyethyl)-7-(6-methoxypyridin-3-yl)-2-oxo-1 ,2-dihvdropyridor2.3-bipyrazin-3-yll-
N~1 ~.N~1 —diethvl-beta-alaninamide
Figure imgf000077_0002
Example 38 was prepared by a method similar to that described in Example 36 using diethylamine in place of methylamine. 1H NMR (400 MHz, CD3OD) δ 0.70 (t, 3 H), 1.10 (t, 3 H), 1.15 (t, 3 H), 1.42 (m, 2 H), 2.82 (t, 2 H), 3.38 (m, 6 H), 3.80 (t, 2 H), 3.86 (t, 2 H), 3.95 (s, 3 H), 4.55 (t, 2 H), 6.91 (d, 1 H), 8.01 (dd, 1 H), 8.14 (d, 1 H), 8.45 (d, 1 H), 8.48 (d, 1 H). HRMS m/z 483.2703 (calculated for M+H, 483.2714).
Example 39
N~1 ~-isopropyl-N~3~-r7-(6-methoxypyridin-3-yl)-2-oxo-1-(2-propoxyethyl)-1 ,2- dih vdropyridof2.3-b1pvrazin-3-vll-beta-alan inam ide
Figure imgf000078_0001
Example 39 was prepared by a method similar to that described in Example 36 using isopropylamine in place of methylamine. 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.70 (t,
3 H) 1.10 (S, 3 H) 1.12 (s, 3 H) 1.42 (m, 2 H) 2.58 (t, 2 H) 3.35 (t, 2 H) 3.80 (m, 4 H) 3.96 (m,
4 H) 4.55 (t, 2 H) 6.91 (m, 1 H) 8.01 (m, 1 H) 8.15 (m, 1 H) 8.45 (m, 1 H) 8.50 (m, 1 H). HRMS m/z 469.2537 (calculated for M+H, 469.2558).
Example 40 tert-butyl 4-((f7-(6-methoxypyridin-3-yl)-2-oxo-1 -(2-propoxyethyl)-1 ,2-dihvdropyridof2,3- blpyrazin-3-vHamino)methyl)piperidine-1-carboxvlate
Figure imgf000078_0002
Example 40 was prepared by a method similar to that described in Example 4 using tert- butyl 4-(aminomethyl)piperidine-1-carboxylate in place of N~1 ~,N~1 ~-dimethylglycinamide in step 6. 1 H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.74 (t, 3 H) 1.24{m, 2 H) 1.44 (s, 9 H) 1.48 (m, 2 H) 1.77 (d, 2 H) 1.91 (m, 1 H) 2.68 (m, 2 H) 3.34 (t, 2 H) 3.56 (m, 2 H) 3.79 (t, 2 H) 3.98 (S, 3 H) 4.12 (br. s., 2 H) 4.46 (t, 2 H) 6.72 (t, 1 H) 6.84 (d, 1 H) 7.80 (dd, 1 H) 7.91 (d, 1 H) 8.40 (d, 1 H) 8.58 (d, 1 H). HRMS m/z553.3143 (calculated for M+H, 553.3133).
Example 41
7-(6-methoxypyridin-3-yl)-3-r(piperidin-4-ylmethyl)amino1-1-(2-propoxyethyl)pyridof2,3- blpyrazin-2(1 H)-one trifluoroacetate
Figure imgf000078_0003
Example 41 was obtained from Example 40 by treatment with a 0.3 M solution of 20% trifluoroacetic acid and 80% methylene chloride (v/v). 1H NMR (400 MHz, CHLOROFORM- D) δ ppm 0.71 (t, 3 H) 1.44 (m, 2 H) 1.69 (m, 2 H) 1.97 (d, 2 H) 2.19 (m, 1 H) 2.91 (m, 2 H) 3.32 (t, 2 H) 3.44 (m, 2 H) 3.61 (s, 2 H) 3.80 (s, 2 H) 3.99 (s, 3 H) 4.48 (s, 2 H) 6.87 (d, 1 H) 7.56 (S1 1 H) 7.80 (d, 1 H) 8.27 (s, 1 H) 8.40 (s, 1 H) 8.51 (s, 1 H) 9.04 (s, 1 H). HRMS m/z 453.2601 (calculated for M+H, 453.2609).
Example 42
7-(6-methoxypyridin-3-yl)-3-(piperidin-4-ylamino)-1-(2-propoxyethyl)pyridor2.3-blpyrazin-
2(1HVone trifluoroacetate
Figure imgf000079_0001
Example 42 was obtained from Example 34 by treatment with a 0.3 M solution of 20% trifluoroacetic acid and 80% methylene chloride (v/v). 1 H NMR (400 MHz, METHANOL-D4) δ ppm 0.70 (t, 3 H) 1.42 (m, 2 H) 1.94 (m, 2 H) 2.32 (m, 2 H) 3.20 (m, 2 H) 3.35 (t, 2 H) 3.50 (m, 2 H) 3.81 (t, 2 H) 3.96 (s, 3 H) 4.37 (m, 1 H) 4.57 (t, 2 H) 6.92 (d, 1 H) 8.02 (dd, 1 H) 8.20 (d, 1 H) 8.46 (d, 1 H) 8.53 (d, 1 H). HRMS m/z 439.2449 (calculated for M+H, 439.2452).
Example 43
7-(6-methoxypyridin-3-yl)-3-((ri-(methylsulfonyl)piperidin-4-vnmethyllamino)-1-(2- propoxyethvl)pyridor2.3-blPvrazin-2( 1 H)-one
Figure imgf000079_0002
Example 43 was obtained from Example 41 by the following acid chloride reaction. To 7-
(6-methoxypyridin-3-yl)-3-[(piperidin-4-ylmethyl)amino]-1-(2-propoxyethyl)pyridot2,3- b]pyrazin-2(1 H)-one trifluoroacetate (250 mg, 0.4 mmol), triethylamine (307 DL, 2.2 mmol) in methylene chloride was added methanesulfonyl chloride (38 DL, 0.5 mmol) at room temperature. The reaction mixture stirred for 10 min and the solvent was removed in vacuo. The crude material was purified via Biotage column chromatography (eluent = 2% methanol/methylene chloride to 5% methanol/methylene chloride (1.5 L, linear gradient) which resulted in 110 mg 7-(6-methoxypyridin-3-yl)-3-({[1-(methylsulfonyl)piperidin-4- yl]methyl}amino)-1-(2-propoxyethyl)pyridot2,3-b]pyrazin-2(1 H)-one as a white solid. 1 H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.74 (t, 3 H) 1.45 (m, 4 H) 1.93 (m, 3 H) 2.66 (m, 2 H) 2.75 (s, 3 H) 3.34 (t, 2 H) 3.59 (t, 2 H) 3.80 (m, 4 H) 3.98 (s, 3 H) 4.47 (t, 2 H) 6.76 (t, 1 H) 6.85 (d, 1 H) 7.80 (dd, 1 H) 7.93 (d, 1 H) 8.40 (d, 1 H) 8.58 (d, 1 H). HRMS m/z 531.2382 (calculated for M+H, 531.2384).
Example 44
S-IFd-acetylpiperidin^-vDmethyllaminol^-fe-metrioxypyridin-S-vD-i^- propoxyeth yl)pyridof2.3-blpyrazin-2( 1 Ht-one
Figure imgf000080_0001
Example 44 was prepared by a method similar to that described in Example 43 using acetyl chloride in place of methanesulfonyl chloride. 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.71 (t, 3 H) 1.27 (m, 2 H) 1.42 (m, 2 H) 1.85 (m, 2 H) 2.08 (s, 3 H) 2.12 (m, 1 H) 2.63 (m, 1 H) 3.10 (m, 1 H) 3.36 (t, 2 H) 3.49 (m, 2 H) 3.81 (t, 2 H) 3.91 (m, 1 H) 3.95 (s, 3 H) 4.51 (m, 1 H) 4.56 (t, 2 H) 6.91 (d, 1 H) 8.01 (dd, 1 H) 8.13 (d, 1 H) 8.45 <d, 1 H) 8.48 (d, 1 H)HRMS m/z 495.2721 (calculated for M+H, 495.2714).
Example 45
3-(r(1-αlvcoloylpiperidin-4-yl)methvnamino>-7-(6-methoxypyridin-3-ylV1-(2- propoxyethvl)pyrido[2.3-blPvrazin-2(1 H)-one
Figure imgf000080_0002
Example 45 was obtained from Example 41 by the following peptide coupling reaction.
To 7-(6-methoxypyridin-3-yl)-3-[(piperidin-4-ylmethyl)amino]-1-(2-propoxyethyl)pyrido[2,3- b]pyrazin-2(1 H)-one trifluoroacetate (250.0 mg, 0.4 mmol) in Λ/,Λ/-dimethylformamide (2.0 mL) was added glycolic acid (37.0 mg, 0.5 mmol), triethylamine (307 DL, 2.2 mmol), and O-(7- azabenzotriazol-1-yl)-Λ/,Λ/,Λ/',Λ/-tetramethyluronium hexafluorophosphate (201.0 mg, 0.5 mmol) at room temperature. The reaction mixture stirred at room temperature for 30 min, and the solvent was removed in vacuo. The contents were partitioned between ethyl acetate and water, followed by ethyl acetate and brine. The solvent was removed in vacuo. The crude material was purified via Biotage column chromatography (eluent = 3% methanol/methylene chloride to 5% methanol/methylene chloride (1.3 L, linear gradient) which resulted in 70 mg 3- {[(1-glycoloylpiperidin-4-yl)methyl]amino}-7-(6-methoxypyridin-3-yl)-1-(2- propoxyethyl)pyrido[2,3-b]pyrazin-2(1H)-one as a white solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.74 (t, 3 H) 1.27 (m, 2 H) 1.46 (m, 2 H) 1.89 (m, 2 H) 2.10 (m, 1 H) 2.70 (m, 1 H) 2.97 (m, 1 H) 3.34 (t, 2 H) 3.53 (m, 2 H) 3.64 <m, 2 H) 3.80 (t, 2 H) 3.98 <s, 3 H) 4.13 (S, 2 H) 4.47 (t, 2 H) 4.60 (d, 1 H) 6.76 (t, 1 H) 6.85 (d, 1 H) 7.80 (dd, 1 H) 7.95 (d, 1 H) 8.40 (d, 1 H) 8.59 (d, 1 H). HRMS m/z511.2643 (calculated for M+H, 511.2663).
Example 46
4-(([7-(6-methoxypyridin-3-yl)-2-oxo-1-(2-propoxyethyl)-1,2-dihvdropyridof2.3-blpyrazin-3- yllamino}methyl)-N,N-dimethylpiperidine-1-carboxamide
Figure imgf000081_0001
Example 46 was prepared by a method similar to that described in Example 43 using dimethylcarbamyl chloride in place of methanesulfonyl chloride. 1 H NMR (400 MHz, METHANOL-D4) δ ppm 0.71 (t, 3 H) 1.29 (m, 2 H) 1.42 (m, 2 H) 1.79 (m, 2 H) 2.02 (m, 1 H) 2.75 (m, 2 H) 2.81 (s, 6 H) 3.36 (t, 2 H) 3.50 (d, 2 H) 3.68 (m, 2 H) 3.81 (t, 2 H) 3.95 (s, 3 H) 4.55 (t, 2 H) 6.91 (d, 1 H) 8.00 (dd, 1 H) 8.12 (d, 1 H) 8.44 (d, 1 H) 8.47 (d, 1 H). HRMS m/z 524.2989 (calculated for M+H, 524.2980).
Example 47
3-(([1-(2-methoxyethyl)piperidin-4-yllmethyl)amino)-7-(6-methoxypyridin-3-yl)-1-(2- propoxyethyl)pyridor2.3-blPvrazin-2(1H)-one
Figure imgf000081_0002
Example 47 was obtained from Example 41 by the following reaction. To 7-(6- methoxypyridin-3-yl)-3-[(piperidin-4-ylmethyl)amino]-1-(2-propoxyethyl)pyrido[2,3-b]pyrazin- 2(1H)-one trifluoroacetate (250 mg, 0.4 mmol) in Λ/,Λ/-dimethylformamide (1.5 mL) was added potassium carbonate (304 mg, 2.2 mmol), and 2-bromoethyl methyl ether (46.0 DL, 0.5 mmol) at room temperature. The reaction mixture was warmed to 5O0C for 5 hours and the solvent was removed in vacuo. The contents of the reaction vessel were partitioned between methylene chloride and water, followed by methylene chloride and brine. The crude material was purified via Biotage column chromatography (eluent = 5% methanol/methylene chloride to 9% methanol/methylene chloride (1.3 L, linear gradient) which resulted in 26 mg of 3-({[1- (2-methoxyethyl)piperidin-4-yl]methyl}amino)-7-(6-methoxypyridin-3-yl)-1-(2- propoxyethyl)pyrido[2,3-b]pyrazin-2(1H)-one as a white solid. 1 H NMR (400 MHz, METHANOL-D4) δ ppm 0.71 (t, 3 H) 1.42 (m, 4 H) 1.83 (d, 2 H) 1.90 (m, 1 H) 2.19 (m, 2 H) 2.66 (m, 2 H) 3.07 (d, 2 H) 3.32 (s, 3 H) 3.36 (t, 2 H) 3.49 (d, 2 H) 3.54 (t, 2 H) 3.81 (t, 2 H) 3.95 (s, 3 H) 4.56 (t, 2 H) 6.91 (d, 1 H) 8.01 (dd, 1 H) 8.14 (d, 1 H) 8.45 (d, 1 H) 8.48 (d, 1 H). HRMS m/z 511.3057 (calculated for M+H, 511.3027).
Example 48 3-(iri-(2-hvdroxyethyl)piperidin-4-vnmethyllamino)-7-(6-methoxyoyridin-3-yl)-1-,(2- propoxyethvl)pvridof2,3-blpvrazin-2( 1 HVone
Figure imgf000082_0001
Example 48 was prepared by a method similar to that described in Example 47 using 2- bromoethanol in place of 2-bromoethyl methyl ether. 1 H NMR (400 MHz, METHANOL-D4) δ ppm 0.69 (t, 3 H) 1.39 (m, 2 H) 1.49 (m, 2 H) 1.89 (d, 2 H) 1.98 (m, 1 H) 2.48 (m, 2 H) 2.81 (t, 2 H) 3.23 (m, 2 H) 3.34 (t, 2 H) 3.50 (d, 2 H) 3.73 (t, 2 H) 3.79 (t, 2 H) 3.94 (s, 3 H) 4.54 (t, 2 H) 6.89 (d, 1 H) 7.99 (dd, 1 H) 8.12 (d, 1 H) 8.43 (d, 1 H) 8.47 (d, 1 H). HRMS m/z 497.2875 (calculated for M+H, 497.2871).
Example 49
4-((r7-(6-methoxypyridin-3-ylV2-oxo-1-(2-propoxyethyl)-1 ,2-dihvdropyridof2,3-bipyrazin-3- yllamino)methyl)-N-methvlpiperidine-1-carboxamide
Figure imgf000083_0001
Example 49 was obtained from Example 42 by the following isocyanate reaction. To 7- (6-methoxypyridin-3-yl)-3-[(piperidin-4-ylmethyl)amino]-1-(2-propoxyethyl)pyrido[2,3- b]pyrazin-2(1 H)-one trifluoroacetate (250 mg, 0.4 mmol) in methylene chloride (1.5 ml.) was added Λ/,Λ/-diisopropylethylamine (383 DL, 2.2 mmol) at room temperature and stirred for 5 min. The reaction mixture was cooled to 0 0C and methyl isocyanate (28.0 mg, 0.5 mmol) was added and the mixture warmed to room temperature then stirred for 20 min. Diethyl ether was added to the mixture, stirred for 10 min, then filtered to afford 165 mg of 4-({[7-(6- methoxypyridin-3-yl)-2-oxo-1-(2-propoxyethyl)-1 ,2-dihydropyrido[2J3-b]pyrazin-3- yl]amino}methyl)-N-methylpiperidine-1-carboxamide as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 0.69 (t, 3 H), 1.18 (m, 2 H), 1.40 (m, 2 H), 1.76 (m, 2 H), 2.02 (m, 1 H), 2.67 (s, 3 H), 2.74 (m, 2 H), 3.34 (t, 2 H), 3.47 (d, 2 H), 3.79 (t, 2 H), 3.93 (s, 3 H), 3.97 (m, 2 H), 4.54 (t, 2 H), 6.98 (d, 1 H), 7.99 (dd, 1 H), 8.11 (d, 1 H), 8.43 (d, 1 H), 8.46 (d, 1 H). HRMS m/z 510.2822 (calculated for M+H, 510.2823). Example 50
3-(fri-(3-hvdroxypropyl)piperidin-4-vnmethyl)amino)-7-(6-methoxypyridin-3-yl)-1-(2- propoxyethvl)pyrido[2.3-blpvrazin-2(1 H)-one
Figure imgf000083_0002
Example 50 was prepared by a method similar to that described in Example 47 using 3- bromo-1-propanol in place of 2-bromoethyl methyl ether. 1H NMR (400 MHz, CD3OD) δ 0.69 (t, 3 H), 1.41 (m, 4 H), 1.76 (m, 2 H), 1.87 (d, 2 H), 1.94 (m, 1 H), 2.26 (m, 2 H), 2.65 (m, 2 H), 3.14 (d, 2 H), 3.34 (t, 2 H), 3.48 (d, 2 H), 3.59 (t, 2 H), 3.79 (t, 2 H), 3.94 <s, 3 H), 4.54 (t, 2 H), 6.89 (d, 1 H), 7.99 (dd, 1 H), 8.12 (d, 1 H), 8.43 (d, 1 H), 8.46 (d, 1 H). HRMS m/z 511.3045 (calculated for M+H, 511.3027). Example 51
3-r(1-acetylpiperidin-4-yl)amino1-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyridor2,3- bipyrazin-2(1 H)-one
Figure imgf000084_0001
Example 51 was prepared from Example 42 by a method similar to that described in
Example 43 using acetyl chloride in place of methanesulfonyl chloride. 1 H NMR (400 MHz, METHANOL-D4) δ ppm 0.70 (t, 3 H) 1.42 (m, 2 H) 1.60 (m, 2 H) 2.11 (m, 5 H) 2.86 (m, 2 H) 3.35 (t, 2 H) 3.80 (t, 2 H) 3.97 (m, 4 H) 4.36 (m, 1 H) 4.54 (m, 3 H) 6.91 (d, 1 H) 8.01 {dd, 1 H) 8.13 (d, 1 H) 8.45 (d, 1 H) 8.49 (d, 1 H). HRMS m/z 481.2565 (calculated for M+H, 481.2558).
Example 52
7-(6-methoxypyridin-3-yl)-3-(ri-(methylsulfonyl)piperidin-4-yl]aminoH-(2- propoxyethvl)pyrido[2,3-blpvrazin-2( 1 HVone
Figure imgf000084_0002
Example 52 was prepared from Example 42 by a method similar to that described in
Example 43. 1H NMR (400 MHz, CDCI3) δ 0.73 (t, 3 H), 1.45 (m, 2 H), 1.71 (m, 2 H), 2.26<m, 2 H), 2.81 (s, 3 H), 2.91 (m, 2 H), 3.34 (t, 2 H), 3.81 (m, 4 H), 3.98 (s, 3 H), 4.37 (m, 1 H), 4.47 (t, 2 H), 6.59 (d, 1 H), 6.85 (d, 1 H), 7.80 (dd, 1 H), 7.96 (d, 1 H), 8.40 (d, 1 H), 8.58 (d, 1 H). HRMS m/z 517.2238 (calculated for M+H, 517.2228). Example 53
4-fr7-(6-methoxypyridin-3-yl)-2-oxo-1-(2-propoxyethyl)-1.2-dihvdropyridof2,3-blpyrazin-3- Vllaminol-N .N-dimethvlpiperidine-1-carboxam ide
Figure imgf000084_0003
Example 53 was prepared from Example 42 by a method similar to that described in Example 43 using dimethylcarbamyl chloride in place of methanesulfonyl chloride. 1H NMR (400 MHz, CD3OD) δ 0.70 (t, 3 H), 1.42 (m, 2 H), 1.65 (m, 2 H), 2.08 (m, 2 H), 2.85 (s, 6 H), 2.98 (m, 2 H), 3.35 (t, 2 H), 3.72 (m, 2 H), 3.80 (t, 2 H), 3.95 (s, 3 H), 4.29 (m, 1 H), 4.55 (t, 2 H), 6.90 (d, 1 H), 8.00 (dd, 1 H), 8.12 (d, 1 H), 8.44 (d, 1 H), 8.48 (d, 1 H). HRMS m/z 510.2779 (calculated for M+H, 510.2823).
Example 54
4-(F7-(6-methoxypyridin-3-yl)-2-oxo-1-(2-propoxyethylV1.2-dihvdropyridor2.3-blPyrazin-3- yliaminol-N-methylpiperidine-i-carboxamide
Figure imgf000085_0001
Example 54 was prepared from Example 42 by a method similar to that described in Example 49. 1H NMR (400 MHz, CD3OD) δ 0.71 (t, 3 H), 1.42 (m, 2 H), 1.57 (m, 2 H), 2.06 (d, 2 H), 2.72 (S, 3 H), 2.98 (m, 2 H), 3.35 (t, 2 H), 3.80 (t, 2 H), 3.96 (s, 3 H), 4.03 (d, 2 H), 4.31 (m, 1 H), 4.56 (t, 2 H), 6.91 (d, 1 H), 8.01 (dd, 1 H), 8.15 (d, 1 H), 8.45 (d, 1 H), 8.49 (d, 1 H). HRMS m/z 496.2698 (calculated for M+H, 496.2667).
Example 55
3-f(1-qlvcoloylpiperidin-4-yl)amino1-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyridof2,3- bipyrazin-2(1 H)-one
Figure imgf000085_0002
Example 55 was prepared from Example 42 by a method similar to that described in
Example 45. 1 H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.73 (m, 3 H) 1.46 (m, 4 H) 2.24 (dd, 2 H) 2.97 (m, 1 H) 3.19 (m, 1 H) 3.34 (t, 2 H) 3.57 (m, 2 H) 3.80 (m, 2 H) 3.98 (s, 3 H) 4.18 (s, 2 H) 4.47 (m, 2 H) 4.59 (d, 1 H) 6.56 (m, 1 H) 6.85 (d, 1 H) 7.80 (dd, 1 H) 7.97 (s, 1 H) 8.41 (d, 1 H) 8.59 (d, 1 H). HRMS m/z 497.2512 (calculated for M+H, 497.2507). Example 56
3-(π-(2-hvdroxyethyl)piperidin-4-vnamino)-7-(6-methoxypyridin-3-yl)-1-(2- propoxyethvl)pvridor2.3-bipyrazin-2( 1 H)-one
Figure imgf000086_0001
Example 56 was prepared from Example 42 by a method similar to that described in Example 47 using 2-bromoethanol in place of 2-bromoethyl methyl ether. 1H NMR (400 MHz, CD3OD) δ 0.69 (t, 3 H), 1.40 (m, 2 H), 1.72 (m, 2 H), 2.07 (d, 2 H), 2.32 (t, 2 H), 2.59 (t, 2 H), 3.03 (d, 2 H), 3.33 (t, 2 H), 3.69 (t, 2 H), 3.78 (t, 2 H), 3.93 (s, 3 H), 4.14 (m, 1 H), 4.53 (t, 2 H), 6.89 (d, 1 H), 7.98 (dd, 1 H), 8.11 (d, 1 H), 8.42 (d, 1 H), 8.46 (d, 1 H). HRMS m/z 483.2748 (calculated for M+H, 483.2714).
Example 57
3-{f1-(3-hvdroxypropyl)piperidin-4-vnamino)-7-(6-methoxypyridin-3-yl)-1-(2- propoxyeth yl)pyridor2,3-blpyrazin-2( 1 H)-one
Figure imgf000086_0002
Example 57 was prepared from Example 42 by a method similar to that described in Example 47 using 3-bromo-1-propanol in place of 2-bromoethyl methyl ether. 1 H NMR (400 MHz, METHAN0L-D4) δ ppm 0.71 (t, 3 H) 1.42 (m, 2 H) 1.75 (m, 4 H) 2.11 (d, 2 H) 2.26 (m, 2 H) 2.54 (m, 2 H) 3.04 (m, 2 H) 3.36 (t, 2 H) 3.63 (t, 2 H) 3.81 (t, 2 H) 3.96 (s, 3 H) 4.18 (m, 1 H) 4.56 (t, 2 H) 6.92 (d, 1 H) 8.01 (dd, 1 H) 8.15 (d, 1 H) 8.45 (d, 1 H) 8.49 (d, 1 H). HRMS m/z 497.2839 (calculated for M+H, 497.2871).
Example 58
3-(ri-(2-methoxyethyl)piperidin-4-yllamino)-7-(6-methoxypyridin-3-vπ-1-(2- propoxyethyl)pyrido[2,3-blPyrazin-2( 1 H)-one
Figure imgf000086_0003
Example 58 was prepared from Example 42 by a method similar to that described in Example 47. 1H NMR (400 MHz, CD3OD) δ 0.70 <t, 3 H), 1.42 (m, 2 H), 1.72 (m, 2 H), 2.07 (d, 2 H), 2.27 (t, 2 H), 2.62 (t, 2 H), 3.01 (d, 2 H), 3.35 (m, 5 H), 3.55 (t, 2 H), 3.80 (t, 2 H), 3.95 (s, 3 H)1 4.14 (m, 1 H), 4.55 (t, 2 H), 6.90 (d, 1 H), 8.00 (dd, 1 H), 8.12 (d, 1 H), 8.44 (d, 1 H), 8.47 (d, 1 H). HRMS m/z 497.2861 (calculated for M+H, 497.2871).
Example 59
3-((2-rbis(2-hvdroxyethyl)aminolethyllamino)-7-(6-methoxypyridin-3-yl)-1-(2- propoxyethyl)pyridor2,3-bipyrazin-2(1 H)-one
Figure imgf000087_0001
Example 59 was obtained by a method similar to that described in Example 4 using N1N- bis(2-hydroxyethyl)ethylene diamine in place of N~1 ~,N~1 ~-dimethylglycinamide in step 6. 1H NMR (400 MHz, CD3OD) δ 0.71 (t, 3 H), 1.42 (m, 2 H), 2.78 (m, 4 H), 2.91 (m, 2 H), 3.35 (t, 2 H), 3.63 (m, 4 H), 3.69 (t, 2 H), 3.80 (t, 2 H), 3.95 (s, 3 H), 4.55 (t, 2 H), 6.91 (d, 1 H), 8.00 (dd, 1 H), 8.13 (d, 1 H), 8.44 (d, 1 H), 8.48 (d, 1 H). HRMS m/z 487.2668 (calculated for M+H, 487.2663).
Example 60 3-r(2-aminoethyl)aminol-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyridor2.3-blpyrazin-
2(1H)-one hydrochloride
Figure imgf000087_0002
Example 60 was prepared from Example 35 by a method similar to that described in Example 41. 1 H NMR (400 MHz, METHANOL-D4) δ ppm 0.72 (t, 3 H) 1.42 (m, 2 H) 3.37 (m, 4 H) 3.85 (t, 2 H) 3.98 (t, 2 H) 4.15 (s, 3 H) 4.67 (t, 2 H) 7.38 (d, 1 H) 8.50 (dd, 1 H) 8.67 (d, 1 H) 8.74 (d, 1 H) 8.78 (d, 1 H). HRMS m/z 399.2142 (calculated for M+H, 399.2139).
Example 61
2-hvdroxy-N-(2-(f7-(6-methoxypyridin-3-yl)-2-oxo-1-(2-propoxyethyl)-1.2-dihvdropyridof2.3- blpvrazin-3-vnam inoleth vDacetam ide
Figure imgf000088_0001
Example 61 was prepared from Example 60 by a method similar to that described in Example 45. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.73 (t, 3 H) 1.46 (m, 3 H) 3.34 (t, 2 H) 3.65 (m, 2 H) 3.80 (m, 4 H) 3.99 (s, 3 H) 4.11 (s, 2 H) 4.46 (t, 2 H) 6.86 (d, 1 H) 7.15 (t, 1 H) 7.79 (dd, 1 H) 8.02 (d, 1 H) 8.06 (m, 1 H) 8.40 (d, 1 H) 8.51 (d, 1 H). HRMS m/z 457.2203 (calculated for M+H, 457.2194).
Example 62
3-(f2-f(2-hvdroxyethyl)aminolethyl)amino)-7-(6-methoxypyridin-3-yl)-1-(2- propoxyeth yl)pyridor2,3-blpvrazin-2( 1 H)-one
Figure imgf000088_0002
Example 62 was prepared by a method similar to that described in Example 4 using 2-(2- aminoethylamino)ethanol in place of N~1 ~,N~1 ~-dimethylglycinamide in step 6. 1 H NMR (400 MHz, METHANOL-D4) δ ppm 0.70 (t, 3 H) 1.42 (m, 2 H) 3.21 (m, 2 H) 3.37 (m, 4 H) 3.81 (m, 4 H) 3.89 (t, 2 H) 3.96 (s, 3 H) 4.54 (t, 2 H) 6.93 (d, 1 H) 8.02 (dd, 1 H) 8.18 (d, 1 H) 8.45 (d, 1 H) 8.53 (d, 1 H). HRMS m/z 443.2383 (calculated for M+H, 443.2401).
Example 63
3-rethyl(methyl)amino1-7-(6-methoxypyridin-3-yl)-1-/2-propoxyethyl)pyridor2,3-b1pyrazin-
2(1 H)-one
Figure imgf000088_0003
Example 63 was prepared by a method similar to Example 4 using N-methyl-N- ethylamine in place of N~1 ~,N~1 — dimethylglycinamide in step 6. 1H NMR (CD3SOCD3) § 8.55 (dd, 2H), 8.10 (dd, 1 H), 8.05 (d, 1 H), 6.92 (d, 1 H), 4.45 (t, 2H), 3.87 (bs, 6H), 3.66 (t, 2H), 3.65 (m, 2H),3.29 (m, 2H), 1.32 (m, 2H), 1.18 (t, 3H), 0.66 (t, 3H). HRMS m/z398.2161 (calculated for M+H, 398.2187).
Example 64 3-(isopropoxyamino)-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyridor2.3-blpyrazin-2(1 H)- one
Figure imgf000089_0001
Example 64 was prepared by a method similar to that described in Example 4 using isoporpoxyamine in place of of N~1 ~,N~1 ~-dimethylglycinamide in step 6. 1H NMR (400 mHz, (CDg)2SO) .510.15 (s, 1H), 8.51 (m, 1H), 8.25 (bs, 1H), 8.05 (dd,1H), 7.89 (s, 1H), 6.90 (d,
1 H), 4.31 (m, 3H), 3.86 (s, 3H), 3.63 (t, 2H), 3.28 (m, 2H), 1.36 (m, 2H), 1.24 (d, 6H), 0.68 (t, 3H). HRMS m/z 414.2135 (calculated for M+H, 414.2136).
Example 65
3-(methoxyamino)-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyridor2,3-blpyrazin-2(1 H)- one
Figure imgf000089_0002
Example 65 was prepared by a method similar to that described in Example 4 using methoxyamine in place of of N~1~,N~1— dimethylglycinamide in step 6. 1H NMR (400 mHz, (CDg)2SO) 810.42 (s, 1H), 8.49 (d, 1 H), 8.23 (d, 1 H), 8.03, (dd, 1 H), 7.87 (d, 1H), 6.89 (d,1H), 4.31 (t, 2H), 3.85 (m, 6H), 3.61 (t, 2H), 3.27 (t, 2H), 1.32 (m, 2H), 0.66 (t, 3H). HRMS m/z 386.1841 (calculated for M+H, 386.1823).
Example 66
3-rmethoxy(methyl)aminol-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyridor2.3-blpyrazin-
2(im-one
Figure imgf000090_0001
Example 66 was prepared by a method similar to that described in Example 4 using N1O- dimethylhydroxylamine in place of of N~1 ~,N~1 ~-dimethylglycinamide in step 6. 1H NMR (400 mHz, (CDa)2SO) δ 8.69 (d, 1H), 8.63 (d, 1H), 8.19 (d, 1H), 8.17 (dd, 1H), 6.95 (d, 1 H), 4.51 (t, 2H), 3.89 (s, 3H), 3.79 (s, 3H), 3.68 (t, 2H), 3.36 (s, 3H), 3.30 (t, 2H), 1.31 (m, 2H), 0.63 (t, 3H). HRMS m/z 400.1979 (calculated for M+H, 400.1979).
Example 67 3-(isobutylamino)-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[2,3-blpyrazin-2(1H)-one
Example 67 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and isobutylamine in place of 4-(2- aminoethyl)morpholine in step 5. 1H NMR ((CD3)2SO) δ 8.56 (d, 2H, J = 12.5 Hz), 8.11 (d, 1 H, J = 8.5 Hz), 8.07 (s, 2H), 6.92 (d, 1H, J = 8.5 Hz), 4.52 (s, 2H), 3.88 (s, 3H), 3.70 (d, 2H, J = 8.2 Hz), 3.26 (m, 4H), 2.03 (m, 1H), 1.33 (m, 2H), 0.88 (d, 6H, J = 6.6 Hz), 0.65 (t, 3H, J = 7.4 Hz). HRMS m/z 412.2326, (calculated for M+H, 412.2343).
Example 68
7-(3.5-dimethylisoxazol-4-vπ-3-(isobutylamino)-1-(2-propoxyethyl)pyridor2,3-blpyrazin-2(1 H)- one
Example 68 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , isobutylamine in place of 4-<2- aminoethyl)morpholine in step 5, and 3,5-dimethylisoxazole-4-boronic acid in place of 2- methoxy-5-pyridineboronic acid in step 6. 1H NMR ((CD3)2SO) δ 8.23 (d, 1H, J = 1.9 Hz), 8.11 (m, 1 H), 7.82 (d, 1H, J = 2.0 Hz), 4.44 (t, 2H, J = 5.4 Hz), 3.66 (t, 2H, J = 5.4 Hz), 3.26 (m, 4H), 2.41 (s, 3H), 2,23 (s, 3H), 2.03 (m, 1H), 1.32 (m, 2H), 0.88 (d, 6H, J = 6.7 Hz), 0.65 (t, 3H, J = 7.4 Hz). HRMS m/z 400.2373, (calculated for M+H, 400.2343).
Example 69 7-(4-fluorophenyl)-3-(isobutylamino)-1-(2-propoxyethyl)pyridor2.3-biPyrazin-2(1H)-one
Figure imgf000091_0001
Example 69 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , isobutylamine in place of 4-(2- aminoethyl)morpholine in step 5, and 4-fluorophenylboronic acid in place of 2-methoxy-5- pyridineboronic acid in step 6. 1H NMR ((CDg)2SO) δ 8.53 (d, 1 H, J = 2.0 Hz), 8.07 (m, 2H), 7.80 (m, 2H), 7.31 (t, 2H, J = 8.9 Hz), 4.52 (t, 2H, J = 5.3 Hz), 3.69 (t, 2H, J = 5.4 Hz), 3.29 (m, 4H), 2.04 (m, 1H), 1.33 (m, 2H), 0.88 (d, 6H, J = 6.7 Hz), 0.65 (t, 3H, J = 7.4 Hz). HRMS m/z 399.2204, (calculated for M+H, 399.2191).
Example 70 3-(isopropylam ino)-7-(6-m ethoxypyridin-3-yl)- 1 -(2-propoxyethyl)pyridof2,3-biPyrazin-2( 1 H)- one
Figure imgf000091_0002
Example 70 was prepared by a method similar to that described in Example 4 using isoproylamine in place of N~1 ~,N~1 ~-dimethylglycinamide in step 6. 1H NMR ((CD3)2SO) δ 8.58 (d, 1H, J = 2.1 Hz), 8.56 (d, 1H, J = 2.2 Hz), 8.12 (d of d, 1H, J = 8.7 Hz, J' = 2.6 Hz), 8.10 (m, 1 H), 8.07 (d, 1 H, J = 2.1 Hz), 6.93 (d, 1H, J = 8.6 Hz), 4.51 (t, 2H, J = 5.4 Hz), 4.29 (m, 1H), 3.88 (s, 3H), 3.69 (t, 2H, J = 5.5 Hz), 3.29 (m, 2H), 1.33 (m, 2H), 1.22 (d, 6H, J = 6.6 Hz), 0.65 (t, 3H, J = 7.5 Hz). HRMS m/z 398.2161, (calculated for M+H, 298.2187).
Example 71 : 3-(cvclohexylamino)-7-(6-methoxypyridin-3-vh-1-/2-propoxyethyl)pyridof2,3-blpyrazin-2(1 H)- one
Figure imgf000092_0001
Example 71 was prepared by a method similar to that described in Example 4 using cyclohexylamine in place of N~1 ~,N~1 ~-dimethylglycinamide in step 6. 1H NMR ((CD3)2SO) δ 8.58 (d, 1H, J = 2.0 Hz), 8.55 (d, 1H, J = 2.0 Hz), 8.12 (d of d, 1H, J = 8.7 Hz, J' = 2.6 Hz), 8.07 (d, 1 H, J = 2.2 Hz), 7.70 (d, 1 H, J = 8.6 Hz), 6.93 (d, 1 H, J = 8.6 Hz), 4.51 (t, 2H, J = 5.4 Hz), 3.98 (m, 1H), 3.88 (s, 3H), 3.69 (t, 2H, J = 5.5 Hz), 3.29 (m, 2H), 1.86 (m, 2H)1 1.73 (m, 2H), 1.60 (m, 1H), 1.37 (m, 6H)1 1.15 (m, 1 H)1 0.65 (t, 3H, J = 7.4 Hz). HRMS m/z 438.2492, (calculated for M+H, 438.2500).
Example 72
3-(cvclopropylamino)-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyridor2,3-bipyrazin-2(1H)- one
Figure imgf000092_0002
Example 72 was prepared by a method similar to that described in Example 4 using cyclopropylamine in place of N~1 ~,N~1 ~-dimethylglycinamide in step 6. 1H NMR ((CD3)2SO) δ 8.59 (m, 2H), 8.13 (d of d, 1 H1 J = 8.7 Hz, J1 = 2.6 Hz), 8.09 (m, 2H), 6.93 (d, 1 H, J = 8.6 Hz)1 4.51 (t, 2H, J = 5.4 Hz), 3.88 (s, 3H)1 3.68 (t, 2H, J = 5.4 Hz), 3.29 (m, 2H), 3.00 (m, 1H), 1.33 (m, 2H), 0.72 (m, 4H), 0.65 (t, 3H, J = 7.4 Hz). HRMS m/z 396.2024, (calculated for M+H, 396.2030).
Example 73 3-(diethylamino)-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyridor2.3-blpyrazin-2(1H)-one
Figure imgf000092_0003
Example 73 was prepared by a method similar to that described in Example 4 using diethylamine in place of N~1~,N~1~-dimethylglycinamide in step 6. 1H NMR ((CD3)2SO) δ 8.57 (d, 1 H, J = 2.3 Hz)1 8.52 (d, 1H1 J = 1.9 Hz)1 8.11 (d of d, 1H, J = 8.7 Hz, J' = 2.4 Hz)1 8.01 (d, 1H1 J = 1.9 Hz), 6.93 (d, 1H1 J = 8.6 Hz), 4.46 (t, 2H, J = 5.4 Hz)1 3.88 (s, 3H)1 3.79 (m, 4H)1 3.66 (t, 2H, J = 5.4 Hz)1 3.30 (m, 2H), 1.34 (m, 2H)1 1.21 (t, 6H, J = 6.9 Hz), 0.66 (t, 3H, J = 7.4 Hz). HRMS m/z 412.2328, (calculated for M+H, 412.2343).
Example 74
7-(6-methoxypyridin-3-ylV1-(2-propoxyethyl)-3-(tetrahvdro-2H-pyran-4-ylamino)pyridor2,3- blpyrazin-2(1 HVone
Figure imgf000093_0001
Example 74 was prepared by a method similar to that described in Example 4 using aminotetrahydropyran in place of N~1 ~,N~1 ~-dimethylglycinamide in step 6. 1H NMR ((CDs)2SO) δ 8.58 (d, 1 H, J = 2.3 Hz), 8.56 (d, 1 H, J = 2.0 Hz), 8.12 (d of d, 1H1 J = 8.6 Hz, J' = 2.6 Hz), 8.08 (d, 1 H, J = 2.0 Hz)1 7.91 (d, 1 H, J = 8.3 Hz), 6.93 (d, 1 H, J = 8.6 Hz), 4.52 (t, 2H, J = 5.4 Hz), 4.22 (m, 1H), 3.88 9m, 5H), 3.69 (t, 2H, J = 5.4 Hz), 3.41 (t, 2H1 J = 9.7 Hz)1 3.29 (m, 2H)1 1.74 (m, 4H), 1.33 (m, 2H), 0.65 (t, 3H, J = 7.4 Hz). HRMS m/z 440.2296, (calculated for M+H, 440.2292).
Example 75 3-(cvclopentylaminoV7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyridor2.3-blpyrazin-2(1HV one
Figure imgf000093_0002
Example 75 was prepared by a method similar to that described in Example 4 using cyclopentylamine in place of N~1 ~,N~1 —dimethylglycinamide in step 6. 1H NMR ((CD3)2SO) δ 8.58 (d, 1 H1 J = 2.0 Hz)1 8.56 (d, 1 H, J = 2.2 Hz), 8.12 (d of d, 1 H, J = 8.7 Hz1 J' = 2.6 Hz), 8.07 (d, 1 H, J = 2.2 Hz), 7.81 (d, 1 H, J = 7.8 Hz), 6.93 (d, 1 H, J = 8.6 Hz), 4.51 (t, 2H, J = 5.4 Hz), 4.39 (m, 1H), 3.88 (s, 3H), 3.69 (t, 2H, J = 5.4 Hz), 3.29 (m, 2H), 1.94 (m, 2H), 1.62 (m, 6H), 1.33 (m, 2H), 0.65 (t, 3H1 J = 7.4 Hz). HRMS m/z 424.2315, (calculated for M+H, 424.2343). Example 76
7-(2-methoxypyrimidin-5-ylV3-?f3-(2-oxopyrrolidin-1-yl^propynamino)-1-(2- propoxyethvDpyridor2,3-biPvrazin-2( 1 H)-one
Figure imgf000094_0001
Example 76 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , 1-(3-aminopropyl)pyrrolidin-2-one in place of 4-(2-aminoethyl)morpholine in step 5, and 2-methoxypyrimidin-5-ylboronic acid in place of 2-methoxy-5-pyridineboronic acid in step 6. 1H NMR (CDCI3) δ 8.72 (s, 2H), 8.51 (d, 1 H), 7.91 (d, 1H), 7.41-7.44 (m, 1 H), 4.43 (t, 2H), 4.04 (s, 3H), 3.78 (t, 2H), 3.65 (q, 2H), 3.37-3.41 (m, 4H), 3.32 (t, 2H), 2.39 (t, 2H), 1.98-2.06 (m, 2H), 1.88-1.92 (m, 2H), 1.38-1.47 (m, 2H), 0.70 (t,3H). ). HRMS m/z 482.2487, (calculated for M+H, 482.2510).
Example 77
7-(4-fluorophenyl)-3-ff3-(2-oxopyrrolidin-1-yl)propyπaminoM-(2-propoxyethyl)pyrido[2,3- blpyrazin-2(1 H)-one
Figure imgf000094_0002
Example 77 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , 1-(3-aminopropyl)pyrrolidin-2-one in place of 4-(2-aminoethyl)morpholine in step 5, and 4-flouroboronic acid in place of 2-methoxy-5- pyridineboronic acid in step 6. 1H NMR (CDCI3) δ 8.54 (d, 1 H), 7.90 (d, 1 H), 7.51-7.55 (m, 2H), 7.28-7.31 (m, 1H), 7.10-7.14 (m, 2H), 4.43 (t, 2H), 3.77 (t, 2H), 3.63 (q, 2H), 3.36-3.40 (m, 4H), 3.31 (t, 2H), 2.37 (t, 2H), 1.97-2.03 (m, 2H), 1.84-1.91 (m, 2H), 1.38-1.47 (m, 2H), 0.72 (t, 3H). HRMS m/z 468.2428, (calculated for M+H, 468.2405).
Example 78
7-(4-fluorophenyl)-3-(r(5-methylpyrazin-2-yl)methyllamino)-1-(2-propoxyethyl)pyridof2.3- bipyrazin-2(1 H)-one
Figure imgf000094_0003
Example 78 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , (5-methylpyrazin-2-yl)methylamine in place of 4-(2-aminoethyl)morpholine in step 5, and 4-flouroboronic acid in place of 2-methoxy- 5-pyridineboronic acid in step 6.
1H NMR (CDCI3) δ 8.59 (d, 1 H), 8.56 (d, 1H), 8.40 (s, 1H), 7.95, (d, 1 H), 7.53-7.57 (m, 2H), 7.47-7.50 (m, 1 H), 7.14 (t, 2H), 4.95 (d, 2H), 4.47 (t, 2H), 3.32 (t, 2H), 2.53 (s, 3H), 1.59 (s, 2H), 1.40-1.48 (m, 2H), 0.72 <t, 3H). HRMS m/z 449.2135 , (calculated for M+H, 449.2096).
Example 79
7-(3.5-dimethylisoxazol-4-yl)-3-fr(5-methylpyrazin-2-yl)methyllamino)-1-(2- propoxyethyl)pyridor2,3-bipyrazin-2(1 HVone
Figure imgf000095_0001
Example 79 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1, (5-methylpyrazin-2-yl)methylamine in place of 4-(2-aminoethyl)morpholine in step 5, and 4-3,5-dimethylisoxazol-4-ylboronic acid in place of 2-methoxy-5-pyridineboronic acid in step 6. 1H NMR (CDCI3) δ 8.59 (d, 1 H), 8.56 (d, 1 H), 8.29 (d, 1 H), 7.67 (d, 1 H), 7.51-7.54 (m, 1 H), 4.95 (d, 2H), 4.40 (t, 2H), 3.76 (t, 2H), 3.29 (t, 2H), 2.53 (s, 3H), 2.40 (s, 3H), 2.26 (s, 3H), 1.59 (s, 2H), 1.35-1.44 (m, 2H), 0.69 (t, 3H). HRMS m/z 450.2284, (calculated for M+H, 450.2248).
Example 80
7-(6-methoxypyridin-3-yl)-3-(r(5-methylpyrazin-2-yl)methvnamino)-1-(2- propoxyethyl)pyrido[2.3-biPvrazin-2( 1 H)-one
Figure imgf000095_0002
Example 80 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and (5-methylpyrazin-2-yl)methylamine in place of 4-(2-aminoethyl)morpholine in step 5. 1H NMR (CDCI3) δ 8.55-8.57 (m, 2H), 8.39- 8.40 (m, 2H), 7.92 (d, 1 H), 7.77-7.80 (m, 1H), 7.48-7.51 (m, 1 H), 6.82-6.84 (m, 1H), 4.96 (d, 2H), 4.46 (t, 2H), 3.96 (s, 3H), 3.78 (t, 2H), 3.31 (t, 2H), 2.53 (s, 3H), 1.60 (s, 2H), 1.41 -1.46 (m, 2H), 0.71 (t, 3H). HRMS m/z 462.2293, (calculated for M+H, 462.2248).
Example 81 7-(4-fluorophenylV1-(2-propoxyethyl)-3-r(pyridin-2-ylmethyl)aminolpyridor2,3-blpyrazin-2(1H)- one
Figure imgf000096_0001
Example 81 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , 2-aminomethylpyridine in place of 4-(2- aminoethyl)morpholine in step 5, and 4-flouroboronic acid in place of 2-methoxy-5- pyridineboronic acid in step 6. 1H NMR (CDCI3) δ 8.56-8.58 (m, 2H), 7.93 (d, 1H), 7.77-7.80 (m, 1 H), 7.62-7.66 (m, 1 H), 7.52-7.56 (m, 2H), 7.33 (d, 2H), 7.11-7.19 (m, 3H), 4.93 (d, 2H), 4.47 (t, 2H), 3.79 (t, 2H), 3.32 (t, 2H), 1.72 (s, 2H), 1.41-1.46 (m, 2H)1 0.72 (t, 3H). HRMS m/z 434.2013, (calculated for M+H, 434.1987).
Example 82
7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-f(pyridin-2-ylmethyl)aminolpyridor2,3- bipyrazin-2(1 H)-one
Figure imgf000096_0002
Example 82 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and 2-aminomethylpyridine in place of 4- (2-aminoethyl)morpholine in step 5. 1H NMR (CDCI3) δ 8.56-8.58 <m, 2H), 8.39 (d, 1H), 7.91 (d, 1H), 7.77-7.80 (m, 2H), 7.62-7.67 (m, 1 H), 7.34 (d, 1 H), 7.17-7.20 (m, 1H), 6.83 (d, 1H), 4.94 (d, 2H), 4.46 (t, 2H), 3.96 (s, 3H), 3.78 (t, 2H), 3.31 (t, 2H), 1.63 (s, 2H), 1.41-1.46 (m, 2H), 0.71 (t, 3H). HRMS m/z 447.2160, (calculated for M+H, 447.2139).
Example 83
7-(3,5-dimethylisoxazol-4-yl)-1-(2-propoxyethyl)-3-r(pyridin-2-ylmethyl)amino1pyridof2,3- blpyrazin-2(1HVone
Figure imgf000097_0001
Example 83 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , 2-aminomethylpyridine in place of 4-(2- aminoethyl)morpholine in step 5, and ,5-dimethylisoxazol-4-ylboronic acid in place of 2- methoxy-5-pyridineboronic acid in step 6. 1H NMR (CDCI3) δ 8.56-8.58 (m, 2H), 8.28 (d, 1H), 7.84-7.86 (m, 1 H), 7.63-7.67 (m, 2H), 7.34 (d, 1 H), 7.17-7.20 (m, 2H), 4.93 (d, 2H), 4.40 (t, 2H), 3.77 (t, 2H), 3.29 (t, 2H), 2.40 (s, 3H), 2.26 (s, 3H), 1.65 (s, 2H), 1.37-1.42 (m, 2H), 0.69 (t, 3H). HRMS m/z 435.2139, (calculated for M+H, 435.2139).
Example 84
7-(4-fluorophenyl)-1-(2-propoxyethyl)-3-r(Pyrazin-2-ylmethyl)aminolPyridor2,3-b1pyrazin-
2(im-one
Figure imgf000097_0002
Example 84 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1, pyrazin-2-ylmethylamine in place of 4-(2- aminoethyl)morpholine in step 5, and 4-fluorophenylboronic acid in place of 2-methoxy-5- pyridineboronic acid in step 6. 1H NMR (CDCI3) δ 8.69 (s,1 H), 8.59 (d, 1 H), 8.53-8.54 (m, 1 H), 8.44-8.49 (m, 1 H), 7.96 (d, 1 H), 7.53-7.57 (m, 3H), 7.12-7.16 (m, 2H), 5.01 (d, 2H), 4.48 (t, 2H), 3.79 (t, 2H), 3.32 (t, 2H), 1.65 (s, 2H), 1.39-1.46 (m, 2H), 0.72 (t, 3H). HRMS m/z 435.1913, (calculated for M+H, 435.1939).
Example 85
7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-f(pyrazin-2-ylmethyl)aminolPyridof2,3- b1pyrazin-2(1 H)-one
Figure imgf000097_0003
Example 85 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and pyrazin-2-ylmethylamine in place of 4- (2-aminoethyl)morpholine in step 5. 1H NMR (CDCj3 δ 8.69 (s,1H), 8.57 <d, 1H), 8.53-8.54 (m, 1 H), 8.48-8.49 (m, 1 H), 8.39-8.40 (m, 1H), 7.93 <d, 1H), 7.77-7.80 (m, 1H), 7.53-7.56 (m, 1 H), 6.82-6.84 (m, 1H), 5.01 (d, 2H), 4.47 (t, 2H), 3.96 (s, 3H), 3.79 (t, 2H), 3.31 (t, 2H), 1.62 (s, 2H), 1.39-1.48 (m, 2H)1 0.71 (t, 3H). HRMS m/z 448.2078, (calculated for M+H, 448.2092).
Example 86
7-(3.5-dimethylisoxazol-4-yl)-1-(2-propoxyethylV3-r(pyrazin-2-ylmethyl)aminoipyridor2.3- bipyrazin-2(1 HVone
Figure imgf000098_0001
Example 86 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , pyrazin-2-ylmethylamine in place of 4-(2- aminoethyl)morpholine in step 5, and 4-3,5-dimethylisoxazol-4-ylboronic acid in place of 2- methoxy-5-pyridineboronic acid in step 6. 1H NMR (CDCI3) δ 8.68 (s,1H), 8.53-8.54<m, 1H), 8.48-8.49 (m, 1 H), 8.29 (d, 1 H), 7.67 (d, 1 H), 7.77-7.80 (m, 1H), 7.57-7.60 (m, 1H), 5.01 (d, 2H), 4.41 (t, 2H), 3.77 (t, 2H), 3.29 (t, 2H), 3.31 (t, 2H), 2.40 (s, 3H), 2.25 <s, 3H), 1.37-1.42 (m, 2H), 0.69 (t, 3H). HRMS m/z 436.2082, (calculated for M+H, 436.2092).
Example 87
7-(4-fluorophenyl)-3-r(2-isopropoxyethvπaminol-1-(2-propoxyethyl)pyridof2.3-blpyrazin-2(1H')- one
Figure imgf000098_0002
Example 87 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , 2-isopropoxyethylamine in place of 4-(2- aminoethyl)morpholine in step 5, and 4-fluorophenylboronic acid in place of 2-methoxy-5- pyridineboronic acid in step 6. 1H NMR (CDCI3) δ 8.56 (d,1H), 7.91 (d, 1H), 7.52-7.56 (m, 2H), 7.10-7.16 (m, 2H), 6.96-6.98 (m, 1H), 4.45 (t, 2H), 3.76-3.82 (m, 4H), 3.57-3.66 (m, 3H), 3.33 (t, 2H), 1.39-1.48 (m, 2H), 1.15 (s, €H), 0.72 (t, 3H). HRMS m/z 429.2259, {calculated for M+H, 429.2296).
Example 88 3-r(2-isopropoxyethyl)aminol-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyridor2,3- blpvrazin-2(1 H)-one
Figure imgf000099_0001
Example 88 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and 2-isopropoxyethylamine in place of 4- (2-aminoethyl)morpholine in step 5. 1H NMR (CDCI3) δ 8.54 (d,1 H), 8.38 (d, 1 H), 7.87 (d, 1H), 7.76-7.79 (m, 1H), 6.95-6.98 (m, 1H), 6.81 (d, 1 H), 4.43 (t, 2H), 3.95 (s, 3H), 3.75-3.81 (m, 4H), 3.56-3.65 (m, 3H), 3.30 (t, 2H), 1.40-1.45 (m, 2H), 1.14 (s, 6H), 0.70 (t, 3H). HRMS m/z 442.2403, (calculated for M+H, 442.2449).
Example 89
7-(3,5-dimethylisoxazol-4-yl)-3-r(2-isopropoxyetriyl)amino1-1-(2-propoxyethyl)pyrido[2,3- blpyrazin-2(1 HVone
Figure imgf000099_0002
Example 89 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , 2-isopropoxyethylamine in place of 4-(2- aminoethyl)morpholine in step 5, and 3,5-dimethylisoxazol-4-ylboronic acid in place of 2- methoxy-5-pyridineboronic acid in step 6. 1H NMR (CDCI3) δ 8.26 (d,1 H), 7.62 (d, 1 H), 6.98- 7.01 (m, 1H), 4.38 (t, 2H), 3.73-3.82 (m, 4H), 3.56-3.65 (m, 3H), 3.28 (t, 2H), 2.39 (s, 3H) , 2.24 (s, 3H), 1.35-1.42 (m, 2H), 1.15 (s, 6H), 0.69 (t, 3H). HRMS m/z 430.2425, (calculated for M+H, 430.2449).
Example 90
7-(3.5-dimethylisoxazol-4-yl)-3-r(2-isopropoxyethyl)aminol-1-(2-propoxyethyl)pyridor2,3- blpyrazin-2(1 HVone
Figure imgf000099_0003
Example 90 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , cyclohexanemethylamine in place of 4-(2- aminoethyl)morpholine in step 5, and 4-fluorophenyl boronic acid in place of 2-methoxy-5- pyridineboronic acid in step 6. 1H NMR (CDCI3) δ 8.56 (d,1H), 7.89 (s, 1 H), 7.52-7.55 (m, 2H), 7.13 (t, 2H), 6.66 (t, 1 H), 4.44 (t, 2H), 3.77 <t, 2H), 3.48 (t, 2H), 3.32 (t, 2H), 1.68-1.81 (m, 6H), 1.40-1.48 (m, 2H), 1.13-1.26 (m, 3H), 0.96-1.05 (m, 2H) , 0.73 (t, 3H). HRMS m/z 439.2475, (calculated for M+H, 439.2504).
Example 91
3-r(cvclohexylmethvπamino1-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyridor2.3-b1pyrazin- 2(1 H)-one
Figure imgf000100_0001
Example 91 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and cyclohexanemethylamine in place of 4-(2-aminoethyl)morpholine in step 5. 1H NMR (CDCI3) δ 8.56 (d,1 H), 8.38 (d, 1H), 7.93 (s, 1 H), 7.76-7.79 (m, 1H), 6.82 (d, 1 H), 6.74 (s, 1H), 4.44 <t, 2H), 3.96 (s, 3H), 3.77 (t, 2H), 3.48 (t, 2H), 3.31 (t, 2H)1 1.63-1.81 (m, 6H), 1.41-1.47 (m, 2H), 1.13-1.26 (m, 3H), 0.96-1.06 (m, 2H) , 0.72 (t, 3H). HRMS m/z 452.2638, (calculated for M+H, 452.2656).
Example 92
3-f(cvclohexylmethvπaminol-7-(3.5-dimethylisoxazol-4-yl)-1-(2-propoxyethyl)pyridof2,3- frlpyrazin-2(1 H)-one
Figure imgf000100_0002
Example 92 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , cyclohexanemethylamine in place of 4-(2- aminoethyl)morpholine in step 5, and 3,5-dimethylisoxazol-4-ylboronic acid in place of 2- methoxy-5-pyridineboronic acid in step 6. 1H NMR (CDCI3) δ 8.28 (d,1H), 7.64 (s, 1H), 6.75 (S, 1 H), 4.38 (t, 2H), 3.75 (t, 2H), 3.49 (t, 2H), 3.30 (t, 2H), 2.39 (s, 3H), 2.25 (s, 3H), 1.62- 1.81 (m, 6H), 1.36-1.43 (m, 2H), 1.13-1.25 (m, 3H), 0.96-1.06 (m, 2H) , 0.70 <t, 3H). HRMS m/z 440.2652, (calculated for M+H, 440.2656).
Example 93 3-(ethylaminoV7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyridor2,3-blpyrazin-2(1H)-one
Figure imgf000101_0001
Example 93 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and ethylamine in place of 4-(2- aminoethyl)morpholine in step 5. 1H NMR (CDCI3) δ 8.55 (d,1 H), 8.38 (d, 1H), 7.92 (d, 1H), 7.76-7.79 (m, 1 H), 6.82 (d, 1 H), 6.64 (t, 1 H), 4.44 (t, 2H), 3.95 (s, 3H)1 3.75 (t, 2H), 3.64-3.71 (m, 2H), 3.30 (t, 2H), 1.39-1.46 (m, 2H), 1.30 (t, 3H), 0.71 (t, 3H). HRMS m/z 385.2066, (calculated for M+H, 385.2030).
Example 94 7-(3,5-dimethylisoxazol-4-yl)-3-(ethylamino)-1-(2-propoxyethyl)pyridor2.3-bipyrazin-2(1H')-one
Figure imgf000101_0002
Example 94 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , ethylamine in place of 4-(2- aminoethyl)morpholine in step 5, and 3,5-dimethylisoxazol-4-ylboronic acid in place of 2- methoxy-5-pyridineboronic acid in step 6. 1H NMR (CDCI3) δ 8.28 (d,1H), 7.69 (d, 1 H), 6.73 (s, 1H), 4.39 (t, 2H), 3.66-3.77 (m, 4H), 3.29 (t, 2H), 2.40 (s, 3H), 2.25 (s, 3H), 1.29-1.42 (m, 5H), 0.69 (t, 3H). HRMS m/z 372.2063, (calculated for M+H, 372.2030).
Example 95
3-(ethylamino)-7-(4-fluorophenyl)-1-(2-propoxyethyl)pyridor2,3-bipyrazin-2(1H)-one
Figure imgf000101_0003
Example 95 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , ethylamine in place of 4-(2- aminoethyl)morpholine in step 5, and 4-fluorophenylboronic acid in place of 2-methoxy-5- pyridineboronic acid in step 6. 1H NMR (CDCI3) δ 8.58 (d,1H), 8.00 (d, 1H), 7.7.52-7.57 (m, 2H), 7.11-7.17 (m, 2H), 6.70 (s, 1 H), 4.46 (t, 2H), 3.78 (t, 2H), 3.66-3.71 (m, 2H), 3.33 (t, 2H), 1.39-1.48 (m, 2H), 1.31 (t, 3H), 0.71 (t, 3H). HRMS m/z 371.1888, (calculated for M+H, 371.1878).
Example 96 3-amino-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyridor2.3-biPyrazin-2(1H)-one
Figure imgf000102_0001
Example 96 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and ammonia in place of 4-(2- aminoethyl)morpholine in step 5. 1H NMR (CDCI3) δ 8.59 (d, 1 H), 8.39 (m, 1H), 7.93 (d, 1 H), 7.77-7.80 (m, 1H), 6.82-6.84 (m, 1H), 4.64 (t, 2H), 3.97 (s, 3H), 3.78 (t, 2H), 3.32 (t, 2H), 1.41- 1.46 (m, 2H), 0.71 (t, 3H). HRMS m/z 356.1726, (calculated for M+H, 356.1717).
Example 97
7-(3,5-dimethylisoxa2ol-4-yl)-3-(r(5-methylpyrazin-2-yl)methyllaminoM-(2- propoxyethyl)pyridor2,3-bipvrazin-2(1H)-one
Figure imgf000102_0002
Example 97 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 , ammonia in place of 4-(2- aminoethyl)morpholine in step 5, and 3,5-dimethylisoxazol-4-ylboronic acid in place of 2- methoxy-5-pyridineboronic acid in step 6. 1H NMR (CDCI3) δ 8.13 (s, 1H), 8.02 <s, 1H), 4.48 (t, 2H), 3.77 (t, 2H), 3.28 (t, 2H), 2.48 (s, 3H), 2.31 (s, 3H), 1.34-1.40 (m, 2H), 0.66 (t, 3H). HRMS m/z 344.1700, (calculated for M+H, 344.1717).
Example 98
3-r(3-hvdroxypropyl)aminol-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[2.3-blpyrazin-
2(1 H)-one
Figure imgf000102_0003
Example 98 was prepared by a method similar to that described in Example 4 using 3- hydroxypropylamine in place of N~1 ~,N~1 "—dimethylglycinamide in step 6. 1H NMR (CDCI3) δ 8.55 (d, 1 H), 8.38 (d, 1H), 7.94 <s, 1H), 7.58-7.78 (m, 1 H), 7.04 (s, 1H), 6.83 (d, 1H), 4.42- 4.46 (m, 2H), 3.96 (s, 3H), 3.76-3.82 (m, 4H), 3.70 (t, 2H), 3.31 (t, 2H), 1.85-1.91 (m, 2H), 1.39-1.48 (m, 2H), 0.71 (t, 3H). HRMS m/z 414.2109, (calculated for M+H, 414.2136).
Example 99
3-r(2-isopropoxyethyl)aminol-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl^pyridof2,3- blpyrazin-2(1 H)-one
Figure imgf000103_0001
Example 99 was prepared by a method similar to that described in Example 4 using 2- ethoxyethylamine in place of N~1~,N~1 ~-dimethylglycinarmde in step 6. 1H NMR (CDCI3) δ 8.54 (d, 1H), 8.38 (d, 1H), 8.02 (d, 1H), 7.64-7.79 (m, .1H), 7.14 (s, 1H), 6.83 (d, 1H), 4.45 (t, 2H), 3.96 (s, 3H), 3.82-3.86 (m, 2H), 3.77 (t, 2H), 3.65 (t, 2H), 3.51 (q, 2H), 3.30 (t, 2H), 1.37- 1.46 (m, 2H), 1.19 (t, 3H), 0.69 (t, 3H). HRMS m/z 428.2274, (calculated for M+H, 428.2292).
Example 100
7-(6-methoxypyridin-3-yl)-3-r(3-methylbutyl)amino1-1-(2-propoxyethyl)pyridof2.3-bipyrazin-
2(i m-one
Figure imgf000103_0002
Example 100 was prepared by a method similar to that described in Example 4 using 3- methylbutylamine in place of N~1 ~,N~1 —dimethylglycinamide in step 6. 1H NMR (CDCI3) δ 8.57 (d, 1H), 8.38 (d, 1H), 8.02 (s, 1H), 7.76-7.79 (m, 1H), 6.83<d, 1H), 6.74 (s, 1 H), 4.45 (t, 2H), 3.96 (s, 3H), 3.77 (t, 2H), 3.64-3.69 (m, 2H), 3.31 (t, 2H), 1.65-1.75 (m, 1H), 1.58 (q, 2H), 1.39-1.47 (m, 2H), 0.94 (d, 6H), 0.70 (t, 3H). HRMS m/z 426.2534, (calculated for M+H, 426.2500).
Example 101
3-(tert-butylamino)-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyridof2,3-bipyrazin-2(1HV one
Figure imgf000104_0001
Example 101 was prepared by a method similar to that described in Example 4 using t- butylamine in place of N~1 ~,N~1~-dimethylglycinamide in step 6. 1H NMR (CDCI3) δ 8.56 (d, 1H)1 8.38 (d, 1 H)1 7.87 (S1 1 H), 7.76-7.79 (m, 1H), 6.82 (d, 1 H)1 6.61 (S1 1 H), 4.43 (t, 2H), 3.96 (s, 3H), 3.76 (t, 2H), 3.32 (t, 2H), 1.57<s, 9H), 1.40-1.48 (m, 2H), 0.73 (t, 3H). HRMS m/z 412.2360, (calculated for M+H, 412.2343).
Example 102
3-(dimethylamino)-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethvπpyridor2.3-blpyrazin-2(1H)-one
Figure imgf000104_0002
Example 102 was prepared by a method similar to that described in Example 4 using dimethylamine in place of N~1 ~,N~1 --dimethylglycinamide in step 6. 1H NMR (CDCI3) δ 8.49 (d, 1 H), 8.37 (m, 1 H), 7.86 (d, 1H)1 7.75-7.78 (m, 1 H), 6.80-6.82 (m, 1 H), 4.37 (t, 2H), 3.95 (s, 3H), 3.74 (t, 2H)1 3.49 (s, 6H), 3.31 (t, 2H)1 1.39-1.46 (m, 2H), 0.71 (t, 3H). HRMS m/z 384.2080, (calculated for M+H, 384.2030).
Example 103 7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-(propylamino)pyridor2,3-b1pyrazin-2(1 H)-one
Figure imgf000104_0003
Example 103 was prepared by a method similar to that described in Example 4 using propylamine in place of N~1~,N~1 —dimethylglycinamide in step 6. 1H NMR<CDCI3) δ 8.56 (d, 1 H), 8.38 (d, 1 H), 7.98 (s, 1 H), 7.76-7.79 (m, 1H), 6.83 (d, 1 H), 6.77 (s, 1H), 4.45 (t, 2H), 3.96 (s, 3H), 3.77 (t, 2H)1 3.62 (q, 2H), 3.29-3.33 (m, 2H), 1.67-1.75 (m, 2H), 1.39-1.46 (m, 2H), 0.99 (t, 3H), 0.71 (t, 3H). HRMS m/z 398.2164, (calculated for M+H, 398.2187).
Example 104
3-r(2-hvdroxyethyl)aminol-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethvπpyridor2.3-blpyrazin-
2(im-one
Figure imgf000105_0001
Example 104 was prepared by a method similar to that described in Example 4 using ethanolamine in place of N~1 ~,N~1 —dimethylglycinamide in step 6. 1H NMR (CDCI3) δ 8.53 (d, 1 H), 8.38 (d, 1 H), 7.96 (d, 1 H), 7.76-7.79 (m, 1H), 7.15 (t, 1 H), 6.82 (d, 1 H)1 4.44 (t, 2H)1 3.96 (s, 3H), 3.91 (t, 2H)1 3.83 (q, 2H)1 3.76 (t, 2H)1 3.32 (t, 2H)1 1.38-1.46 (m, 2H)1 0.71 (t, 3H). HRMS m/z 400.1973, (calculated for M+H, 400.1979).
Example 105
7-(6-methoxypyridin-3-yl)-3-(methylamino)-1-(2-propoxyethyl)pyridor2,3-bipyrazin-2(1 H)-one
Figure imgf000105_0002
Example 105 was prepared by a method similar to that described in Example 4 using methylamine in place of N~1~,N~1 —dimethylglycinamide in step 6. 1H NMR (CDCI3) δ 8.56 (d, 1 H)1 8.38 (d, 1 H), 7.93 (d, 1H), 7.76-7.79 (m, 1 H), 6.82 (d, 1 H)1 6.69 <d, 1H)1 4.44 (t, 2H), 3.96 (s, 3H), 3.76 (t, 2H)1 3.30 (t, 2H)1 3.19 (d, 3H)1 1.38-1.46 (m, 2H)1 0.70 (t, 3H). HRMS m/z 370.1865, (calculated for M+H, 370.1874).
Example 106
7-(6-methoxypyridin-3-ylV1 -(2-oropoxyethylV3-r(3,3,3-trifluoropropyl)aminoiPyridof2,3- blpvrazin-2(1 HVone
Figure imgf000106_0001
Example 106 was prepared by a method similar to that described in Example 4 using 3,3,3-trifluoropropylamine in place of N~1~,N~1 ~-dimethylglycinamide in step 6. 1H NMR (CDCI3) δ 8.57 (d, 1H), 8.38 (d, 1H), 7.93 (d, 1H), 7.77-7.79 (m, 1H), 6.80-6.84 (m, 2H), 4.45 (t, 2H), 3.96 (s, 3H), 3.91 (q, 2H), 3.77 (t, 2H), 3.31 (t, 2H), 2.50-2.61 (m, 2H), 1.38-1.47 (m, 2H), 0.71 (t, 3H). HRMS m/z 452.1927, (calculated for M+H, 452.1904).
Example 107
7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-(r(2S)-tetrahvdrofuran-2- ylmethvπaminotoyridor2.3-blpvrazin-2(1 H)-one
Figure imgf000106_0002
Example 107 was prepared by a method similar to that described in Example 4 using (S)-(+)-tetrahydrofurfurylamine in place of N~1~,N~1 — dimethylglycinamide in step 6. 1H NMR (CDCI3) δ 8.57 (d, 1H), 8.38 (d, 1H), 7.95 (s, 1H), 7.76-7.79 (m, 1H), 7.02 (s, 1H), 6.83 (d, 1H), 4.45 (t, 2H), 4.11-4.19 (m, 1 H), 3.87-3.98 (m, 5H), 3.73-3.78 (m, 3H), 3.52-3.59 (m, 1H), 3.31 (t, 2H), 1.93-2.08 (m, 1H), 1.86-1.93 (m, 2H), 1.57-1.66 (m, 1H), 1.38-1.47 (m, 2H), 0.71 (t, 3H). HRMS m/z 440.2301 , (calculated for M+H, 440.2292).
Example 108
7-(6-methoxypyridin-3-yl)-3-{|'3-(2-oxopyrrolidin-1-yl)propyπamino}-1-{2- propoxyethvDpyridor2,3-b1pvrazin-2(1 H.)-one
Figure imgf000106_0003
Example 108 was prepared by a method similar to that described in Example 4 using 1- (3-aminopropyl)-2-pyrrolidinone in place of N~1~,N~1 —dimethylglycinamide in step 6. 1H NMR (CDCI3) δ 8.52 (d, 1H), 8.38 (d, 1H), 7.90 (d, 1H), 7.36 (s, 1H), 6.80-6.83 (m, 2H), 4.43 (t, 2H), 3.95 (S, 3H), 3.75 (t, 2H), 3.64 (q, 2H), 3.37-3.40 (m, 4H), 3.30 (t, 2H), 2.38 <t, 2H), 1.98-2.05(m, 2H), 1.85-1.92 (m, 2H), 1.38-1.46 (m, 2H), 0.71 (t, 3H). HRMS m/z 481.2547, (calculated for M+H, 481.2558).
Example 109
7-(6-methoxypyridin-3-yl)-1 -(2-propoxyethyl)-3-ir(2R)-tetrarivdrofuran-2- vlmethvnamino)pvridor2.3-blpvrazin-2(1H)-one
Figure imgf000107_0001
Example 109 was prepared by a method similar to that described in Example 4 using (R)-(-)-tetrahydrofurfurylamine in place of N~1 ~,N~1 ~-dimethylglycinamide in step 6. 1H NMR (CDCI3) δ 8.54 (d, 1 H), 8.38-8.39 (m, 1 H)1 7.91 (d, 1 H), 7.76-7.79 (m, 1 H), 6.96 (d, 1H), 6.81- 6.83 (m, 1H), 4.45 (t, 2H), 4.13-4.18 (m, 1 H), 3.86-3.96 (m, 5H), 3.73-3.78 (m, 3H), 3.52-3.59 (m, 1 H), 3.31 (t, 2H), 1.99-2.07 (m, 1 H), 1.85-1.93 (m, 2H), 1.58-1.65 (m, 1H), 1.38-1.47 (m, 2H), 0.71 (t, 3H). HRMS m/z 440.2317, (calculated for M+H, 440.2292).
Example 110
3-f(3-methoxypropyl)aminol-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyridor2.3-blPyrazin-
2(i m-one
Figure imgf000107_0002
Example 110 was prepared by a method similar to that described in Example 4 using 3- methoxypropyl amine in place of N~1 ~,N~1 —dimethylglycinamide in step 6. 1H NMR (CDCI3) δ 8.54 (d, 1 H), 8.37-8.38 (m, 1H), 7.89 (d, 1 H), 7.76-7.79 (m, 1 H), 7.12 (s, 1 H), 6.81-6.83 (m, 1 H), 4.43 (t, 2H), 3.96 (s, 3H), 3.71-3.78 (m, 4H), 3.52 (t, 2H), 3.35 (s, 3H), 3.31 (t, 2H), 1.92- 1.98 (m, 2H), 1.40-1.46 (m, 2H), 0.71 (t, 3H). HRMS m/z 428.2262, (calculated for M+H, 428.2292).
Example 111
3-r(2-methoxyethyl)aminol-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyridor2,3-b1pyrazin-
2(i m-one
Figure imgf000108_0001
Example 111 was prepared by a method similar to that described in Example 4 using 2- methoxyethyl amine in place of N~1 ~,N~1 —dimethylglycinamide in step 6. 1H NMR (CDCI3) δ 8.54 (d, 1 H), 8.38 (d, 1 H), 7.90 (d, 1 H), 7.76-7.79 (m, 1 H), 6.94 (t, 1 H), 6.82 (d, 1H), 4.44 (t, 2H), 3.96 (S, 3H), 3.81-3.85 (m, 2H), 3.76 (t, 2H), 3.62 (t, 2H), 3.36 (s, 3H), 3.32 (t, 2H), 1.40- 1.45 (m, 2H), 0.71 (t, 3H). HRMS m/z 414.2107, (calculated for M+H, 414.2136).
Example 112
3-r(2-hvdroxyethyl)(methyl)amino1-7-(6-methoxypyridin-3-yl)-1-(2- propoxyethyl)pyridof2,3-bipvrazin-2(1 H)-one
Figure imgf000108_0002
Example 112 was prepared by a method similar to that described in Example 4 using 2- (methylamino)ethanol in place of N~1 ~,N~1 —dimethylglycinamide in step 6. 1H NMR (CDCI3) § 8.52 (d, 1H), 8.38 (d, 1 H), 7.85 (d, 1 H), 7.76-7.78 (m, 1 H), 6.82 (d, 1H), 4.39 (s, 2H), 4.03-4.06 (m, 2H), 3.92-3.97 (m, 5H), 3.75 (t, 2H), 3.45 (s, 3H), 3.31 <t, 2H), 1.40-1.47 (m, 2H), 0.72 (t, 3H). HRMS m/z 414.2103, (calculated for M+H, 414.2136).
Example 113
7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-f(2.2,2-trifluoroethyl)aminoipyridof2,3- blPvrazin-2(1 H.Vone
Figure imgf000108_0003
Example 113 was prepared by a method similar to that described in Example 4 using 2,2,2-trifluoroethylamine in place of N~1 ~,N~1 —dimethylglycinamide in step 6. 1H NMR (CDCI3) δ 8.61 (d, 1H), 8.40 (d, 1H), 7.98 (d, 1 H), 7.77-7.80 (m, 1H), 6.84 (d, 1 H), 6.79 <t, 1H), 4.47 (t, 2H), 4.31-4.40 (m, 2H), 3.97 (s, 3H), 3.79(t, 2H), 3.31 (t, 2H), 1.39-1.48 (m, 2H), 0.71 (t, 3H). HRMS m/z 438.1735, (calculated for M+H, 438.1748). Example 114
3-(cvclobutylamino)-7-(6-methoxypyridin-3-ylV1-(2-propoxyethyl)pyridor2.3-blpyrazin-2(iH)- one
Figure imgf000109_0001
Example 114 was prepared by a method similar to that described in Example 4 using cyclobutylamine in place of N~1 ~,N~1 —dimethylglycinamide in step 6. 1H NMR (CDCI3) δ 8.55 (d, 1H), 8.38 (d, 1 H), 7.87 (d, 1H), 7.76-7.79 (m, 1 H), 6.82 (d, 1 H), 6.74 (d, 1 H), 4.74- 4.84 (m, 1H), 4.43 (t, 2H), 3.96 (s, 3H), 3.75 (t, 2H), 3.30 (t, 2H), 2.45-2.53 (m, 2H), 1.95-2.02 (m, 2H), 1.73-1.81 (m, 2H), 1.39-1.47 (m, 2H), 0.71 (t, 3H). HRMS m/z 410.2181 , (calculated for M+H, 410.2187).
Example 115
N-r7-(6-methoxypyridin-3-vπ-2-oxo-1-(2-propoxyethyl)-1 ,2-dihvdropyridor2,3-blpyrazin-3- yllacetamide
Figure imgf000109_0002
Example 115 was prepared from Example 97 by the following reaction. A mixture of 3- amino-7-(6-methoxypyridin-3-yl)-1 -(2-propoxyethyl)pyrido[2,3-b]pyrazin-2(1 H)-one (300 mg, 0.84 mmol), acetic anhydride (400 mg, 3.92 mmol), and triethylamine (500 mg, 4.95 mmol) in dichloromethane (5.0 mL) was stirred for 16 hours at room temperature. The solution became homogeneous and was poured into ethyl acetate (25 mL). The solution was extracted with 10% aqueous acetic acid (2 x 10 mL), saturated aqueous sodium bicarbonate (2 x 10 mL), and brine (1 x 10 mL). The solvent was dried over sodium sulfate and solvent removed at reduced pressure. The N-[7-(6-methoxypyridin-3-yl)-2-oxo-1-(2-propoxyethyl)- 1 ,2-dihydropyrido[2,3-b]pyrazin-3-yl]acetamide (158 mg, 0.44 mmol) was isolated as white crystals by crystallization from ethyl acetate. 1H NMR (400 mHz, (CD3)2SO) δ 9.88 (s, 1 H), 8.78 (d, 1 H), 8.67 (d. 1 H), 8.29 (d, 1 H), 8.20 (dd, 1 H), 6.96 (s, 1 H), 4.57 (t, 2H), 3.90 (s, 3H), 3.70 (t, 2H), 3.29 (t, 2H), 2.38 (s, 3H), 1.30 (m, 2H), 0.63 (t, 3H). HRMS m/z398.1814 (calculated for M+H, 398.1823).
Example 116 N-f7-(6-nnethoxypyridin-3-yl)-2-oxo-1-(2-propoxyethyl)-1,2-dihvdropyridor2.3-blPyrazin-3- vlim ethanesulf onam ide
Figure imgf000110_0001
Example 116 was prepared from Example 97 by the following reaction. To a mixture of 3-amino-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[2,3-b]pyrazin-2(1 H)-one (301 mg, 0.84 mmol) and triethylamine (505 mg, 5.0 mmol) in dichloromethane (5.0 ml_) was added methanesulfonylchloride (300 mg, 2.65 mmol) and the solution stirred at room temperature for 16 hours. An additional aliquot of methanesulfonylchloride (300 mg, 2.65 mmol) added and the reaction stirred for 4 hours. The solution was poured into ethyl acetate (25 ml_) and the solution was extracted with 5% aqueous citric acid ( 2 x 10 ml_), saturated aqueous sodium bicarbonate (2 x 10 ml_), and brine (10 ml_). The solution was dried over sodium sulfate and solvent removed at reduced pressure. The N-[7-(6-methoxypyridin-3-yl)-2-oxo-1-(2- propoxyethyl)-1 ,2-dihydropyrido[2,3-b]pyrazin-3-yl]methanesulfonamide (132 mg, 0.50 mmol) was isolated as a yellow powder by automated flash chromatography (10 g silica isolute silica column, 0-8% methanol in ethyl acetate over 20 min, 15 mL/min). 1H NMR (400 mHz,
(CDg)2SO) δ 8.9 (bs, 1 H), 8.65 (d, 1 H), 8.28 (d, 1 H), 8.19 (dd, 1 H), 6.96 (d, 1 H), 4.54 (m,2H), 3.89 (s, 3H), 3.69 (t, 2H), 3.42 (m, 2H), 1.33 (m, 2H), 0.64 (t, 3H). HRMS m/z 434.1477 (calculated for M+H, 434.1493).
Example 117 1-(2-ethoxyethyl)-7-(6-methoxypyridin-3-vπ-3-r(2-morpholin-4-ylethyl)aminolpyrido[2,3- blpyrazin-2(1 HVone
Figure imgf000110_0002
Example 117 was prepared by a method similar to that described in Example 1 using 6- methoxypyridin-3-ylboronic acid in place of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)pyridine in step 7. 1HNMR (CDCI3, 400MHz) δ 8.60 (s, 1 H), 8.40 (s, 1 H), 7.90 (s, 1 H), 7.80 (d, 1 H), 7.15 (br s, 1 H), 6.85 (d, 1 H1), 4.8 (t, 2 H), 4.7 (m, 6 H), 4.5 (t, 2 H) 4.0 (s, 3 H), 3.5 (q, 2 H), 2.7 (t, 2 H), 2.5 (m, 4 H), 1.1 (t, 3 H). LRMS ES+ 455 [M+Hf. Example 118
7-(3,4-difluorophenvπ-1-(2-ethoxyethyl)-3-r(2-morpholin-4-ylethvπaminoipyridof2,3-blpyrazin-
2(1H)-one
Figure imgf000111_0001
Example 118 was prepared by a method similar to that described in Example 1 using 3,4-difluorophenylboronic acid in place of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)pyridine in step 7. 1HNMR (CDCI3, 400MHz) § 8.60 (s, 1 H), 7.95 <s, 1 H), 7.40 (m, 1 H), 7.30 (m, 2 H), 4.50 (t, 2 H) 3.80 (m, 8 H), 3.50 (q, 2 H), 2.60 (m, 6 H), 1.10 (t, 3 H). LRMS ES+ 460 [MH-H]+.
Example 119
7-(3.4-difluorophenylV3-fr2-(dimethylamino)ethvnamino>-1-(2-ethoxyethyl)pyridor2,3- bipyrazin-2(1 H)-one
Figure imgf000111_0002
Example 119 was prepared by a method similar to that described in Example 1 using N,N-dimethylethane-1 ,2-diamine in place of 4-(2-aminoethyl)morpholine in step 5 and 3,4- difluorophenylboronic acid in place of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine in step 7. 1H NMR (400 MHz, CDCI3) δ 8.58 (s, 1 H), 7.92 (s, 1 H), 7.40 (m, 1 H), 7.35 (m, 1 H), 7.26 (m, 1 H), 7.20 (br S, 1 H), 4.42 (t, 2 H), 3.80 (t, 2 H), 3.72 (q, 2 H), 3.42 (q, 2 H), 2.81 (t, 2 H), 2.25 (s, 6 H), 1.04 (t, 3 H). LRMS ES+ 418 [M+H]+.
Example 120
3-(r2-(dimethylamino)ethvnaminoM-(2-ethoxyethyl)-7-(6-methoxyj3yridin-3-yl)pyridor2,3- blpyrazin-2(1 H)-one
Figure imgf000111_0003
Example 120 was prepared by a method similar to that described in Example 1 using N,N-dimethylethane-1 ,2-diamine in place of 4-(2-aminoethyl)morpholine in step 5 and 6- methoxypyridin-3-ylboronic acid in place of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)pyridine in step 7. 1H NMR (400 MHz, CDCI3) δ 8.60 (s, 1 H), 8.40 (d, 1 H), 7.92 (s, 1 H), 7.82 (q, 1 H), 7.13 (bs, 1 H), 6.85 (d, 1 H), 4.45 (t, 2 H), 4.00 (s, 3 H), 3.80 (t, 2 H), 3.75 (q, 2 H), 3.42 (q, 2 H), 2.42 (t, 2 H), 2.30 (s, 6 H), 1.04 (t, 3 H). LRMS ES+ 413.
Example 121
7-(3-chloro-4-fluorophenyl)-3-(r2-(dimethylamino)ethvnamino)-1-(2-ethoxyethyl)pyridor2.3- blpyrazin-2(1 H)-one
Figure imgf000112_0001
Example 121 was prepared by a method similar to that described in Example 1 using N,N-dimethylethane-1 ,2-diamine in place of 4-(2-aminoethyl)morpholine in step 5 and 3-- chloro-4-fluorophenylboronic acid in place of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridine in step 7. 1H NMR (400 MHz, CDCI3) δ 8.60 (s, 1 H), 7.95 (s, 1 H), 7.65 (m, 1 H), 7.45 (m, 1 H), 7.26 (m, 1 H)1 7.20 (br s, 1 H), 4.45 (t, 2 H), 3.80 (t, 2 H), 3.75 (q, 2 H), 3.45 (q, 2 H), 2.65 (t, 2 H), 2.39 (s, 6 H), 1.05 (t, 3 H). LRMS ES+ 434[M+H]+.
Example 122 N-r7-(6-methoxypyridin-3-yl)-2-oxo-1-pentyl-1 ,2-dihvdropyridof2,3-biPyrazin-3-vn-L-alanine
Figure imgf000112_0002
Example 122 was prepared by a method similar to that described in Example 1 using pentanoic acid in place of ethoxyacetic acid in step 1 and L-alanine methyl ester in place of 4-(2-aminoethyl)morpholine in step 5. In step 7 a solution of methyl N-(7-bromo-2-oxo-1- pentyi-1 ,2-dihydropyrido[2,3-b]pyrazin-3-yl)-L-alaninate from step 5 (75mg, 0.19mmol) in dioxane/water (8 mL = 5 mL dioxane/3 mL water) was treated with 2-methoxy-5- pyridineboronic acid (66 mg, 0.28 mmol), sodium carbonate (50 mg, 0.47 mmol), and tetrakis(triphenylphosphine)-palladium (0) (22 mg, 0.019 mmol) at room temperature. The mixture was heated to 1000C for 2 hours. The mixture was cooled to room temperature, acidified with 2N HCI, extracted into dichloromethane, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was chromatographed eluting in a gradient of 100% DCM to 95/5/0.5 DCM/MeOH/AcOH to afford 15 mg of the cross coupled acid as a white solid. 1HNMR (CDCI3, 400MHz) δ. 8.60 (s, 1 H), 8.40 (s, 1 H), 7.80 (d, 1 H), 7.70 (s, 1H), 7.30 (d, 1 H), 6.90 (d, 1 H), 4.90 (m, 1H), 4.30 (m, 2H)1 4.00 (s, 3H), 1.70 (m, 2H), 1.65 (d, 3H), 1.40 (m, 4H), 0.9Q.t3H) LRMS ES+ 412 [M+H]+.
Example 123 N-[7-(3,4-difluorophenyl)-2-oxo-1-pentyl-1.2-dihvdropyridor2.3-bipyrazin-3-yll-L-alanine
Figure imgf000113_0001
Example 123 was prepared by a method similar to that described in Example 1 using pentanoic acid in place of ethoxyacetic acid and L-alanine methyl ester in place of 4-{2- aminoethyl)morpholine in step 5. In step 7 a solution of methyl N-(7-bromo-2-oxo-1-pentyl- 1,2-dihydropyrido[2,3-b]pyrazin-3-yl)-L-alaninate from step 5 (75mg, O.19mmol) in dioxane/water (8 ml_ = 5 ml_ dioxane/3 ml_ water) was added 3,4-difluorobenzeneboronic acid (44 mg, 0.28 mmol), sodium carbonate (50 mg, 0.47 mmol), and tetrakis(triphenyl-phosphine) palladium (0) (22 mg, 0.019 mmol) at room temperature. The mixture was heated to 1000C for 2 hours. The mixture was cooled to room temperature, acidified with 2N HCI, extracted into dichloromethane, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was chromatographed eluting in a gradient of 100% DCM to 95/5/0.5 DCM/MeOH/AcOH to afford 26 mg of the cross coupled acid as a pale yellow solid. 1HNMR (CDCI3, 400MHz) δ 8.55 (s, 1 H), 7.6 (s, 1 H), 7.35 (t, 1 H), 7.3 (d, 1 H), 7.0 (d, 1 H), 4.95 (m, 1 H), 4.3 (m, 2 H), 1.7 (m, 2 H), 1.65 (d, 3 H), 1.4 (m, 4 H), 0.9 (t, 3 H) LRMS ES+ 417 f.M+H]+.
Example 124 1-(2-ethoxyethvπ-7-(6-methoxypyridin-3-yl)-3-r(2-pyrrolidin-1-ylethyl)aminolpyridor2,3-
Figure imgf000113_0002
Example 124 was prepared by a method similar to that described in Example 1 using 2- pyrrolidin-1-ylethanamine in place of 4-(2-aminoethyl)morpholine in step 5 and 6- methoxypyridin-3-ylboronic acid in place of 2-fluoro-5-(4,4,5,5-tetramethyl-1)3,2-dioxaborolan- 2-yl)pyridine in step 7. 1H NMR (400 MHz, CDCI3) δ 8.58 (s, 1 H), 8.40 (s, 1 H), 7.90 (s, 1 H), 7.80 (q, 1 H), 7.18 (br s, 1 H), 6.82 (d, 1 H), 4.42 (t, 2 H), 4.00 (s, 3 H), 3.80 (t, 2 H), 3.75 (q, 2 H), 3.42 (q, 2 H), 2.80 (t, 2 H), 2.60 (m, 4 H), 1.80 (m, 4 H), 1.04 (t, 3 H). LRMS ES+ 439 [M+H]+.
Example 125 1-(2-ethoxyethyl)-7-(6-nnethylpyπdin-3-yl)-3-r(2-nnorpholin-4-ylethyl)aminoiPyridor2.3-
Figure imgf000114_0001
Example 125 was prepared by a method similar to that described in Example 1 6- methylpyridin-3-ylboronic acid in place of 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine in step 7. 1HNMR (CDCI3, 400MHz) δ 8.80 (s, 1 H), 8.60 (s, 1 H), 8.00 <s, 1 H), 7.80 (d, 1 H), 7.30 (s, 1 H), 4.50 (t, 2 H), 3.80 (m, 8 H), 3.50 (t, 2 H), 2.70 (m, 3 H), 2.60 <s, 3 H), 2.50 (m, 3 H), 1.10 (t, 3 H). LRMS ES+ 439 [M+H]+.
Example 126
7-(4-fluorophenyl)-3-[(2-morpholin-4-ylethyl)aminol-1-(2-propoxyethyl)pyridor2,3-b1pyrazin- 2(im-one
Figure imgf000114_0002
Example 126 was prepared by a method similar to that described in Example 3 using propanol in place of 2,2,2-trifluoroethanol in step 1 and 4-fluorophenylboronic acid in place of 2-methoxy-5-pyridineboronic acid in step 6. 1 H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.75 (t, 3 H) 1.46 (m, 2 H) 2.53 (s, 4 H) 2.70 (s, 2 H) 3.34 (t, 2 H) 3.79 (m, 8 H) 4.47 (t, 2 H) 7.16 (m, 3 H) 7.57 (m, 2 H) 7.93 (d, 1 H) 8.59 (d, 1 H). HRMS m/z 456.2390 (calculated for M+H, 446.2405).
Additional compounds of Formula I that can be prepared in accordance with the synthetic methods of the present invention include those compounds described in Table B: TABLE B
Figure imgf000114_0003
Figure imgf000115_0001
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Figure imgf000116_0001
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Figure imgf000117_0001
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Figure imgf000124_0001
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Figure imgf000127_0001
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Figure imgf000130_0001
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Figure imgf000131_0001
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Figure imgf000132_0001
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Figure imgf000137_0001
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Figure imgf000137_0004
Figure imgf000138_0001
K. In Vitro Assays
Method 1 : Human Platelet PDE5 Enzyme Inhibition Scintillation Proximity Assay
The IC50 of test compounds can be measured using an in vitro assay using PDE5 enzyme isolated from human platelets. The IC50 is the concentration of test compound required to inhibit the hydrolysis of cGMP to GMP by the PDE5 enzyme by 50% relative to the activity of uninhibited controls. The PDE5 enzyme for use in the assay can be obtained from human platelets by appropriate modification of the method of Thompson, WJ etal.; Biochemistry 18(23), 5228-5237, 1979, as described by Ballard SA et al.; J. Urology 159(6), 2164-2171 , 1998. The PDE5 enzyme so obtained can be used to catalyze the hydrolysis of [3H]CGMP (Amersham Biosciences) to 5' nucleotide [3H]GMP. The [3H]GMP binds to yttrium silicate SPA beads (Amersham Biosciences) and is detected by scintillation counting. More specifically, the effect of the test compound at different concentrations can be evaluated in the assay by contacting the compound with a fixed amount of PDE5 enzyme in the presence of substrate (cGMP or cAMP in a 3:1 ratio unlabelled to [3H]-labeled). Scintillation counting can be used as described above to determine relative PDE5 enzyme activity. The inhibition of PDE5 enzyme activity is then calculated relative to total PDE5 enzyme activity of uninhibited controls.
PDE5 IC50 Assay: 96-well microtiter plate format
Reagents
Buffer A: 20 mM Tris-HCI, 5 mM MgCI2, pH 7.4
Buffer B: 2 mg/ml BSA in Buffer A (enzyme buffer) cGMP substrate: Final concentration of 500 nM in assay The amount of 3H-labeled substrate added depends upon the specific activity of [3H]cGMP, and the cGMP substrate is diluted with a 10 mM stock of cold cGMP in Buffer A for a final substrate concentration of 500 nM in the assay.
PDE enzyme: Prepared in Buffer B. The dilution factor is determined by enzyme activity.
SPA beads: 20 mg/ml suspension prepared in dH2O. Positive Control Negative Control Standard/Test compound
2 μl 100% DMSO 2 μl 100% DMSO 2 μl Standard/Test compound 25 μl Buffer A 25 μl Buffer A 25 μl Buffer A
25 μl Enzyme 25 μl Buffer B 25 μl Enzyme 50 μl Substrate 50 μl Substrate 50 μl Substrate
50 μl SPA to stop 50 μl SPA to stop 50 μl SPA to stop
Stocks of standard and test compounds are prepared at 5 mM in 100% DMSO. The compound is serially diluted in a dilution plate using a 10-point Vz log dilution format. 2 μl of the compound dilution is added in duplicate to the wells of the assay plate. 2 μl of 100%
DMSO are added to designated control wells. 25 μl of Buffer A are added to all wells. 25 μl of Buffer B are added to the negative control wells. 25 μl of enzyme are added to the remaining wells. 50 μl of substrate are added to each well. Plates are sealed and incubated for 60 minutes on a plate shaker at 30 C. 50 μl of SPA beads are added to stop the reaction. The plates are again sealed and shaken for 15 minutes to allow the beads to bind the GMP product. The beads are allowed to settle for 30 minutes and then read on a NXT TopCount scintillation counter. Data are analyzed with a curve fitting application for plate-based screening. Percent inhibition in this assay is calculated as follows:
Inhibition (%) = [(mean maximum - compound value/ (mean maximum - mean minimum)] x 100.
The IC50 value is determined from sigmoid dose-response curves of enzyme activity versus compound concentration.
Method 2: Alternative Human Platelet PDE5 Enzyme Inhibition Scintillation Proximity Assay The IC50 of test compounds also can be measured in an alternative in vitro assay that varies from Method 1 as described below:
PDE5 ICgn Assay: 96-well microtiter plate format
Reagents
Buffer A: 20 mM Tris-HCI, 5 mM MgCI2, pH 7.4 Buffer B: 2 mg/ml BSA in Buffer A (enzyme buffer) cGMP substrate: Final concentration of 50 nM in assay
The amount of 3H-labeled substrate added depends upon the specific activity of [3H]cGMP, and it is diluted in Buffer A.
PDE enzyme: Prepared in Buffer B. The dilution factor is determined by enzyme activity. SPA beads: 4 mg/ml suspension prepared in dH2O.
Positive Control Negative Control Standard/Test compound
3 μl 100% DMSO 3 μl 100% DMSO 3 μl Standard/Test compound 27 μl Buffer A 27 μl Buffer A 27 μl Buffer A 30 μl Enzyme 30 μl Buffer B 30 μl Enzyme
30 μl Substrate 30 μl Substrate 30 μl Substrate
30 μl SPA to stop 30 μl SPA to stop 30 μl SPA to stop
Stocks of standard and test compound are prepared at 2 mM in 100% DMSO. The test compound is serially diluted in a dilution plate using an 8-point 1/5 log dilution format such that the starting concentration in the assay is 2 μM for an initial IC50 screen. 27 μl of Buffer A are added to the wells of the assay plates. From the dilution plate, 3 μl of diluted compound is delivered in duplicate or 3 μl of 100 % DMSO (for positive and negative controls) are added. 30 μl of enzyme are added. For the negative control wells, Buffer B is substituted in place of the enzyme. 30 μl of labeled substrate are added to all wells.
After incubating for 60 minutes at room temperature, the reaction is stopped with the addition of 30 μl of the yttrium silicate beads. These beads are dense and require constant agitation while being added to the plate. The plates are sealed and shaken on a plate shaker for fifteen minutes to allow the beads to bind the GMP product.
After allowing the beads to settle for 30 minutes, plates are read on a NXT TopCount scintillation counter and the data are analyzed as follows. Percent inhibition values are calculated using the means of the 0% and 100% controls on each plate. The estimates of the 4-parameters of the logistic, sigmoid dose-response model are then calculated using the well- level percent inhibition value for the compound. The formula for the four-parameter logistic model may be expressed as Y = ( (a - d) / (1 + ( X / c) Λ b) ) + d, where Y is the response, X is the concentration, a is the lower asymptote (minimum response), d is the upper asymptote (maximum response), c is the model IC50 (in the same units as X), and b is the slope (as described in De Lean, A., P. J. Munson, and D. Rodbard ("Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose- response curves." Am. J. Physiol. 235(2): E97-E102, 1978). These estimates are used to calculate the concentration that corresponds to 50% inhibition.
IC50 values are shown in Table C for compounds tested in accordance with Method 2 above.
Figure imgf000141_0001
Figure imgf000141_0002
Figure imgf000142_0001
Figure imgf000142_0002
L. Biological Protocols--//? Vivo Assays Method 5: Culex™ Assay
The effect of the test compound on systemic arterial blood pressure can be evaluated in a conscious pre-cannulated spontaneously hypertensive rat ("SHR") model. This assay is conducted using an automated blood sampler ("ABS") system. The Culex™ ABS system (Bioanalytical System, Inc., West Lafayette, IN) comprises a laptop computer, four control units and metabolic cages. This ABS system allows for the collection of multiple blood samples from a single rat without causing undue stress to the animal. In addition, the ABS system allows for the collection of urine samples that can be potentially used for biomarker identifications. Through this approach, efficacy and standard pharmacokinetic studies are conducted in the conscious unrestrained SHR rats simultaneously to define the relationship between plasma free drug concentration or potential biomarker(s) and pharmacological effect (reduction of mean arterial blood pressure).
SHR rats at 12 to 16 weeks of age, weighing about 30Og, undergo surgerical cannulation of both jugular veins and the right carotid artery. After surgical recovery, animals are placed in the Culex™ cages and tethered to a movement-responsive arm with a sensor that controls cage movement when the animal moves to prevent the catheters from being twisted. Connections are made between the right jugular catheter and the Culex™ sterile tubing set for blood sampling, and the left jugular catheter for compound administration, and the catheter in the right carotid artery is connected to a pressure transducer for monitoring blood pressure. To keep the patency of the catheters, the right jugular cannula is maintained by the "tend" function of the Culex™ that flushes the catheter with 20 μl_ heparin saline (10 units/mL) every 12 minutes or between sampling events, and the left jugular cannula is filled with heparin saline (20 units/mL). The patency of the right carotid cannula is maintained by slow infusion of heparin saline either directly into the extend tubing when blood pressure is not recorded or through the pressure transducer during the blood pressure monitoring. Animals are allowed to acclimate for at least two hours before compound evaluation. The test compound may be administered intravenously or by oral gavage. Blood sampling protocols (sampling time and volume) are programmed using the Culex™ software. The total amount of blood withdrawn from each animal will not exceed 750 μL/24 hrs and 10 ml_/kg within two weeks. Heart rate, blood pressure, and drug concentration are monitored. Systemic arterial blood pressure and heart rate are recorded by PONEMAH (Gould Instrument System, Valley View, OH), a pressure transducer through a data acquisition system for recording blood pressure and heart rate, for 6 to 24 hours based on experimental protocol. Mean arterial blood pressure (primary endpoint) is analyzed for assessing the efficacy of the compound.
Blood samples are analyzed for measuring plasma drug concentration, using the LC/MS/MS method described below, and for evaluating potential biomarkers.
LC/MS/MS Method
Sample Preparation: Plasma samples (50 μL unknown, control or blank) are mixed with 10 μL acetonitrile:water or a standard solution of the test compound and 150 μL of internal standard solution (100 ng/mL of the test compound in acetonitrile). The mixture is centrifuged at 3000 rpm for 5 min, and 125 μL of the supernatant transferred to a 96 well plate. The solvent is evaporated under a stream of nitrogen and the residue is reconstituted with 80 μL acetonitrile/0.1% aqueous formic acid (20:80 v/v).
A 20 μL volume of each prepared sample is injected onto a Phenomenex Synergi 4 μm MAX-RP 2.0 x 75 mm column and eluted at 0.4 ml_/min using gradient elution from 0.1% aqueous formic acid (mobile phase A) to acetonitrile (mobile phase B). The gradient program consists of initial application of 90% mobile phase A, followed by a linear gradient to 75% mobile phase B from 0.2 to 1.15 min after injection and held at 75% mobile phase B until 2.0 min. The mobile phase was linearly changed back to 90% mobile phase A from 2.00 to 2.10 minutes, and the next injection took place at 3.00 min. Detection was performed by mass spectrometry using positive ion electrospray (ESI) with multiple reaction monitoring of the transitions m/z 454.00 (MH+ the Carboxypiperidine Compound) → m/z 408.00, m/z 466.24 (MH+ the Carboxypiperidine Compound) → 409.33 . The ion spray voltagea is set at 5000. A calibration curve is constructed by using peak area ratios of the analyte relative to the internal standard. Subject concentrations are determined by inverse prediction from their peak area ratios against the calibration curve.
Method 6: Implantation of Radio Transmitters and Subsequent Blood Pressure Screening by Telemetry in Spontaneously Hypertensive Rats
SHR Rats are anesthetized with isoflurane gas via an isoflurane anesthesia machine that is calibrated to deliver isoflurane over a range of percentages as oxygen passes through the machine's inner chambers. The animals are placed in an induction chamber and administered isoflurane at 4-5% to reach a surgical plane of anesthesia. They are then maintained at 1-2% during the surgical procedure via a nose cone, with isoflurane delivered via a smaller isoflurane anesthesia device on the surgical table. Following administration of anesthesia, the rats are implanted with transmitters using aseptic procedures with commercially available sterile radio-telemetry units (Data Sciences, International, Roseville, MN 55113-1136). Prior to surgery the surgical field is shaved, scrubbed with Dial™ brand antimicrobial solution (containing 4% chlorhexidine gluconate and 4% isopropyl alcohol) followed by an application of iodine (10%) spray solution. A 2.5 to 3.0 cm laparotomy is preformed and the radio-telemetry units implanted into the abdomen, with the catheter tip inserted into the abdominal aorta. Baby Weitlaner retractors are used to retain soft tissue. A 1 cm section of the abdominal aorta is partially dissected and that section cross-clamped briefly, punctured with a 21 -gauge needle and the transmitter catheter tip introduced into the vessel and secured by a single 4.0 silk suture anchored to the adjacent psoas muscle. The transmitter body is then inserted into the abdominal cavity and simultaneously secured to the abdominal muscle wall while closing with running 4.0 silk suture. The skin layer is closed with subdermal continuous 4.0 absorbable suture. A subcutaneous (s.c.) administration of marcaine followed by a topical application of iodine is administered into and around the suture line, respectively, upon closing. All rats receive a postoperative injection of buprenorphine @ 0.05mg/kg, s.c. before regaining consciousness. A typical dose volume for a 0.300kg rat will be 0.050ml. The rats must be fully recovered from their operative anesthesia before the administration of buprenorphine. They then receive the same dose once daily for 2 consecutive days, unless the animal demonstrates that it is in compromising postoperative pain. Following surgery, the rats are returned to their cages and housed individually on solid bottom caging with paper bedding. A period of no less than 7 days is allowed for recovery before experimental procedures are initiated. It has been observed that the rats are typically hypertensive for several days following surgery and return to "normotensive" levels by approximately the 7th day post-surgery. They are fed standard rat chow and water ad libitum throughout the experimental time line.
Test compounds are administered intragastrically (i.g.) via gavage, using of a stainless steel, 21/a inch, 18 gauge gavage needle with a balled end. For single daily dosing, the target volume is 3.33 ml/kg, i.g. The dose volume for the test compound is approximately 1 ml/ rat. The vehicles in which the test compound is administered is methylcellulose (0.5%) + Tween 80 (0.1%) in 5OmM citrate buffer pH=5.0.
As various changes could be made in the above invention(s) without departing from the scope of the invention(s), it is intended that all matter contained in the above description be interpreted as illustrative and not in a limiting sense. All documents mentioned in this application are expressly incorporated by reference as if fully set forth at length, with the definitions of the present application controlling. When introducing elements of the present invention or the various embodiment(s) thereof, the articles "a", "an", "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

Claims

We claim:
1. A compound of Formula I:
Figure imgf000146_0001
wherein:
R2 is selected from the group consisting of aryl and 3 to 10 membered ring heterocyclyl, R2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, -OR100, -C(O)R100, - OC(O)R100, -C(O)OR100, -NR100R101, -N(R100)C(O)R101, -C(O)NR100R101, -C(O)NR100C(O)R101, - SR100 -S(O)R100 and -S(O)2R100, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl wherein (a) the alkyl, alkenyl, alkylnyl and cycloalkyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OR102, and -C(O)OR102; and (b) the aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl substituents are optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy and alkoxy;
R100, R101 and R102 are independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, alkoxy, -C(O)OH and -C(O)NH2;
Y6 represents a bond or is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl, Y6 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cyano, oxo, cycloalkyl, - OR103, -C(O)R103, -C(O)OR103, -OC(O)R103, -NR103R104, -N(R103)C(O)R10\ and -C(O)NR103R104; R103 and R104 are independently selected from the group consisting of hydrogen and alkyl, wherein the alkyl is 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;
R6 is selected from the group consisting of hydrogen, halogen, oxo, hydroxy, amino, aminoalkyl, alkyl, alkynyl, alkoxy, alkylamino, cycloalkyl, aryl, aryl-C(O)-, heterocyclyl, heteroaryl, mercapto, sulfonyl, aryl-C(O)-NR105-, heterocyclyl-C(O)-, and heterocyclyl-C(O)-NR105- , R6 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, mercapto, oxo, alkyl, alkenyl, alkynyl, alkoxy, aminoalkyl, haloalkyl, hydroxyalkyl, hydroxyalkoxy, carboxyalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, - OR106, -C(O)R106, -C(O)OR106, -OC(O)R106, -NR106R107, -N(R106)C(O)R107, -
C(O)NR106R107, -C(O)NR106C(O)R107, -SR106, -S(O)R106, -S(O)2R106, -N(R106)S(O)2R107, and - S(O)2NR106R107; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy; R105 is independently selected from the group consisting of hydrogen and alkyl;
R106 and R107 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and cycloalkyl wherein (a) the R106 and R107 alkyl and alkenyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy, and (b) the R106 and R107 alkynyl and cycloalkyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy; R6A is selected from the group consisting of hydrogen, alkyl, and aminoalkyl, R6A is optionally substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, oxo, hydroxy, alkyl, and alkoxy;
R8 is alkyl; R8 is optionally substituted with one or more R8 substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, alkynyl, cycloalkyl, heterocyclyl, - OR108, -C(O)R108, -C(O)OR108, -OC(O)R108, -NR108R109, -N(R108)C(O)R109, -C(O)NR108R109, - SR108, -S(O)R108, and -S(O)2R108, wherein the alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkyl, and alkoxy; and
R108 and R109 are independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl, wherein (a) when the alkyl is methyl, the methyl is optionally substituted with 1 , 2, or 3 fluoro substituents, (b) when the alkyl comprises at least two carbon atoms, the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy, and (c) the R108 and R109 alkynyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy.
R8 is alkyl, R8 is optionally substituted with one or more R8 substituents independently selected from the group consisting of alkoxy, cycloalkyl, and heterocyclyl, said R8 substituents are optional substituted with halogen.
2. The compound of claim 1 , wherein R6A is selected from the group consisting of hydrogen, C1 to C4 alkyl, wherein said C1 to C4 alkyl is optionally substituted with one or more substituents selected from the group consisting of C1 to C4 alkoxy and hydroxy.
3. The compound of claim 1 , wherein R2 is selected from the group consisting of
Figure imgf000148_0001
R9, R10, R11, R12 and R13 are independently selected from the group consisting of hydrogen, halogen, oxo, alkyl, -OR100, -C(O)R100, -OC(O)R100, -C(O)OR100, -NR100R101 and -C(O)NR100R101, wherein the alkyl substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, - OR102, and -C(O)OR102; and
R100, R101, and R102 are independently selected from the group consisting of hydrogen and C1 to C4 alkyl.
4. A compound of claim 1 , wherein R is selected from the group consisting of
Figure imgf000148_0002
R9, R10, R11, R12 and R13 are independently selected from the group consisting of hydrogen, fluoro, methyl, trifluoromethyl, and methoxy.
5. A compound of claim 1 , wherein Y6 represents a bond or is selected from the group consisting of alkyl and hydroxyalkyl.
6. A compound of claim 1 , wherein Y6 represents a bond or is selected from the group consisting of methyl, ethyl, propyl, butyl, tert-butyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, dihydroxyethyl,
Figure imgf000149_0001
7. A compound of claim 2, wherein R6 is selected from the group consisting of hydrogen, halogen, oxo, hydroxy, amino, aminoalkyl, alkyl, alkynyl, alkoxy, alkylamino, and cycloalkyl, wherein (a) the alkyl, alkynyl, alkoxy, aminoalkyl and alkylamino substituents are optionally substituted with one or more substituents independently selected from the group consisting of - OR105, -C(O)R105, -C(O)OR105, -NR105R106, -N(R105)C(O)R106, -N(R105)C(O)COR106, - N(R105)C(O)OR106, -C(O)NR105R106, -NHC(O)NR105R106, -N(R105)S(O)2R106; and (b) the cycloalkyl substituent is optionally substituted with one or more -OR105, wherein R105 and R106 are independently selected from the group consisting of hydrogen and alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, cyano, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy.
8. A compound of claim 2, wherein R6 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, tert-butyl, and cyclohexyl, wherein (a) the methyl R6 substituent is optionally substituted with one or more substituents independently selected from the group consisting of -OH, -OCH3, -OCH2CH3, -OCH2(CH3)CH3, -C(O)CH2CH2OH, -C(O)OH, - C(O)OCH2(CH3)(CH3)(CH3), -NH2, -NH(CH2CH3), -N(CH3)(CH3), -N(CH2CH3)CH2CH3, - N(H)CH2(CH3)CH3, -N(H)CH2CH2CH2OH, -N(H)CH2C(O)CH3, -NH(CH2CH2OH), -N(H)C(O)OCH3, -N(H)C(O)CH2(CH3)(CH3)(CH3), -NHC(O)OCH2(CH3)(CH3)(CH3), -NHC(O)COCH3, - NHC(O)NHCOCH3, -NCH3C(O)CH3, -NCH3(O)C(O)CH3, N(CH(O)CH3)C(O)CH3, -C(O)NH2, - C(O)NH(CH3), -C(O)NCH3(CH3), -C(O)NHCH2(CH3)(CH3)(CH3), -C(O)NHR106, -N(H)S(O)2CH3, - N(H)S(O)2CHF3, wherein R106 is independently selected from the group consisting of cyclopentyl and cyclohexyl, and wherein the R106 cyclohexyl substituent is optionally substituted with hydroxy; and wherein (b) the cyclohexyl R6 substituent is optionally substituted with hydroxy.
9. A compound of claim 1 , wherein R6 is selected from the group consisting of phenyl- C(O)NH-
Figure imgf000149_0002
Figure imgf000150_0001
, and
10. A compound of claim 1 , wherein R is alkoxyalkyl optionally substituted as described in claim 1.
11. A compound of claim 1, wherein
R2 is selected from the group consisting of phenyl and pyridinyl, optionally substituted as described in claim 1 ;
R6A is hydrogen;
Y6 represents a bond or is selected from the group consisting of methyl, ethyl, propyl, butyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, dihydroxyethyl,
H
Figure imgf000150_0002
and
R8 is selected from the group consisting of ethoxyethyl and propoxyethyl.
12. A compound of claim 1 , wherein: R
Figure imgf000151_0001
;
R9, R10, R11, R12 and R13 are independently selected from the group consisting of hydrogen, fluoro, methyl, trifluoromethyl, and methoxy;
R6A is hydrogen;
Y6 represents a bond;
R8 is selected from the group consisting of ethoxyethyl and propoxyethyl; and
R6 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, and cyclohexyl, optionally substituted with one or more substituents independently selected from the group consisting of -OR105, -C(O)R105, -C(O)OR105, -NR105R106, -N(R105)C(O)R106, - N(R105)C(O)OR106, -C(O)NR105R106, -NHC(O)NR105R106, -N(R105)S(O)2R106, wherein R105 and R106 are independently selected from the group consisting of hydrogen, methyl, ethyl, butyl, cyclopentyl, cyclohexyl, optionally substituted with one or more substituent selected from the group consisting of halogen, oxo, hydroxy, and methyl.
13. A compound of claim 1 , wherein;
Figure imgf000151_0002
R2 is
R11 is selected from the group consisting of hydrogen, chloro, fluoro, methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluoromethyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, amino, methylamino, dimethylamino, ethylamino, and diethylamino;
R6A is hydrogen;
Y6 is selected from the group consisting of methyl and ethyl;
R8 is selected from the group consisting of ethoxyethyl and propoxyethyl; and
R6 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, and cyclohexyl, optionally substituted with one or more substituents independently selected from the group consisting of -OR105, -C(O)R105, -C(O)OR105, -NR105R106, -N(R105)C(O)R106, - N(R105)C(O)OR106, -C(O)NR105R106, -NHC(O)NR105R106, -N(R105)S(O)2R106, wherein R105 and R106 are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, cyclopentyl, cyclohexyl, optionally substituted with one or more substituent selected from the group consisting of halogen, oxo, hydroxy, and methyl.
14. A pharmaceutical composition comprising a therapeutically-effective amount of a compound of claim 1.
15. A method of treating a PDE-5 mediated condition selected from the group consisting of cardiovascular disease, metabolic disease, pain, central nervous system disease, pulmonary disease, sexual dysfunction, and renal dysfunction in a subject, comprising administering to the subject a therapeutically-effective amount of a compound of claim 1.
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